* 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.
Reference：
[1] Gazzetta Chimica Italiana, 1886, vol. 16, p. 278[2] Gazzetta Chimica Italiana, 1887, vol. 17, p. 185
[3] Chemische Berichte, 1886, vol. 19, p. 1694[4] Gazzetta Chimica Italiana, 1887, vol. 17, p. 127,186
[5] Angewandte Chemie - International Edition, 2003, vol. 42, # 25, p. 2898 - 2901
[6] Marine Drugs, 2014, vol. 12, # 4, p. 1815 - 1838
[7] Journal of Molecular Catalysis B: Enzymatic, 2014, vol. 109, p. 122 - 129
2
[ 6384-18-5 ]
[ 1783-96-6 ]
Yield
Reaction Conditions
Operation in experiment
82.5%
for 3 h;
In the reaction vessel,Join4.85 g (0.03 mol)D-aspartic acid dimethyl ester,Join6NSodium hydroxide50 ml,Heating hydrolysis for 3 hours,use6NHydrochloric acidPH = 6.5,The reaction solution was passed through a regenerated cation exchange resin column,collectPH = 4Previous effluent,After concentration to a fifth of the original volume under reduced pressure,use95percentEthanol so that precipitation,Filtered and dried to obtain D-aspartic acid3.3 g, yield 82.5percent.
Reference：
[1] Patent: CN105503628, 2016, A, . Location in patent: Paragraph 0026
3
[ 328-42-7 ]
[ 338-69-2 ]
[ 1783-96-6 ]
[ 127-17-3 ]
Reference：
[1] Journal of Molecular Catalysis B: Enzymatic, 2013, vol. 94, p. 15 - 22
4
[ 56-84-8 ]
[ 1783-96-6 ]
Reference：
[1] Journal of Organic Chemistry, 1989, vol. 54, # 19, p. 4529 - 4535
[2] Chemistry Letters, 1984, p. 1661 - 1664
[3] Angewandte Chemie - International Edition, 2003, vol. 42, # 30, p. 3521 - 3523
[4] Bulletin of the Chemical Society of Japan, 2004, vol. 77, # 5, p. 1029 - 1030
[5] Chemistry - A European Journal, 2010, vol. 16, # 16, p. 4932 - 4937
[6] Bioscience, Biotechnology and Biochemistry, 2013, vol. 77, # 2, p. 416 - 418
5
[ 617-45-8 ]
[ 1783-96-6 ]
[ 56-84-8 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 2, p. 653 - 654
[2] Analytical Chemistry, 2001, vol. 73, # 22, p. 5499 - 5508
[3] Analytical Chemistry, 2003, vol. 75, # 6, p. 1508 - 1513
[4] Asian Journal of Chemistry, 2010, vol. 22, # 6, p. 4945 - 4946
[5] Chirality, 2013, vol. 25, # 11, p. 768 - 779
[6] Catalysis Science and Technology, 2015, vol. 5, # 2, p. 1106 - 1114
[7] Journal of the American Chemical Society, 2017, vol. 139, # 25, p. 8562 - 8569
[8] Chinese Journal of Chemistry, 2017, vol. 35, # 7, p. 1037 - 1042
[9] Angewandte Chemie - International Edition, 2018, vol. 57, # 51, p. 16754 - 16759[10] Angew. Chem., 2018, vol. 130, p. 16996 - 17001,6
6
[ 67036-33-3 ]
[ 1783-96-6 ]
Reference：
[1] Journal of the American Chemical Society, 1953, vol. 75, p. 4058
[2] Journal of Biological Chemistry, 1949, vol. 179, p. 1173
7
[ 923-06-8 ]
[ 1783-96-6 ]
Reference：
[1] Chemische Berichte, 1907, vol. 40, p. 1054
8
[ 617-45-8 ]
[ 1783-96-6 ]
Reference：
[1] Chemische Berichte, 1899, vol. 32, p. 2454
[2] Patent: US2790001, 1954, ,
[3] Journal of the American Chemical Society, 1958, vol. 80, p. 953,954, 957
[4] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1888, vol. 106, p. 1736[5] Bulletin de la Societe Chimique de France, 1888, vol. <2>50, p. 151
[6] Gazzetta Chimica Italiana, 1887, vol. 17, p. 520[7] Gazzetta Chimica Italiana, 1890, vol. 20, p. 169,170
[8] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 2, p. 653 - 654
9
[ 97032-53-6 ]
[ 1783-96-6 ]
Reference：
[1] Monatshefte fuer Chemie, 1913, vol. 34, p. 721,725
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1991, vol. 40, # 7, p. 1361 - 1365[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1991, # 7, p. 1542 - 1547
13
[ 2545-40-6 ]
[ 1783-96-6 ]
Reference：
[1] Journal of Biological Chemistry, 1952, vol. 194, p. 455,458
14
[ 105-53-3 ]
[ 1783-96-6 ]
[ 56-84-8 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1988, # 19, p. 1336 - 1338
Reference：
[1] Chemische Berichte, 1907, vol. 40, p. 1054
[2] Chemische Berichte, 1908, vol. 41, p. 842
17
[ 1783-96-6 ]
[ 74-88-4 ]
[ 6384-92-5 ]
Reference：
[1] Journal of Medicinal and Pharmaceutical Chemistry, 1962, vol. 5, p. 1187 - 1199
18
[ 1783-96-6 ]
[ 77-78-1 ]
[ 6384-92-5 ]
Reference：
[1] Journal of Medicinal and Pharmaceutical Chemistry, 1962, vol. 5, p. 1187 - 1199
19
[ 1783-96-6 ]
[ 501-53-1 ]
[ 78663-07-7 ]
Yield
Reaction Conditions
Operation in experiment
59%
With sodium hydroxide In water at 0 - 20℃; for 48 h;
Example 2 (R)-4-(4-morpholino-l-(phenylthio)butan-2-ylamino)-3- nitrobenzene-sulfonamideCbzCI ^O NHCbz morpholine ii i MsCI/NEt3 PhSH/NaHDioxane 1 , Et3N dioxaneA solution of NaOH (6M, 500 ml) in distilled H2O was added with (R)-aspartic acid a (65 g, 489 mmol ) to adjust the pH=13 of the solution at O0C, then added with 1.7 eq of <n="33"/>benzyl chloro formate (141 g, 831 mmol) under magnetic stirring. The mixture was warmed at room temperature and reacted for 2 days. Subsequently, the mixture was washed with ether and the aqueous phase was acidified with 6N HCl, then extracted with AcOEt. Finally, the organic phase was dried over dry Na2SO4, filtered through paper filter and concentrated in rotary evaporator. 80 g of product b in the form of a transparent, colorless gluey residue was obtained (yield: 59percent). MS (ESI) m/e (M-H"): 266; 1H-NMR (CDCl3, 400 MHz): δ 121-121 (m, 5H), 6.14 (d, J = 8.4 Hz, IH), 5.05 (s, 2H), 4.60 (m, IH), 2.99 (m, IH), 2.75 (m, IH).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 1040 - 1044
[2] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 17, p. 2495 - 2511
[3] Asian Journal of Chemistry, 2013, vol. 25, # 11, p. 5948 - 5950
[4] Patent: WO2008/61208, 2008, A2, . Location in patent: Page/Page column 31-32; 34-35
[5] Patent: US6660769, 2003, B1, . Location in patent: Page column 13-14
[6] Patent: US5095009, 1992, A,
Reference：
[1] Journal of the American Chemical Society, 1988, vol. 110, # 25, p. 8557 - 8558
23
[ 67-56-1 ]
[ 1783-96-6 ]
[ 21394-81-0 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 0 - 25℃;
73.7 ml of acetyl chloride (1.4 eq.) was added dropwise to methanol (250 ml) at 0 °C. The mixture was added dropwise to a suspension of 100 g (751 mmol) (R)-2- aminosuccinic acid in MeOH (250 ml) at 0 °C. After stirring for 3 h, the mixture was warmed to room temperature and stirred overnight. Five additional vials were set up as described above. All six reaction mixtures were combined and concentrated under reduce pressure. The residue was treated with MTBE and the precipitate that formed was filtered and dried under reduce pressure. (R)-2-amino-4-methoxy-4-oxobutanoic acid was obtained as a white solid (600 g, 90 percent). 1H NMR (400 MHz, Deuterium oxide): δ 4.33 (t, J=5.5 Hz, 1H), 3.81 (s, 1H), 3.72 (s, 3H), 3.10 (d, J=4.9 Hz, 2H).
Reference：
[1] Patent: WO2017/89458, 2017, A1, . Location in patent: Page/Page column 72
[2] Gazzetta Chimica Italiana, 1986, vol. 116, # 10, p. 607 - 608
[3] Patent: CN106518701, 2017, A, . Location in patent: Paragraph 0021-0022
24
[ 67-56-1 ]
[ 1783-96-6 ]
[ 14358-33-9 ]
Yield
Reaction Conditions
Operation in experiment
107.8 g
at 0 - 29℃; for 30 h;
To the reaction vessel was added 106.8 g (0.8 mol) of D-aspartic acidAnd 700 ml of methanol,84.4 ml (1.2 mol) of thionyl chloride was slowly added with stirring,The reaction temperature was controlled at 0 ° C,After the addition of thionyl chloride,Stirring was continued at room temperature at 29 deg.] C,After 30 hours of reaction,The reaction solution was distilled off to remove excess methanol and thionyl chloride,The remaining oil was crystallized from 3.5 times the ether,Get the white crystal, filter,Washed three times with ether,Dried to give 107.8 g of white solid D-aspartic acid dimethyl ester hydrochloride;
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10460 - 10474
[2] Journal of Organic Chemistry, 2012, vol. 77, # 5, p. 2299 - 2309
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 2936 - 2947
[4] Journal of Medicinal Chemistry, 2006, vol. 49, # 24, p. 7215 - 7226
[5] Patent: WO2010/31184, 2010, A1, . Location in patent: Page/Page column 22
[6] Journal of Medicinal Chemistry, 2016, vol. 59, # 11, p. 5505 - 5519
[7] Chemical Communications, 2017, vol. 53, # 2, p. 447 - 450
[8] Patent: CN106916076, 2017, A, . Location in patent: Paragraph 0019; 0026; 0033; 0040
[9] Patent: CN107540575, 2018, A, . Location in patent: Paragraph 0035; 0064; 0065
25
[ 75-77-4 ]
[ 1783-96-6 ]
[ 14358-33-9 ]
Yield
Reaction Conditions
Operation in experiment
99.9%
at 20℃; for 16 h; Cooling with ice
General procedure: Under ice cooling, chlorotrimethylsilane (33.2ml, 263.0mmol) was added dropwise to a suspension of (S)-aspartate (10g, 75.1mmol, 98percent ee) in methanol abs. (150ml) and the reaction mixture was stirred for 16h at room temperature. The solvent and volatile byproducts were evaporated in vacuo. The residue was suspended in methanol (1×30ml) and the solvent was removed in vacuo. Then diethyl ether was added (30ml) and the solvent was removed under reduced pressure. This procedure was repeated three times. The product was dried in high-vacuum. Colorless solid, mp 112–115°C, yield 15g (100percent).
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 7, p. 2884 - 2894
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 221 - 233
26
[ 64-17-5 ]
[ 1783-96-6 ]
[ 112018-26-5 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: at 0 - 20℃; for 0.5 h; Stage #2: for 2 h; Heating / reflux
[00222] Acetyl chloride (54.6 mL, 0.75 mol) was added drop- wise into ethanol (316 mL) at 0-5 0C. When the addition was completed, the ice bath was removed and the solution allowed to stir while warming to room temperature for another 30 min. D-aspartic acid 19.1 (25 g, 0.188 <n="77"/>mol) was then added. The reaction mixture was refluxed for 2 hours. The reaction solution was then concentrated in vacuo and placed under high vacuum (0.4 mm Hg) overnight. Compound 19.2 was obtained as a white solid (42 g, 99percent) and used directly in the next step.
The D- aspartate (160g, 1.2mol) were suspended in 850mL of methanol, cooled to -5 ~ 0 , was slowly added dropwise thionyl chloride (178.4g, 1.5mol), Bi dropwise, warmed to 25 ~ 35 , stirring the reaction 4 ~ 5h, the reaction is completed, methanol was distilled off under reduced pressure, and the resulting white solid was stirred in 500mL ethyl acetate was added and washed 0.5h, filtered and dried to give a compound of formula II 192 g, yield 87percent, mp: 185 ~ 186 .
77.6%
at -5 - 5℃; for 12.5 h;
-5 ° C-0 ° C Under stirring conditions,108.8 ml (1.5 mol) of thionyl chloride was slowly added dropwise to 1 L of methanol (this process had an exothermic effect)Control the temperature at 0 ° C, 2h drop finished, after dripping, stirring reaction 30min,Control the temperature at 0 ° C to 5 ° C and then add 200g (1.5 mol) of D-aspartic acid, add the reaction solution into a clear solution, slowly return to room temperature, HPLC monitoring reaction process, room temperature reaction 12 hour,After completion of the reaction, 1 L of ethyl acetate was added to precipitate a large amount of white solid, filtered, and the filter cake was washed with ethyl acetate. The filter cake was collected and dried at 45 ° C to give the compound II 214.1 g,Yield 77.6percent
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 17, p. 2513 - 2526
[2] Patent: CN103992337, 2016, B, . Location in patent: Paragraph 0031; 0032
[3] Patent: CN104497010, 2016, B, . Location in patent: Paragraph 0035; 0036; 0037
[4] Journal of Medicinal Chemistry, 1994, vol. 37, # 5, p. 674 - 688
28
[ 1783-96-6 ]
[ 22728-89-8 ]
Yield
Reaction Conditions
Operation in experiment
78%
With thionyl chloride In methanol
A. D-Aspartic Acid b-Methyl Ester Hydrochloride A suspension of D-aspartic acid (10.0 g, 75.1 mmol) in 50 mL methanol is treated with thionyl chloride (8.94 g, 75.1 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min, then at RT for 2 h. The resulting clear solution is diluted with 200 mL diethyl ether with rapid stirring. A white precipitate is formed which is collected by vacuum filtration, washed with diethyl ether and dried to yield 10.7 g (78percent) of D-aspartic acid b-methyl ester hydrochloride.
With hydrogenchloride; water; In methanol; at 110℃; for 24h;Inert atmosphere; Sealed tube;
General procedure: To nine glass tubes that one terminal has been sealed was added each 50 muL of 1-9 solutions in MeOH at 1 mg/mL, respectively. After blown inside the tubes with nitrogen gas to dryness, 100 muL of aqueous 6 N HCl solution was added into each tube. After the open terminal of the tubes was sealed by blast burner, the tubes were kept at 110 C for 24 h to hydrolyze 1-9. Then, one sealed terminal of the tubes was cut out, reaction solutions were blown with nitrogen gas to dryness, and the tubes were maintained in vacuo overnight to clean up remained HCl. At the same time, each 500 mug of standards in 500 muL of aqueous 6 N HCl solution, L-Asn, D-Asn, L-Gln, D-Gln, L-Leu, D-Leu, L-Leu amide and D-Leu amide, was also hydrolyzed in the same manner and same conditions. At this condition, the L-Leu amide and D-Leu amide were hydrolyzed to L-Leu and D-Leu, respectively. Both hydrolyzates of the standards and 1-9 were dissolved in each 10 muL of distilled water, mixed with 10 muL of 10 mM L-FDAA in acetone and 10 muL of 1 N NaHCO3 aqueous solution, respectively, and reacted at 45 C for 1.5 h. The reaction mixtures were neutralized with 5 muL of 2 N HCl, respectively. Then, the reaction mixtures were filtered, and the filtrates were subjected to HPLC analysis.
With L-asparaginase from Thermococcus gammatolerans EJ3; In aq. buffer; at 85℃;pH 8.5;Enzymatic reaction;Kinetics;
General procedure: The determination of kinetic parameters was carried out by incubating the enzyme with diverse concentrations of different substrate (l-asparagine, d-asparagine, l-glutamine, and d-glutamine) in 50 mM Tris-HCl buffer (pH 8.5). The Michaelis-Menten constant (Km), turnover number (kcat), and catalytic efficiencie (kcat/Km) were calculated on the basis of one active site per subunit. Km (mM) and kcat (s-1) were determined by Lineweaver-Burk plots from the Michaelis-Menten equation.
73.7 ml of acetyl chloride (1.4 eq.) was added dropwise to methanol (250 ml) at 0 C. The mixture was added dropwise to a suspension of 100 g (751 mmol) (R)-2- aminosuccinic acid in MeOH (250 ml) at 0 C. After stirring for 3 h, the mixture was warmed to room temperature and stirred overnight. Five additional vials were set up as described above. All six reaction mixtures were combined and concentrated under reduce pressure. The residue was treated with MTBE and the precipitate that formed was filtered and dried under reduce pressure. (R)-2-amino-4-methoxy-4-oxobutanoic acid was obtained as a white solid (600 g, 90 %). 1H NMR (400 MHz, Deuterium oxide): delta 4.33 (t, J=5.5 Hz, 1H), 3.81 (s, 1H), 3.72 (s, 3H), 3.10 (d, J=4.9 Hz, 2H).
The sulfuric acid at a concentration of 30% was added to the first stirred tank and then the aspartic acid powder was added. The weight ratio of the two raw materials was 30% sulfuric acid: aspartic acid powder = 4.50: 5.50, The reaction was carried out at room temperature for 2 hours to obtain a solid-liquid mixture of aspartic acid sulfate, which was fed into a filter to remove the liquid fraction and the resulting solid was fed to a second stirred tank. Adding the methanol solution to the second stirred tank, stirring the catalyst solid acid, the ratio of the three raw materials is aspartic acid sulfate: methanol solution: solid acid = 4.98: 5.00: 0.02, stirring at room temperature, At the same time with the concentration of 30% sulfuric acid or the amount of alkali control reaction solution pH value of 1. 4, stirring reaction 7. 5 hours after the aspartic acid methyl ester solid solution mixture, sent to the filter In addition to the liquid fraction, the resulting solid was sent to a vacuum dryer and dried in vacuum at a temperature of 45 C for 5 hours to give the aspartic acid methyl ester produc
The D- aspartate (160g, 1.2mol) were suspended in 850mL of methanol, cooled to -5 ~ 0 , was slowly added dropwise thionyl chloride (178.4g, 1.5mol), Bi dropwise, warmed to 25 ~ 35 , stirring the reaction 4 ~ 5h, the reaction is completed, methanol was distilled off under reduced pressure, and the resulting white solid was stirred in 500mL ethyl acetate was added and washed 0.5h, filtered and dried to give a compound of formula II 192 g, yield 87%, mp: 185 ~ 186 .
77.6%
With thionyl chloride; at -5 - 5℃; for 12.5h;
-5 C-0 C Under stirring conditions,108.8 ml (1.5 mol) of thionyl chloride was slowly added dropwise to 1 L of methanol (this process had an exothermic effect)Control the temperature at 0 C, 2h drop finished, after dripping, stirring reaction 30min,Control the temperature at 0 C to 5 C and then add 200g (1.5 mol) of D-aspartic acid, add the reaction solution into a clear solution, slowly return to room temperature, HPLC monitoring reaction process, room temperature reaction 12 hour,After completion of the reaction, 1 L of ethyl acetate was added to precipitate a large amount of white solid, filtered, and the filter cake was washed with ethyl acetate. The filter cake was collected and dried at 45 C to give the compound II 214.1 g,Yield 77.6%
a. Preparation of (R)-Bromosuccinic Acid To a 500 mL round bottom flask was added <strong>[1783-96-6]D-aspartic acid</strong> ((R)-aspartic acid, 25 g, 188 mmol) and 245 mL of 5 N HBr. The reaction was cooled in an ice bath to 0-5 C., followed by the dropwise addition of sodium nitrite (20.7 g, 301 mmol) in 75 mL of water over five hours. The temperature was maintained below 5 C. during the addition. After the addition was complete, the reaction was allowed to stir for 12 hours at 23-25 C. The reaction was diluted with diethyl ether (120 mL). The aqueous layer was removed and the organic phase was washed with 1 N HCl (100 mL). The combined aqueous phases were washed with EtOAc (100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to leave the product as a slightly yellow solid. The solid was recrystallized from EtOAc (~100 mL) and hexanes (~10 mL) to obtain the product (16.58 g, 84 mmol, 45%) as a white crystalline solid.
To a suspension of <strong>[1783-96-6]D-aspartic acid</strong> (25 g, 188 mmol) in methanol (250 mL) at 0 0C was added dropwise over 30 min. thionyl chloride (15.1 mL,207 mmol). After a period of 24 h at room temperature, the solvent was removed under reduced pressure and the residue was co- evaporated two times with methanol. To the residue was added THF and co-evaporated two times with THF. The title compound was suspended in 400 mL of THF and used as such for the next step.
107.8 g
With thionyl chloride; at 0 - 29℃; for 30h;
To the reaction vessel was added 106.8 g (0.8 mol) of <strong>[1783-96-6]D-aspartic acid</strong>And 700 ml of methanol,84.4 ml (1.2 mol) of thionyl chloride was slowly added with stirring,The reaction temperature was controlled at 0 C,After the addition of thionyl chloride,Stirring was continued at room temperature at 29 deg.] C,After 30 hours of reaction,The reaction solution was distilled off to remove excess methanol and thionyl chloride,The remaining oil was crystallized from 3.5 times the ether,Get the white crystal, filter,Washed three times with ether,Dried to give 107.8 g of white solid <strong>[1783-96-6]D-aspartic acid</strong> dimethyl ester hydrochloride;
With hydrogenchloride; thionyl chloride; In water; at 0 - 30℃;
20L clean reactor, equipped with hydrochloric acid exhaust gas absorption device,Add 6.8kg methanol, compound 7 (1.0kg), control the temperature 0-15 C, add dropwise 2.58kg thionyl chloride,Stir the reaction overnight at 25-30C,TLC detection,Vacuum distillation of methanol at 35-45C to essentially no fractions,Add 7.1kg of dichloromethane, control the temperature at 0-15C,2.28kg of triethylamine was added dropwise and the addition was complete.Control temperature is 15-25C,A solution of 1.64 kg of Boc anhydride and 1.2 kg of methylene chloride was added dropwise, and the mixture was reacted at a temperature of 23-28 C. overnight. 1.5 kg of water was added through a TLC plate, and the temperature was controlled at 0-10 C., about 4.5 kg of 3N hydrochloric acid, and the pH was adjusted. From 2.5-3, the liquid was separated and the organic phase was retained. The aqueous phase was extracted once with dichloromethane. The organic phases were combined and washed once with water. Distillation of methylene chloride under reduced pressure at a temperature of 30-40C to essentially no fractions, addition of 1.5 kg of tetrahydrofuran, dissolution, continued concentration to substantially no fractions, addition of 9 kg of tetrahydrofuran, drying of the molecular sieves for the next reaction.
With chloro-trimethyl-silane; at 0 - 20℃; for 16h;Inert atmosphere;
A suspension of <strong>[1783-96-6]D-aspartic acid</strong> (15; 1.331 g, 10.00 mmol, 1.00 equiv) in MeOH (27 mL) was treated dropwise with TMSCl (5.5 mL, 44.00 mmol, 4.40 equiv) at 0 C. The reaction mixture was warmed to r.t. after 1 h and stirred at this temperature for 16 h. The mixture was cooled again to 0 C and treated with Et3N (9 mL, 65.00 mmol, 6.50 equiv) and Boc2O (2.401 g, 11.00 mmol, 11.00 equiv). The reaction was warmed to r.t., stirred for a further 16 h at this temperature, and diluted with EtOAc and H2O. The aqueous phase was extracted with EtOAc (3 50 mL), and the combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (cyclohexane/EtOAc, 4:1) to afford the title compound. Yield: 1.802 g (6.897 mmol, 69%); colourless solid; mp 64-65 C (lit.11b isomer mp 58-60 C); [alpha]D25 -32.7 (lit.11b isomer +30.8) (c = 1.00 CHCl3); Rf = 0.65 (cyclohexane/EtOAc, 2:1). IR (ATR): 3380, 2979, 1738, 1716, 1503, 1438, 1393, 1367, 1347, 1290, 1215, 1163, 1047, 1028, 998, 847, 811, 781 cm-1. 1H NMR (CDCl3, 500 MHz): delta = 5.49 (d, J = 8.4 Hz, 1H, NH), 4.58 (dt, J = 4.5, 8.4 Hz, 1H, 2-H), 3.76 (s, 3 H, OMe), 3.70 (s, 3 H, OMe), 3.01 (dd, J = 4.5, 17.2 Hz, 1H, 3-Ha), 2.83 (dd, J = 4.6, 17.2 Hz, 1H, 3-Hb), 1.45 (s, 9 H, tBu). 13C NMR (CDCl3, 125 MHz): delta = 171.7, 171.6, 155.5, 80.3, 52.9, 52.2, 50.0, 36.8, 28.4. MS (EI): m/z (%) = 41 (71) [C2HO]+, 57 (100) [C4H9]+, 76 (31), 86 (43), 102 (99), 113 (26), 128 (42), 146 (99), 160 (65) [C6H10NO4]+, 174 (39), 188 (20), 202 (82) [C9H16NO4]+.
With thionyl chloride; at 0 - 10℃; for 2h;Reflux;
50 g of aspartic acid, 240 g of methanol was added to a 500 mL reaction flask, the internal temperature was lowered to 0 to 5 C, and 67 g of thionyl chloride was slowly added dropwise.The internal temperature was controlled to 0 to 10 C, and the temperature was raised to reflux reaction for 2 hours. After the completion of the heat preservation, the mixture was concentrated under reduced pressure until no fraction was added; 160 g of methanol was added.Control the temperature 10 ~ 20 C, add 38g of triethylamine,Adjust the pH value of 7~8, and control the temperature to 10~20C.40 g of benzaldehyde was added dropwise,Warm up to 25 ~ 35 C for 1 h,Cool down to 0 ~ 10 C, add 10g of potassium borohydride and 75g of water solution,Control the internal temperature from 0 C to 15 C,Stir for 1 h after the dropwise addition.filter,After the filtrate was concentrated under reduced pressure, 200 g of water and 100 g of toluene were added.Stir for 15 minutes,Let stand layering,The aqueous layer is extracted with toluene and the organic layers are combined.The organic layer is sequentially added with an aqueous solution of ammonium chloride.Washing with salt water;The obtained organic layer was added with 61 g of aqueous formaldehyde solution.35.2 g of formic acid, the temperature is raised to 55-65 C for 1 to 3 h, and the temperature is lowered to room temperature.Let stand layering. The aqueous layer is extracted with toluene,The organic layer was concentrated under reduced pressure until no fraction was obtained.75 g of a yellow oil N-methyl-benzyl-aspartic acid dimethyl ester was obtained in a molar yield of 75.3%, and HPLC (high-performance liquid) purity was 98.5%.
With thionyl chloride; at 0 - 10℃; for 2h;Reflux;
Add 50 g of aspartic acid, 240 g of methanol to a 500 mL reaction flask.The internal temperature dropped to 0 to 5 C, and 67 g of thionyl chloride was slowly added dropwise.Control the internal temperature 0~10 C,The temperature was raised to reflux reaction for 2 h.After the completion of the heat preservation, the mixture was concentrated under reduced pressure until no fraction was added; 160 g of methanol was added.Control the temperature 10 ~ 20 C, add 38g of triethylamine,Adjust the pH value 7~8,Temperature control to 10 ~ 20 C, add 40g benzaldehyde,Warm up to 25 ~ 35 C for 1 h,Cool down to 0 ~ 10 C, add 10g of potassium borohydride and 75g of water solution,The internal temperature was controlled from 0 C to 15 C, and the mixture was stirred for 1 h.After filtration and concentration of the filtrate under reduced pressure, 200 g of water and 100 g of toluene were added.Stir for 15 minutes, let stand for stratification, extract the aqueous layer with toluene, and combine the organic layers.The organic layer is sequentially added with an aqueous solution of ammonium chloride,Washing with brine;The obtained organic layer was added with 61 g of aqueous formaldehyde solution and 35.2 g of formic acid.The temperature is raised to 55-65 C for 1 to 3 hours.Cool to room temperature and let stand for stratification.The aqueous layer is extracted with toluene,The combined organic layers were concentrated under reduced pressure to a fraction.75 g of yellow oil N-methyl-benzyl-aspartic acid dimethyl ester were obtained.The molar yield is 75.3%.HPLC (high performance liquid phase) purity 98.5%.The reaction equation for this experimental example is as follows:
trisodium N-(2-carboxyethyl)-D-aspartate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Except that <strong>[1783-96-6]D-aspartic acid</strong> was used in lieu of L-aspartic acid, the procedure of Production Example 1 was repeated to give an aqueous solution containing 35 mass % of trisodium N-(2-carboxyethyl)-D-aspartate and 8.8 mass % of impurity. The pH of this solution at 25C was 9.7. Except that <strong>[1783-96-6]D-aspartic acid</strong> was used in lieu of L-aspartic acid, the procedure of Production Example 3 was repeated to give an aqueous solution containing 38.3 mass % of trisodium N-(2-carboxyethyl)-D-aspartate and 9.6 mass % of impurity. The pH of this solution at 25C was 5.1.
Acetyl chloride (54.6 mL, 0.75 mol) was added drop-wise into ethanol (316 mL) at 0-5 C. When the addition was completed, the ice bath was removed and the solution was allowed to stir while warming to room temperature for another 30 mins. <strong>[1783-96-6]D-aspartic acid</strong> 1 (25 g, 0.188 mol) was then added. The reaction mixture was refluxed for 2 hours. The reaction solution was then concentrated in vacuo and placed under high vacuum (0.4 mm Hg) overnight. Compound 2 was obtained as a white solid (42g, 99%) and used directly in the next step. [00469] (BOC)20 (44.7 g, 0.21mol) was added portion-wise over 10 mins to a 0 C solution of compound 1 (42 g, 0.19 mol), trimethyl amine (51.9 ml, 0.37 mol), dioxane (140 mL) and water (56 mL). After another 10 min, the ice bath was removed and the reaction mixture was stirred while warming to room temperature for another 2 hours. The reaction mixture was diluted in ethyl acetate (150 mL) and washed with 0.5 N HCI (200 mL x 3). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo giving compound 3 (52 g, yield 97%) which was used directly in the next step. [00470] NaBH4 (54.4 g, 1.44 mol) was added portion-wise over 30 mins to a 0 C solution of compound 3 (52 g, 86.4 mmol) and ethanol (600 mL). The reaction mixture was extremely exothermic and great care was exercised during the addition of reducing agent. After the addition was complete, the reaction mixture was heated to reflux for 1 hour. The solution was cooled to ambient temperature and the reaction mixture solidified. The solid was broken-up to a slurry, which was then poured into brine (250 mL). The resulting mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was vigorously stirred with ether (200 mL x 5). The ether layers were successively decanted from the residue. The combined ether extracts were dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo giving compound 4 as white solid (25.2g, yield 68%). [Note: Yield was 89% when performed on a 25 g (compound 3) scale,] [00471] t-Butyldiphenylchlorosilane (31.9 mL, 0.123 mol) was added to a solution of compound 4 (25.2 g, 0.123 moll, diisopropylethylamine (42.8 mL, 0.245 mol), and CH2Cl2 (500 mL). The reaction solution was stirred at ambient temperature for 24 hrs. The reaction solution was then washed with 0.5 N HCI (150 mL x 3) and brine (150 mL). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, 4:1 hexanes:EtOAc) to give compound 5 (42g, yield 77%). [Note: Yield was 85% when performed on 15 g (compound 4) scale.] [00472] Iodine (24 g, 94.7 mmol) was added portion-wise over 15 mins to a 0 C solution of compound 5 (28 g, 63.1mmol), Ph3P (24.8 g, 94.7 mmol), imidazole (6.4g, 94.7 mmol), diethyl ether (450 mL) and acetonitrile (150mL). The ice bath was removed and the reaction solution was allowed to wann to ambient temperature over 30 mins. The reaction was judged complete by TLC analysis (4:1 hexanes:EtOAc), The reaction was quenched with water (400 mL). The layers were separated and the aqueous layer was extracted by diethyl ether (100 mL). The combined organic layers were washed with saturated aqueous Na2SO3 (100 x 2) and brine (100 mL). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 4:1 hexanes:EtOAc) to give compound 6 (32 g, 92%).
Under ice-bath, to a solution of D-Aspartic acid 1 (59g, 0.376 mol) in methanol (200 mL) was bubbled HCl gas for 10 minutes. After the reacting solution was stirred at RT overnight, the solvent was'evaporated. The resulting residue was dried under Vacuum to have product 2 as HCI salt (0.376 mol). [00474] To a stirred solution of 2 (0.376mol), DIEA (196 mL, 1.13 mol) and THF (200 mL), benzyl chloroformate (59.0 mL, 0.414 mol) was dropped in. After the reaction solution was stirred at room temperature for 1 hr, the solution was concentrated on rot-vap. Then the residue was dissolved in NaHC03 solution (300 mL) and extracted with DCM (100 mL X 3). The combined DCM solution was dried over sodium sulfate, filtered, and the filtrate was concentrated iii vacuum to have the product 3 (0.376 mol). [00475] To a solution of 3 (0.376 mol), THF (200 mL) and Water (100 mL) was added Lithium hydroxide (31.6g, 0.752 mol) and stirred for 2 hours. The reaction mixture was filtered through a silic gel plug (the pH of the filtrate was about 7) and concentrated. The residue was dried under Vacuum to give 4 (0.376 mol). [00476] After a solution of 4 (0.376 mol) and acetic anhydrate (200 mL) was stirred for 1 hour, the reaction mixture was concentrated. The residue was dried under Vacuum to give 5 (0.376 mol). [00477] Under ice-bath, to a solution of 5 (0.376 mol) and THF (1000 mL) was added Sodium borohydride (14.2g, 0.376 mol) during 30 minutes and stirred for 3 hrs. Then HCl solution (4N) was dropped into the reaction solution until the pH was about 2, The solution was concentrated to about a quarter left, diluted with water (300 mL) and extracted by ethyl ether (200 mL X 3). The combined ether solution was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuum. The resulting residue was dissolved in benzene (300 mL) and TsOH (500 mg) was added. Then the reaction mixture was stirred at reflux 3 hrs. The solution was concentrated to about 100 ml and ether (200 mL) was added to form precipitate. The white solid 6 (57.5g, 65% from 1) was filtered out, washed with some ether and dried under Vacuum. [00478] To a solution of 6 (30.0g, 0.128 mol) and methanol (200 mL) was added triethylamine (142 mL, 1.02 mol) and stirred overnight. The reaction mixture was concentrated. The residue was dried under Vacuum to give 7 (LC-MS showed about 20%mol 6 was left) which was directly used in the next step. [00479] Under ice-bath, to a solution of compound 7 (0.128 mol), Ph3P (50.4 g, 0.192 mol), imidazole (13.1 g, 0.192 mol) and DCM (300 mL) was stirred for 10 min. Iodine (48.7 g, 0.192 mol) was added portion-wise over 15 minutes. The ice bath was removed and the reaction solution was stirred at room temperature over 1 hour. The solid was filtered out. The filtrate was washed with saturated aqueous Na2SO3 (200 mL x 2) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by flash silica gel column chromatography (hexanes:EtOAc 4:lto 1:1) to give compound 8 (27.5 g, 59.2% from 6) as a white solid. [00480] To a mixture of zinc powder (Strem, 10.1 g, 0.154 mol) and DMF (15 mL) was purged under Nitrogen for 10 minutes and added 1,2 dibromoethane (0.758 mL, 8.80 mmol). The mixture was heated with a heat gun for -2 minutes, cooled down for 5 minutes and heated with a heat gun again, then cooled to room temperature. TMSCI (281 (at)L, 2.20 mmol) was added to the mixture. After the mixture was stirred for 30 minutes, 8 (9.98 g, 26.5 mmol) was added. After 1 hour, LCNIS showed complete consumption of 8. To above reaction solution was added aryl iodide 9 (7.50 g, 22.0 mmol), Pd2(dba)3 (50.4 mg, 0.55 mmol) and tri-o-tolylphosphine (670 mg, 2.20 mmol). The reaction mixture was maintained at 50 C for 1 hour (monitered on LC-MS analysis). The reaction mixture was directly loaded to a silica gel plug and washed with hexanes:EtOAc (3:1 to 1: 1) to give compound 10 (5.0 g, 49%).
With sodium carbonate; In ethanol; water; at 105℃;
A mixture of 1,2-fluoronitrobenzene (27.5 g, 19.5 mmol), <strong>[1783-96-6]D-aspartic acid</strong> (20.7 g, 15.6 mmol) and sodium carbonate (49.5 g, 46.7 mmol) in a mixed solvent system of ethanol-water (5: 1, 300 mL) was heated at 105 C overnight. The solvent was removed under reduced pressure and DMF (200 mL) was then added to the residue. Methyl iodide (24 mL, 38.5 mmol) was added to the mixture and the resulting mixture was stirred at rt overnight. Solvent was removed under reduced pressure and EtOAc was added to the residue. The heterogeneous mixture was then washed with brine, dried with MgSO4, and concentrated under reduced pressure. The resulting yellow oil was purified by column chromatography over silica gel with EtOAc/hexane (1: 2) as eluent to give a yellow oil as the title compound :'H NMR (CDCl3) a = 10.24 (bs, 1H), 8. 03 (t, 1H, J=5. 4Hz), 7. 30-7.15 (m, 5H), 6.75-6. 70 (m, 3H), 6.61-6. 56 (m, 1H), 5.79 (bs, 1H), 4.08-4. 04 (m, 1H), 3.30-3. 24 (m, 2H), 2.71 (t, 2H, J=7. 8Hz), 2.60 (dd, 1H, J=3. 9,15. 3 Hz), 2.31 (dd, 1H, J=8. 7,15. 3 Hz).
A. D-Aspartic Acid b-Methyl Ester Hydrochloride A suspension of D-aspartic acid (10.0 g, 75.1 mmol) in 50 mL methanol is treated with thionyl chloride (8.94 g, 75.1 mmol) at 0 C. The reaction mixture is stirred at 0 C. for 30 min, then at RT for 2 h. The resulting clear solution is diluted with 200 mL diethyl ether with rapid stirring. A white precipitate is formed which is collected by vacuum filtration, washed with diethyl ether and dried to yield 10.7 g (78%) of D-aspartic acid b-methyl ester hydrochloride.
Compound 51a:; To a 5.5 N HCI solution (30.7 mL) of 4-chloro-1 ,2-diamino-5-fluoro-benzene (4.93 g, 30.7 mmol) was added H-D-Asp-OH (6.12 g, 46.0 mmol). The mixture was refluxed for overnight. It was filtered after cooling down to room temperature. The filtrate was purified by prep. HPLC to give the title compound. 1H NMR (DMSO-d6): delta 7.60 (1 H, d, J=6.6Hz), 7.42 (1 H, d, J=9.4Hz), 3.73 (1 H, dd, J=8.9, 4.8Hz), 3.42-3.30 (2H, m). LCMS (APCI): 258.0 (M+H+).
With hydrogenchloride; In water; for 72h;Heating / reflux;
Compound 60a:; Chiral To a 5.5 N HCI solution (9 mL) of 1 ,2-diamino-3-chloro-benzene (1.3 g, 9.12 mmol) was added H-D- Asp-OH (3.6 g, 27.4 mmol). The mixture was refluxed for 72h. It was filtered after cooling down to EPO <DP n="50"/>room temperature. The filtrate was purified by prep. HPLC to give the title compound in 41% yield (0.9g). 1H NMR (DMSO-d6): delta 7.52 (1 H, dd, J=8.1 , 1 Hz), 7.28 (1 H, dd, J=7.8, 1 Hz), 7.20 (1 H, t, J=7.8Hz), 4.54 (1 H, t, J=6.8Hz), 3.49 (1 H, dd, J=16.4, 5.8Hz), 3.39 (1 H, dd, J=16.2, 7.1 Hz). LCMS (APCI): 240 (M+H+).
Compound 46a:; To a 5.5 N HCI solution (54 mL) of 4-chloro-1 ,2-phenylene diamine (7.74 g, 54.3 mmol) was added H- D-Asp-OH (10.8 g, 81.4 mmol). The mixture was refluxed for 72h. It was filtered after cooling down to room temperature. The filtrate was adjusted to pH 7 with solid sodium carbonate. Solid was collected by filtration and recrystalized with 67% ethanol (50 mL) to give the title compound in 23% yield. 1H NMR (DMSO- d6): delta 7.81 (1 H, d, J=1.8Hz), 7.75 (1 H, d, J=8.6Hz), 7.40 (1 H, dd, J=8.4, 2.1 Hz), 4.05- 3.90 (1 H, m), 3.64 (1 H, dd, J=16.4, 5.6Hz), 3.36 (1 H, dd, J=15.9, 7.4Hz). LCMS (APCI): 240.0 (M+H+).
Compound 53a:; To a 5.5 N HCI solution (12.5 mL) of 1 ,2-diamino-3,4-difluoro-benzene (1.80 g, 12.5 mmol) was added H-D-Asp-OH (6.12 g, 46.0 mmol). The mixture was refluxed for overweekend. It was filtered after cooling down to room temperature. The filtrate was purified by prep. HPLC to give the title compound in 66% yield. LCMS (APCI): 242.1 (M+H+).
Compound 57:; Chiral To a 5.5 N HCI solution (7.2 mL) of 1 ,2-diamino-3,5-difluorobenzene (1.04 g, 7.19 mmol) was added D-aspartic acid (1.44 g, 10.8 mmol). The mixture was refluxed for overnight. The reaction crude was purified by prep. HPLC to give the title compound as an acetic acid salt in 57% yield. 1H NMR (DMSO- d6): delta 7.22 (1 H, dd, J=8.6, 2Hz), 7.02 (1 H, td, J=10.6, 2Hz), 4.21 (1 H, t, J=6.3Hz), 3.44 (1 H, dd, J=16.2, 5.6Hz), 3.29 (1 H, dd, J=16.4, 7Hz). LCMS (API-ES): 242.1 (M+H+).
With hydrogenchloride; In water; for 72h;Heating / reflux;
Compounds 62a & 62b; A solution of 4-methoxy-o-phenylenediamine (5g, 36.1873 mmol), <strong>[1783-96-6]D-aspartic acid</strong> (3.211g, 24.1249 mmol), water (14.6 mL) and concentrated hydrochloric acid (10 ml_) was refluxed for 3 days and then allowed to cool to ambient temperature. The mixture was evaporated to dryness and the regioisomers partially separated by preparative HPLC. LCMS 236 (M+H).
With hydrogenchloride; In water; for 72h;Heating / reflux;
Compound 18a:; To an aqueous HCI solution (5.5 N, 87ml_) was added 4-Fluorobenzene-1 ,2-diamine (1 Og, 79.4mmol) and D-Aspartic acid (15.8g, 119mmol). The mixture was heated at reflux for 72h. The mixture was purified with preparative HPLC and recrystallization from EtOAc, affording the title compound (7.5g, 28% yield) as a pale tan solid. 1H NMR (CD3OD): delta 7.62 (1 H, dd, J=8.9, 4.8Hz), 7.36 (1 H, dd, J=8.9, 2.3Hz), 7.14 (1 H, td, J=9.6, 2.5 Hz), 4.53 (1 H, dd, J=7.4, 5.6Hz), 3.67 (1 H, dd, J=16.4, 5.8Hz), 3.54 (1 H, dd, J=16.2, 7.4Hz). LCMS (APCI): 224 (M+H) (positive).
Compound 48a:; To a 5.5 N HCI solution (50 mL) of 3,4-diamino toluene (6.11 g, 50.0 mmol) was added H-D-Asp-OH (9.98 g, 75.0 mmol). The mixture was refluxed for overnight. It was filtered after cooling down to room temperature. The filtrate was adjusted to pH 1 with solid sodium carbonate. Solid was collected by filtration and recrystalized with 67% ethanol to give the title compound in 30% yield. 1H NMR (DMSO- d6): delta 10.0 (1 H, br s), 7.62 (1 H, d, J=8.3Hz), 7.52 (1 H, s), 7.20 (1 H, d, J=9Hz), 4.33 (1 H, t, J=7Hz), 3.63 (1 H, dd, J=16.2, 5.1 Hz), 3.45 (1 H, dd, J=16.2, 7.3Hz), 2.61 (3H, s). LCMS (APCI): 220.0 (M+H+).
N-[ d,l-2-(5-bromo-6-methoxy-2-naphthyl)-propionyl]-l-aspartic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium hydroxide; formic acid; sodium sulfate; In water; acetone;
EXAMPLE 1 N-[ d,l -2-(5-Bromo-6-methoxy-2-naphthyl)-propionyl]- l -aspartic acid [ d,l + l,l ] A solution of 78.3 g (0.239 moles) of the chloride of the d,l -2-(5-bromo-6-methoxy-2-naphthyl)-propionic acid in 180 ml of anhydrous acetone is slowly poured drop by drop, under strong stirring, into a solution of 31.87 g (0.239 moles) of D-(-)-aspartic acid in a mixture made by 180 ml of water and 47.88 ml (0.478 moles) of a 30% (w/w) aqueous solution of sodium hydroxide, while keeping the temperature at about 10C and the pH value at about 9.5 by means of a 15% (w/w) aqueous solution of sodium hydroxide. The reaction mixture is further stirred for one hour after the end of the dripping while raising the temperature at about 20C, then it is filtered and the acetone is eliminated by evaporation under vacuum. The aqueous solution is acidified to pH 6.5 by means of a concentrated aqueous solution of hydrochloric acid and is sometimes washed with ethyl acetate. The traces of ethyl acetate remained into the aqueous solution are eliminated by evaporation under vacuum and subsequently the aqueous solution is added with 150 ml of formic acid. The precipitate is extracted with methylbutylketone; the organic layer is first washed with water and then with 10% (w/v) aqueous solution of sodium sulfate, dried over sodium sulfate, filtered on decolorating earths and evaporated under vacuum to give 82 g of product, having [alpha]
In dichloromethane; N-ethyl-N,N-diisopropylamine; N,N-dimethyl-formamide;
Step 7a. (D)-N-Benzyloxycarbonylaspartic acid (22) A 50 g (0.375 mol) sample of <strong>[1783-96-6]D-aspartic acid</strong> was dissolved in a mixture of DMF and diisopropylethylamine, and 114 g (0.45 mol) of N-(benzylcarbonyloxy)-succinamide was added and the reaction was stirred at 70 C. for 2 hours. The solvent was removed under vacuum, and the residue dissolved in methylene chloride which was extracted with pH 2 HCl, water, and brine and dried over MgSO4. The solvent was removed and the residual oil triturated with ether and methanol; the title product (92.75 g; 92.5% yield) separated upon cooling.
D-aspartic acid β-methyl ester hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10.7 g (78%)
With thionyl chloride; In methanol;
A. D-Aspartic acid beta-methyl ester hydrochloride A suspension of <strong>[1783-96-6]D-aspartic acid</strong> (10.0 g, 75.1 mmol) in 50 mL methanol is treated with thionyl chloride (8.94 g, 75.1 mmol) at 0 C. The reaction mixture is stirred at 0 C. for 30 min, then at RT for 2 h. The resulting clear solution is diluted with 200 mL diethyl ether with rapid stirring. A white precipitate is formed which is collected by vacuum filtration, washed with diethyl ether and dried to yield 10.7 g (78%) of <strong>[1783-96-6]D-aspartic acid</strong> beta-methyl ester hydrochloride.
β-allyl (2R)-aspartate ester hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With chloro-trimethyl-silane;
D-Aspartic acid gamma-allyl ester hydrochloride D-Aspartic acid (4 g) is suspended in allyl alcohol (100 mL) and trimethylsilyl chloride (9.5 mL) is added dropwise and the reaction mixture is stirred at room temperature for 20 hours. Ether (600 mL) is added and the white precipitate is collected by filtration, eashed with ether and dried to give <strong>[1783-96-6]D-aspartic acid</strong> gamma-allyl ester hydrochloride.
With triethylamine; In dichloromethane; at 20℃; for 96h;
To a suspension of 4-(3-isocyanato-benzyl)-2H-phthalazin-1-one (2)(1.4 g, 4.7 mmol) in dry DCM (40 ml) was added <strong>[1783-96-6]D-aspartic acid</strong> (0.455 g, 5.0 mmol), followed by triethylamine (1.4 ml, 1.0 mmol). The reaction was stirred at room temperature for 4 days. The reaction mixture was then filtered. The filtrate was then diluted with water (20 ml) and washed twice with DCM (2*20 ml). The combined DCM layers were dried over sodium sulfate and then concentrated in vacuo to afford a crude oil which was subjected to flash chromatography eluent neat ethyl acetate to remove impurity and the then 1:1 ethyl acetate/methanol to remove the desired component. (Rf of 0.2 in 1:1 ethyl acetate methanol). Single peak in LC-MS analysis, (0.79 g) requiring no further purification; m/z (LC-MS, ESP), RT=2.70 (M+H) 384;
(Example 23) (R)-3-benzyloxypyrrolidine-(D)-aspartate 0.25 g of a concentrate of (R)-3-benzyloxypyrrolidine obtained separately (purity of 86.6 %, optical purity of 97.0 %ee) containing (R)-3-hydroxypyrrolidine hydrochloride (content of 0.12 wt %) and benzyl alcohol (content of 1.0 wt %) as impurities was dissolved in 10 ml of distilled water, and 325 mg of (D)-asparagic acid was added. After stirring for a while, isopropanol was added and the solution was subjected to azeotropic dehydration, followed by concentration and drying under reduced pressure, thereby obtaining a white crystal. After the crude product was dispersed in 4.00 g of isopropanol and was heated to 40 C, 466 mg of distilled water was added and the crude product was dissolved completely. The solution was gradually cooled to 22 C, and the deposited crystal was filtered under reduced pressure. The resultant wet crystal was washed with 10 ml of ethyl acetate and then the wet crystal was dried under reduced pressure, thereby obtaining 0.17 g of dry crystal of (R) -3-benzyloxypyrrolidine- (D) -aspartate (yield of 22 %, purity of 98.7 %, optical purity of 99.8 %ee). Each of (R)-3-hydroxypyrrolidine hydrochloride and benzyl alcohol in the crystal was 0.01 wt % or less. 1H-NMR(D2O):delta(ppm)2.08-2.34(m,2H),2.67(dd,J=8.9Hz,17.4Hz,1H),2.82(dd,J=3.7Hz,17.4Hz,1H),3.34-3.54(m,4H),3.89(dd,J=3.7H z,8.9Hz,1H),4.49(m,1H),4.61(s,2H),7.40-7.48(m,5H).
Example 3Thionyl chloride (27.9 mL, 0.384 mol) was added to 250 mL of methanol at -30 0C. d- Aspartic acid (50.0 g, 0.376 mol) was added, and the mixture was warmed to room temperature. After stirring for 2.5 h, the reaction mixture was cooled to 10 0C and a 14% K3PO4(aq) solution (570 mL) was added. The reaction mixture was concentrated, removing 300 mL of solvent. Toluene (275 mL) was added, followed by Boc2O (90.3 g, 0.414 mol). The reaction mixture was cooled in an ice bath to 15 0C and K3PO4 (148 g. 0.696 mol) was added in portions. The reaction mixture was stirred vigorously for 12 h and the layers were separated. The aqueous layer was extracted with toluene (250 mL). EPAc (300 mL) was added and 2N HCl was used to acidify the aqueous layer to pH 2. The layers were separated, and the aqueous layer as extracted with BPAc (300 mL). The combined EPAc layers were washed with 2N HCl . The solution was concentrated to approximately 75 mL of solution, and heptane (500 mL) was added slowly, with stirring, to afford white crystals that were filtered and dried (20.1 g, 22%).
SOCI2 (1 62 mL) was added to 13 mL methanol at 0 C. To the solution was added D- aspartic acid (2.90 g) and the mixture was warmed to room temperature. After 3 hours, the mixture was cooled in an ice-water bath and 33 mL of aqueous 14% K3PO4 was added. MeOH was distilled away under vacuum. Toluene (16 mL) was added followed by Cbz-OSu (N-(benzyloxycarbonyloxy)succinimide) (5.97 g). The flask was cooled in an ice-water bath, and 8.65 g K3PO4 was charged. The mixture was stirred at room temperature for 14h.The organic layer was removed, and the aqueous layer was washed with toluene (20 mL). Isopropyl acetate (EPAc) (30 mL) was added to the aqueous layer. Concentrated HCl (8 mL) was then added to acidify the aqueous layer to pH 1. The aqueous layer was removed and the organic layer was washed twice with dilute HCl. <n="16"/>The IPAc solution was concentrated to about 13 mL and heptane (40 mL) was added to crystallize the product. The suspension was filtered, rinsing with heptane, giving 4.22 g (69% yield) of 1-2.
1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3,4]oct-6-yl)-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid[ No CAS ]
1-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid D-aspartic acid salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
In ethanol; at 50℃; for 1h;
[133] Example 1: Preparation of the <strong>[1783-96-6]D-aspartic acid</strong> salt of l-cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-l,4-dih ydro-[l,8]naphthyridine-3-carboxylic acid.; [134][135] l-Cyclopropyl-6-fluoro-7-(8-methoxyimino-2,6-diaza-spiro[3.4]oct-6-yl)-4-oxo-l,4- dihydro-[l,8]naphthyridine-3-carboxylic acid (5.0 g) was added to 50% ethanol (80 mL), and then the mixture was stirred at 50 0C for 10 minutes. D-Aspartic acid (2.0 g) was added and then the mixture was stirred at 50 0C for 1 hour. The mixture was cooled to room temperature, and then the resulting solid was collected by filtration. Ethanol (100 mL) was added to the filtrate, and then the mixture was stirred for 30 minutes. The resulting solid was collected by filtration to obtain a total of 5.55 g of the target compound (yield: 83%). Melting point: 200-201 0C . 1H NMR (D2O): delta 0.97 (bs, 2H), 1.27 (d, 2H), 2.00 (dd, IH, J = 8.8, 17.6 Hz), 2.77 (dd, IH, J = 3.3, 17.0 Hz), 3.53 (bs, IH), 3.84 (dd, IH, J = 3.3, 8.78 Hz), 4.01 (s, 3H), 4.31-4.45 (m, 8H), 7.46 (d, IH, J = 12.2 Hz), 8.42 (s, IH).
N-(2,4-dinitro-5-fluorophenyl)-L-alaninamide[ No CAS ]
L-FDAA-D-Asp-OH[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydrogencarbonate; In water; acetone; at 45℃; for 1.5h;
General procedure: To nine glass tubes that one terminal has been sealed was added each 50 muL of 1-9 solutions in MeOH at 1 mg/mL, respectively. After blown inside the tubes with nitrogen gas to dryness, 100 muL of aqueous 6 N HCl solution was added into each tube. After the open terminal of the tubes was sealed by blast burner, the tubes were kept at 110 C for 24 h to hydrolyze 1-9. Then, one sealed terminal of the tubes was cut out, reaction solutions were blown with nitrogen gas to dryness, and the tubes were maintained in vacuo overnight to clean up remained HCl. At the same time, each 500 mug of standards in 500 muL of aqueous 6 N HCl solution, L-Asn, D-Asn, L-Gln, D-Gln, L-Leu, D-Leu, L-Leu amide and D-Leu amide, was also hydrolyzed in the same manner and same conditions. At this condition, the L-Leu amide and D-Leu amide were hydrolyzed to L-Leu and D-Leu, respectively. Both hydrolyzates of the standards and 1-9 were dissolved in each 10 muL of distilled water, mixed with 10 muL of 10 mM L-FDAA in acetone and 10 muL of 1 N NaHCO3 aqueous solution, respectively, and reacted at 45 C for 1.5 h. The reaction mixtures were neutralized with 5 muL of 2 N HCl, respectively. Then, the reaction mixtures were filtered, and the filtrates were subjected to HPLC analysis.
[00222] Acetyl chloride (54.6 mL, 0.75 mol) was added drop- wise into ethanol (316 mL) at 0-5 0C. When the addition was completed, the ice bath was removed and the solution allowed to stir while warming to room temperature for another 30 min. D-aspartic acid 19.1 (25 g, 0.188 <n="77"/>mol) was then added. The reaction mixture was refluxed for 2 hours. The reaction solution was then concentrated in vacuo and placed under high vacuum (0.4 mm Hg) overnight. Compound 19.2 was obtained as a white solid (42 g, 99%) and used directly in the next step.
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