* 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.
at 150℃; for 0.166667 h; Microwave irradiation; Sealed tube; Green chemistry
2-(2,6-Dioxopiperidin-3-yl)isoindole-1,3-dione. (1): phthalicanhydride (0.10 g, 0.68mmol), glutamic acid (0.10 g,0.68mmol), DMAP (0.02 g, 0.16mmol), and NH4Cl (0.04 g,0.75mmol) were mixed thoroughly in a CEM-sealed vialwith a magnetic stirrer.The sample was heated for 10min at150∘C in a CEM Discover microwave powered at 150W. Itwas then cooled rapidly to 50∘C.When at room temperatureit was dissolved in 15mL of (1 : 1) ethyl acetate : acetone. Theorganic layer was washed with 2x (10 mL) distilled water andthen dried over sodium sulfate (anhydrous). The organiclayer was concentrated under vacuum. The residue wastreated with hexanes (30mL) affording a white solid (0.14 g,80percent). mp 268–270∘C. 1H NMR (400MHz, DMSO-d6) δ 11.14 (s, 1 H, NH), 7.94 (m, 4 H, Ar), 5.17 (dd, 1H, 12.5, 5.5Hz),2.92 (m, 1 H), 2.57 (m, 2), 2.09 (m, 1H); 13C NMR (100MHz,DMSO-d6) 172.7, 169.8, 167.1, 134.9, 131.2,123.4, 49.0, 30.9,22.0; MS m/z 258 (M+); 230, 213, 202, 173, 148, 111, 76,50.
Reference：
[1] Journal of Chemistry, 2017, vol. 2017,
2
[ 617-65-2 ]
[ 498-63-5 ]
Yield
Reaction Conditions
Operation in experiment
36%
With phosphoric acid; ruthenium-carbon composite; hydrogen In water at 180℃; for 24 h;
as a metal-supported catalyst, ruthenium carbon having a dispersity of 17.46percent, a metal surface area of 63.78 (m 2 / g), a particle diameter of 7.73 (nm), and a metal loading of 5percent A catalyst was prepared.In a pressure vessel, 100 g of water, 3.2 g of glutamic acid, 2.86 g of phosphoric acid and 0.16 g of ruthenium carbon catalyst were mixed. The mixture was stirred for 16 hours while pressurizing at 180 ° C. to a hydrogen pressure of 8 MPa. After completion of the reaction, the reaction mixture was filtered. When the components contained in the filtrate were analyzed by LC (liquid chromatography), prolinol was obtained in a yield of 35percent. Prolinol was synthesized under the same conditions as in Example 1. However, the reaction time was 24 hours. The yield of prolinol was 36percent.
Reference：
[1] Patent: JP2017/109940, 2017, A, . Location in patent: Paragraph 0023
3
[ 617-65-2 ]
[ 19365-07-2 ]
Reference：
[1] Patent: CN106748972, 2017, A,
4
[ 617-65-2 ]
[ 4344-84-7 ]
Yield
Reaction Conditions
Operation in experiment
104 g
With hydrogenchloride; sodium nitrite In water at 0 - 20℃; for 0.25 h; Inert atmosphere
(1) at room temperature and under N2 protection,140 ml of concentrated hydrochloric acid was added to a solution of 270 mL of H2O as a solvent in Compound 1 (2-aminoglutaric acid)There is an exothermic phenomenon,After the system becomes clear, the system cools down to 0 ° C.At 0 ° C,To the system was slowly added 70.3 g of NaNO2 H2O solution (200 mL)There is temperature,The system becomes green and turbid.15min after the drop is completed, T = 2 ,Maintain 0 ° C reaction.Solution system directly at 50 under the oil pump concentrated dry,The concentrated dry system was beaten with 400 mL of ethyl acetate,Filtration, filter cake continued with 400mL ethyl acetate beating once,The filter cake was rinsed with 200 mL of ethyl acetate, the filtrates were combined,45 ° C pump to dry to obtain 104 g of a yellow oily liquid (compound 2).
Reference：
[1] Chemische Berichte, 1961, vol. 94, p. 2106 - 2114
[2] Chemistry and Industry (London, United Kingdom), 1959, p. 1413
[3] Justus Liebigs Annalen der Chemie, 1890, vol. 260, p. 128
[4] Patent: CN106748972, 2017, A, . Location in patent: Paragraph 0022; 0023; 0024; 0030
5
[ 7209-05-4 ]
[ 7664-41-7 ]
[ 4344-84-7 ]
[ 617-65-2 ]
Reference：
[1] Nippon Kagaku Zasshi, 1959, vol. 80, p. 1317,1320[2] Chem.Abstr., 1961, p. 4358
Reference：
[1] Helvetica Chimica Acta, 1926, vol. 9, p. 317
[2] Biochemische Zeitschrift, 1928, vol. 203, p. 291
[3] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1927, vol. 170, p. 199
[4] Organic Letters, 2006, vol. 8, # 15, p. 3215 - 3217
[5] Nippon Nogei Kagaku Kaishi, 1954, vol. 28, p. 346,347[6] Chem.Abstr., 1954, p. 10078
10
[ 617-65-2 ]
[ 75-36-5 ]
[ 5817-08-3 ]
Reference：
[1] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1927, vol. 170, p. 199
[2] J.Chin.chem.Soc., 1933, vol. 1, p. 195[3] Chem. Zentralbl., 1934, vol. 105, # II, p. 1114
11
[ 617-65-2 ]
[ 19146-55-5 ]
Reference：
[1] Nippon Nogei Kagaku Kaishi, 1954, vol. 28, p. 346,347[2] Chem.Abstr., 1954, p. 10078
12
[ 617-65-2 ]
[ 16051-87-9 ]
[ 692-29-5 ]
Reference：
[1] Journal of the American Chemical Society, 1936, vol. 58, p. 910,912
13
[ 617-65-2 ]
[ 103-80-0 ]
[ 2752-35-4 ]
Reference：
[1] Tetrahedron Asymmetry, 2006, vol. 17, # 2, p. 245 - 251
[2] Chem. Penicillin, <Princeton 1949>, S. 688, 780,
[3] Journal of Pharmaceutical Sciences, 1996, vol. 85, # 10, p. 1049 - 1052
14
[ 617-65-2 ]
[ 24424-99-5 ]
[ 104-15-4 ]
[ 100-51-6 ]
[ 13574-13-5 ]
Reference：
[1] Chemical communications (Cambridge, England), 2001, # 19, p. 1908 - 1909
15
[ 617-65-2 ]
[ 104-15-4 ]
[ 501-53-1 ]
[ 30924-93-7 ]
Reference：
[1] Chemical communications (Cambridge, England), 2001, # 19, p. 1908 - 1909
16
[ 617-65-2 ]
[ 115-11-7 ]
[ 32677-01-3 ]
Yield
Reaction Conditions
Operation in experiment
86%
With sulfuric acid; nitrogen In sodium hydroxide; chloroform
Example 5 Di-t-butyl L-glutamate Hydrochloride (15A) Glutamic acid 14 (4.4 g, 30 mmol) was suspended in chloroform (120 mL) and sulfuric acid (3 mL, 56 mmol) was added. The suspension was cooled at -78° C. and condensed isobutylene (70 mL) was added. The reaction mixture was stirred allowing to warm to room temperature for 18 h. After 18 hr, all the suspended solid had dissolved to a clear solution. Nitrogen was bubbled through the solution for 10 min, then it was extracted with aqueous NaHCO3 (2*100 mL) and distilled water (100 mL). The organic layer was dried (MgSO4), evaporated, and kept in a dessicator over NaOH pellets for 48 h to afford 15 (6.7 g, 86percent) as an oil. 1H-NMR δH: 1.39 (s, 9H, COO-t-Bu), 1.41 (s, 9H, COO-t-Bu), 1.60-1.90 (2 m, 2H, CH2CH(NH2)-), 2.15-2.35 (m, 2H, CH2COO), 2.85 (s, 2H, NH2), 3.20-3.35 (m, 1H, CH(NH2)-). MS (ESI): 260 (M++H, 100), 283 (M++Na, 10).
4
25 g of glutamic acid was placed in a 500 ml round-bottom flask, a formaldehyde aqueous solution (concentration: 37%, 60 ml), 200 ml of water and 8 g of Pd/C were added sequentially. The air in the flask was displaced by hydrogen, the flask was placed under the hydrogen atmosphere and the reaction was conducted for 48 hours. After the reaction, the remaining hydrogen was displaced by nitrogen and the flask was heated to 90° C. under reflux. Pd/C was filtered out at the high temperature to obtain a colorless aqueous solution. The colorless aqueous solution was concentrated, and azeotroped with 100 ml of toluene to further remove the water. The product was dried under high vacuum to obtain 29 g of N,N-dimethylglutamic acid as a pale yellow solid (Yield: 97.3%).
With hydrogenchloride; sodium nitrite; In water; at 0 - 20℃; for 0.25h;Inert atmosphere;
(1) at room temperature and under N2 protection,140 ml of concentrated hydrochloric acid was added to a solution of 270 mL of H2O as a solvent in Compound 1 (2-aminoglutaric acid)There is an exothermic phenomenon,After the system becomes clear, the system cools down to 0 ° C.At 0 ° C,To the system was slowly added 70.3 g of NaNO2 H2O solution (200 mL)There is temperature,The system becomes green and turbid.15min after the drop is completed, T = 2 ,Maintain 0 ° C reaction.Solution system directly at 50 under the oil pump concentrated dry,The concentrated dry system was beaten with 400 mL of ethyl acetate,Filtration, filter cake continued with 400mL ethyl acetate beating once,The filter cake was rinsed with 200 mL of ethyl acetate, the filtrates were combined,45 ° C pump to dry to obtain 104 g of a yellow oily liquid (compound 2).
With hydrogenchloride for 12h; Ambient temperature;
With thionyl chloride at 20 - 55℃;
1 1. Preparation of dimethyl (tert-butoxycarbonyl) -L glutamate:
Take 147g (1mol) of L-glutamic acid and 588g of methanol into a three-necked flask; stir at room temperature,Take 240 g (2.02 mol) of thionyl chloride and slowly add it to the reaction system through a dropping funnel;After the addition was completed in 45-75min, the internal temperature of the system rose to 55 ° C, and the reaction was held at 55 ° C for 2h; thin layer chromatography (TLC) was used to monitor the end of the reaction.After the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was dissolved in water (825 g).165 g of solid sodium bicarbonate was added to water to adjust the pH to 7-8, and then 350 g of ethyl acetate was added;The resulting mixture was stirred at room temperature for 0.5 h, and 229 g of di-tert-butyl dicarbonate was slowly added dropwise, and the reaction was continued at room temperature for 15 h after the dropwise addition.The layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated to obtain 271 g of dimethyl (t-butoxycarbonyl) -L glutamate as a pale yellow oil (purity: 96%; yield: 98%).
With thionyl chloride at 0℃; Inert atmosphere;
4.6. General method for the synthesis of amino acid esters (39-42)
General procedure: The amino acids (25, 36-38) (20.0 mmol) were taken in a roundbottom flask in methanol under N2, thionyl chloride (22 mmol),44 mmol in the case of glutamic acid (25), was added dropwise tothe mixture. The mixture was stirred for 2 h. The reaction mixturewas concentrated under vacuum. To the concentrated mixtureconcentrated NaHCO3 solution was added until pH is 8-9. Theorganic layer was extracted, and amino esters (39-42) wereobtained.
Glutamic acid derivative
Glutamate (376.5 mg, 2.56 mmol) was dissolved in benzyl alcohol (2 mL), was added a CSA (2.0 eq, 1.18 g), were stirred for 4 days at 60 ° C. the reaction. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution to the reaction mixture was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and subjected to concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1 → 3: 1 → 1: 1 → 1: 2 → 1: 4) to give the corresponding benzyl ester (9a) (286.1 mg, 0.87 mmol, 33%) was obtained. Compound 9a (713.3 mg, 2.18 mmol) was dissolved in ethyl formate (30 mL), p-TsOH (0.1 eq, 41.4 mg) was added and allowed to stir for 2 days to react at 60 ° C.. After completion of the reaction, saturated charcoal to the reaction mixtureAqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, Dried with magnesium sulfate, and after filtration, was concentrated under reduced pressure. The residue was purified by silica gel chromatographyPhotography (hexane: ethyl acetate = 1: 1) to give the corresponding formamide (9 b)It was obtained (557.4 mg, 1.56 mmol, 72%). Compound 9b (259.1 mg, 0.79 mmol) and DCM (5 mL) Were placed in, the mixture resulting from PhOPOCl2 (1.5 eq, 178 μL) and pyridine (5.0 eq, 0.55 mL), and the mixture was subjected to stirring the reaction at room temperature for 2.5 hours. After completion of the reaction, saturated diet reaction mixtureBrine was added and extracted with ethyl acetate. The organic layer, hydrochloric acid, sodium hydrogen carbonate, and saturated dietSuccessively washed with brine, and dried over magnesium sulfate, filtered, subjected to concentration under reduced pressure.The residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to giveTo give the isonitrile (9) (91 mg, 0.28 mmol, 35%). Yellow oil.
With chloro-trimethyl-silane In methanol at 20℃; for 0.5h; Inert atmosphere;
1 2-Amino-5-methoxy-5-oxopentanoic acid
To a suspension of 2-aminopentanedioic acid (250 g, 1.70 mol) in dry methanol (2.5 L) under nitrogen was added trimethylsilyl chloride (277 g, 2.55 mol) over 30 mins. The resulting clear solution was stirred at room temperature (20° C.) for 30 min. 1H NMR showed the starting material was consumed completely. The reaction mixture was used in the next step without further work-up. 1H NMR: 400 MHz CD3OD δ: 4.17-4.15 (m, 1H), 3.71 (s, 3H), 2.70-2.60 (m, 2H), 2.33-2.25 (m, 2H).
With chloro-trimethyl-silane at 20℃; for 1h; Inert atmosphere;
1 2-Amino-5-methoxy-5-oxopentanoic acid.
To a suspension of 2-aminopentanedioic acid (250 g, 1.70 mol) in dry methanol (2.5 L) under nitrogen was added trimethyl silyl chloride (277 g, 2.55 mol) over 30 mins. The resulting clear solution was stirred at room temperature (20 °C) for 30 min. 1 H NMR showed the starting material was consumed completely. The reaction mixture was used in the next step without further work-up. NMR: 400 MHz CD3OD d: 4.17-4.15 (m, 1H), 3.71 (s, 3H), 2.70-2.60 (m, 2H), 2.33-2.25 (m, 2H).
With chloro-trimethyl-silane at 20℃; for 0.5h; Inert atmosphere;
1 2-Amino-5-methoxy-5-oxopentanoic acid
2-Amino-5-methoxy-5-oxopentanoic acid To a suspension of 2-aminopentanedioic acid (250 g, 1.70 mol) in dry methanol (2.5 L) under nitrogen was added trimethylsilyl chloride (277 g, 2.55 mol) over 30 mins. The resulting clear solution was stirred at room temperature (20° C.) for 30 min. 1H NMR showed the starting material was consumed completely. The reaction mixture was used in the next step without further work-up. 1H NMR: 400 MHz CD3OD δ: 4.17-4.15 (m, 1H), 3.71 (s, 3H), 2.70-2.60 (m, 2H), 2.33-2.25 (m, 2H).
With chloro-trimethyl-silane at 20℃; for 0.5h; Inert atmosphere;
11.1 Synthesis of γ-allyl-DL-glutamate
D,L-glutamic acid (10.0 g, 68 mmol) and allyl alcohol (80 mL, 1.2 mol) were mixed in a round-bottom flask (300 mL), followed by addition of chlorotrimethylsilane (10 mL, 0.8 mol) via syringe. The resulting suspension was heated to 60° C. and stirred until it became homogeneous. The solvent was removed at room temperature under vacuum to give a viscous oil. Addition of diethyl ether (200 mL) to the residue yielded a light yellow solid which was collected by filtration. Additional purification by recrystallization in ethanol/diethyl ether afforded the final product as a white solid (14.0 g, yield: 92%). 1H NMR (D2O, δ, ppm): 5.79 (m, 1H, CH2═CHCH2-), 5.13 (m, 2H, CH2═CHCH2-), 4.48 (d, 2H, CH2═CHCH2-), 3.93 (t, 1H, -CHNH2), 2.50 (t, 2H, -COCH2CH2-) and 2.10 (m, 2H, -COCH2CH2-); 13C{1H} NMR (D2O, δ, ppm): 174.24, 172.00, 131.83, 118.77, 66.29, 52.33, 29.74 and 25.01.
With thionyl chloride; water at -10 - 20℃; for 17h;
Dimethyl (RS)-glutamate hydrochloride.
SOCl2 (0.65 mL, 8.87 mmol) was added to 5.5 mL of methanol cooled to -10°C. The mixture was stirred for 15 min at -10 °C, then 0.37 g (2.22 mmol) of (RS)-glutamic acid monohydrate was added. The reaction mixture was stirred at room temperature for 17 h. The solution was evaporated, the residue was treated with 12 mL of Et2O. The precipitate was filtered off, dried in a vacuum over P2O5 and KOH. Yield 0.46 g (99 %). Colorless powder, mp 156-157 °C (149 °C [42]). 1Hand 13C NMR spectra are similar to the spectra of (S)-enantiomer [37]. Found, %: C 39.60; H 6.52; Cl 16.68; N 6.50. C7H14ClNO4. Calculated, %: C 39.72; H 6.67; Cl 16.75; N 6.62.
With thionyl chloride for 12h; Heating;
With chloro-trimethyl-silane at 20℃;
Stage #1: Glutamic acid With chloro-trimethyl-silane at 20℃; for 0.333333h;
Stage #2: methanol at 20℃; for 24h;
With sodium hydroxide In water at 100℃; for 0.0833333h; Microwave irradiation;
4
General procedure: A suspension of suitable amino acid (16-20) (1 mmol) and carbon disulfide (1 mmol, 60 μl) in a solution of NaOH (2 mmol) and water (10 ml) was reacted in a microwave reactor for 5 min at 100 °C. After automated cooling chloroacetic acid (1 mmol) was added and the mixture was reacted again at 100 °C for 5 min. After cooling HCl (3 ml, 6 N) was added and the reaction was finished at 120 °C for 30 min. The mixture was neutralized with a saturated NaHCO3 aqueous solution, extracted with ethyl acetate (10 mL * 3) and dried over Na2SO4. After removal of the solvent under reduced pressure, the crude mixture was purified by flash chromatography using a mixture of CH2Cl2/CH3OH (90:10) as eluent.
1
A mixture of ethanol and glutamic acid was initially charged in a stirred vessel (A). The fraction of glutamic acid was 0.1% of the ethanol fraction. The mixture was conveyed continuously through the reactor (C) at a pressure of 72 bar by a suitable pump (B). The tubular reactor (C) was heated to a temperature of 260° C. by the heater (D). A carrier stream of pure ethanol from the reservoir (F) was heated to the same temperature using the preheater (G). At the mixing point (H), the carrier stream was mixed with the reactant stream (ratio 50/50) and fed to the reactor (C). The preheating temperature selected was so high that there was already reaction temperature at the mixing point, so that the temperature gradient in the reactor (C) was sufficiently small to prevent carbonization at the wall. The residence time in the tubular reactor (C) was 40 sec. With the aid of the control valve (E), the pressure was kept at the target value mentioned. At the outlet of the system, the reacted solution was introduced into 1 molar HCl. According to HPLC, 50% product yield (ethyl pyroglutamate) was obtained.
4-O-(prolyl) des-acetylvinblastine TFA salt[ No CAS ]
N-Acetyl-4-trans-L-Hyp-Ser-Ser-Chg-Gln-Ser-Ser-OH[ No CAS ]
N-acetyl-heptapeptide[ No CAS ]
[ 28230-32-2 ]
[ 617-65-2 ]
Yield
Reaction Conditions
Operation in experiment
With NMM; trifluoroacetic acid In Waters C18; water; acetic acid; N,N-dimethyl-formamide
5 des-Acetylvinblastine-4-O-(N-Acetyl-4-trans-L-Hyp-Ser-Ser-Chg-Gln-Ser-Ser-Pro) ester acetate
EXAMPLE 5 des-Acetylvinblastine-4-O-(N-Acetyl-4-trans-L-Hyp-Ser-Ser-Chg-Gln-Ser-Ser-Pro) ester acetate A sample of 4.50 g (3.7 mmol) of 4-O-(prolyl) des-acetylvinblastine TFA salt, prepared as described in Example 4, Step B, was dissolved in 300 ml of DMF under N2, and the solution was cooled to 0° C. Then 1.72 g (10.5 mmol) of 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (ODHBT) was added, and the pH was adjusted to 7.0 (moistened 5-10 range pH paper) with N-methylmorpholine (NMM), followed by the addition of 4.95 g (5.23 mmol) of the N-acetyl-heptapeptide of Example 4, Step D, portionwise allowing complete dissolution between each addition. The pH was again adjusted to 7.0 with NMM, and 1.88 g (9.8 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) was added, followed by stirring of the solution at 0-5° C. until completion of the coupling as monitored by analytical HPLC (system A), maintaining the pH at ca. 7 by periodic addition of NMM. The analysis showed the major component at 26.3 minutes retention time preceded by a minor component (ca. 10%) at 26.1 min, identified as the D-Ser isomer of the title compound. After 20 hours the reaction was worked up by addition of 30 ml of H2O and, after stirring 1 hour, concentrated to a small volume in vacuo and dissolution in ca. 500 ml of 20% HOAc. and preparative HPLC in 12 portions on a Waters C18 Delta-Pak column 15 mM 300A (A=0.1% TFA/H2O; B =0.1% TFA/CH3CN), gradient elution 85·65% A/90 min) at a flow rate of 80 ml/min. Homogeneous fractions (evaluated by HPLC, system C) representing approx. one-fourth of the total run were pooled and concentrated to a volume of ~150 ml and passed through approx. 200 ml of Bio-Rad AG4*4 ion exchange resin (acetate cycle), followed by freeze-drying of the eluant gave the acetate salt of the title compound as a lyophilized powder: retention time (system A) 26.7 minutes, 98.9% pure; high resolution ES/FT-MS m/e 1636.82; amino acid compositional analysis 20 hours, 100° C., 6N HCl (theory/found), Ser4/3.91 (corrected), Glu 1/0.92 (Gln converted to Glu), Chg 1/1.11,Hyp 1/1.07, Pro 1/0.99, peptide content 0.516 mmol/mg. Further combination of homogeneous fractions and purification from side fractions, processing as above through approx. 500 ml of ion exchange resin, afforded an additional amounts of the title compound.
With NMM; trifluoroacetic acid In water; acetic acid; N,N-dimethyl-formamide
5 des-Acetylvinblastine-4-O-(N-Acetyl-4-trans-L-Hyp-Ser-Ser-Chg-Gln-Ser-Ser-Pro) ester acetate
Example 5 des-Acetylvinblastine-4-O-(N-Acetyl-4-trans-L-Hyp-Ser-Ser-Chg-Gln-Ser-Ser-Pro) ester acetate A sample of 4.50 g (3.7 mmol) of 4-O-(prolyl) des-acetylvinblastine TFA salt, prepared as described in Example 4, Step B, was dissolved in 300 ml of DMF under N2, and the solution was cooled to 0° C. Then 1.72 g (10.5 mmol) of 3,4-dihydro-3-hydroxy4-oxo-1,2,3-benzotriazine (ODHBT) was added, and the pH was adjusted to 7.0 (moistened 5-10 range pH paper) with N-methylmorpholine (NNM), followed by the addition of 4.95 g (5.23 mmol) of the N-acetyl-heptapeptide of Example 4, Step D, portionwise allowing complete dissolution between each addition. The pH was again adjusted to 7.0 with NMM, and 1.88 g (9.8 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) was added, followed by stirring of the solution at 0-5° C. until completion of the coupling as monitored by analytical HPLC (system A), maintaining the pH at ca. 7 by periodic addition of NMM. The analysis showed the major component at 26.3 minutes retention time preceded by a minor component (ca. 10%) at 26.1 minutes, identified as the D-Ser isomer of the title compound. After 20 hours the reaction was worked up by addition of 30 ml of H2O and, after stirring 1 hour, concentrated to a small volume in vacuo and dissolution in ca. 500 ml of 20% HOAc. and preparative HPLC in 12 portions on a Waters C18 Delta-Pak column 15 mM 300A (A=0.1% TFA/H2O; B=0.1% TFA/CH3CN), gradient elution 85→65% A/90 min) at a flow rate of 80 ml/min. Homogeneous fractions (evaluated by BPLC, system C) representing approx. one-fourth of the total run were pooled and concentrated to a volume of ~150 ml and passed through approx. 200 ml of Bio-Rad AG4*4 ion exchange resin (acetate cycle), followed by freeze-drying of the eluant gave the acetate salt of the title compound as a lyophilized powder: retention time (system A) 26.7 min, 98.9% pure; high resolution ES/FT-MS m/e 1636.82; amino acid compositional analysis 20 hours, 100° C., 6N HCl (theory/found), Ser4/3.91 (corrected), Glu 1/0.92 (Gln converted to Glu), Chg 1/1.11, Hyp 1/1.07, Pro 1/0.99, peptide content 0.516 mmol/mg. Further combination of homogeneous fractions and purification from side fractions, processing as above through approx. 500 ml of ion exchange resin, afforded an additional amounts of the title compound.
With NMM; trifluoroacetic acid In water; acetic acid; N,N-dimethyl-formamide
15 des-Acetylvinblastine-4-O-(N-Acetyl-4-trans-L-Hyp-Ser-Ser-Chg-Gln-Ser-Ser-Pro) Ester Acetate
EXAMPLE 15 des-Acetylvinblastine-4-O-(N-Acetyl-4-trans-L-Hyp-Ser-Ser-Chg-Gln-Ser-Ser-Pro) Ester Acetate A sample of 4.50 g (3.7 mmol) of 4-O-(prolyl) des-acetylvinblastine TFA salt, prepared as described in Example 14, Step B, was dissolved in 300 ml of DMF under N2, and the solution was cooled to 0° C. Then 1.72 g (10.5 mmol) of 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (ODHBT) was added, and the pH was adjusted to 7.0 (moistened 5-10 range pH paper) with N-methylmorpholine (NMM), followed by the addition of 4.95 g (5.23 mmol) of the N-acetyl-heptapeptide of Example 14, Step D, portionwise allowing complete dissolution between each addition. The pH was again adjusted to 7.0 with NMM, and 1.88 g (9.8 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) was added, followed by stirring of the solution at 0-5° C. until completion of the coupling as monitored by analytical HPLC (system A), maintaining the pH at ca. 7 by periodic addition of NMM. The analysis showed the major component at 26.3 minutes retention time preceded by aminor component (ca. 10%) at 26.1 minutes, identified as the D-Ser isomer of the title compound. After 20 hours the reaction was worked up by addition of 30 ml of H2O and, after stirring 1 hour, concentrated to a small volume in vacuo and dissolution in ca. 500 ml of 20% HOAc. and preparative HPLC in 12 portions on a Waters C18 Delta-Pak column 15 mM 300A (A=0.1% TFA/H2O; B=0.1% TFA/CH3CN), gradient elution 85→65% A/90 min) at a flow rate of 80 ml/min. Homogeneous fractions (evaluated by HPLC, system C) representing approx. one-fourth of the total run were pooled and concentrated to a volume of ~150 ml and passed through approx. 200 ml of Bio-Rad AG4X4 ion exchange resin (acetate cycle), followed by freeze-drying of the eluant gave the acetate salt of the title compound as a lyophilized powder: retention time (system A) 26.7 minutes, 98.9% pure; high resolution ES/FT-MS m/e 1636.82; amino acid compositional analysis 20 hours, 100° C., 6N HCl (theory/found), Ser4/3.91 (corrected), Glu 1/0.92 (Gln converted to Glu), Chg 1/1.11, Hyp 1/1.07, Pro 1/0.99, peptide content 0.516 mmol/mg. Further combination of homogeneous fractions and purification from side fractions, processing as above through approx. 500 ml of ion exchange resin, afforded an additional amounts of the title compound.
1 Synthesis of N-Acryloylglutamic Acid
EXAMPLE 1 Synthesis of N-Acryloylglutamic Acid A reaction flask was charged with 120 ml distilled water, 48.0 g (1.2 mol) of sodium hydroxide and 58.8 g (0.4 mol) of glutamic acid. After cooling to 0° C., acryloyl chloride, 36 g (0.4 mol) was added over 1 hour to the stirred solution. After stirring for an additional 1 hour, the solution was acidified to pH of 2 with the addition of a concentrated HCl-H2 O (1:1) solution. After saturation of the solution with sodium chloride, ethyl acetate was used to extract the product. After drying the combined extracts over anhydrous magnesium sulfate, the ethyl acetate was evaporated to recover the crude product in greater than 60% yield. After recrystallization from ethyl acetate the white, crystalline N-acryloylglutamic acid had a melting point of 125°-127° C.
3.1 Production of STR44
(1) In 75 ml of water was suspended 6.5 g of DL-glutamic acid, and 5.2 g of sodium hydroxide was added, after which the resulting mixture was cooled to -10° C. to -7° C., and a solution of 6 g of β-(2-furyl)acrylic acid chloride in 75 ml of diethyl ether was added thereto dropwise over a period of 1 hour. After the addition, the mixture thus obtained was subjected to reaction at the same temperature for 5 hours, after which the aqueous layer was separated and then adjusted to pH 5.5 with diluted hydrochloric acid. The aqueous layer was washed with two 50-ml portions of ethyl acetate, and the aqueous layer was separated. This aqueous layer was adjusted to pH 2 with diluted hydrochloric acid and then extracted with 100 ml of ethyl acetate, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 5.5 g (yield 52%) of DL-N-[β-(2-furyl)acryloyl]glutamic acid having a melting point of 174.5°-175.5° C.
3. First carbonation with stirring at 88° C to pH 10.0 at 0.075percent CaO alkalinity. This carbonated juice was directly filtered, cooled and analyzed: Glutamine: 0.83percent of the dry substance Glutamic acid: 0.17percent of the dry substance
36
[ 617-65-2 ]
[ 79617-96-2 ]
sertraline glutamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
In ethyl acetate at 25 - 30℃; for 5h;
2 Preparation of Sertraline Glutamate
Example 2 Preparation of Sertraline Glutamate To a solution of sertraline base (14.38 g) in ethyl acetate (300 ml) was added glutamic acid (7.2 g). The resultant solution was stirred at 25-30° C. temperature for 5 hours. The solvent was distilled off under reduced pressure and the residue obtained triturated with petroleum ether (80 ml). The slurry was filtered, washed with petroleum ether (10 ml) and dried under reduced pressure at 50° C. resulting in 14 g (67%) of sertraline glutamate.
With sulfuric acid; nitrogen In sodium hydroxide; chloroform
5 Di-t-butyl L-glutamate Hydrochloride (15A)
Example 5 Di-t-butyl L-glutamate Hydrochloride (15A) Glutamic acid 14 (4.4 g, 30 mmol) was suspended in chloroform (120 mL) and sulfuric acid (3 mL, 56 mmol) was added. The suspension was cooled at -78° C. and condensed isobutylene (70 mL) was added. The reaction mixture was stirred allowing to warm to room temperature for 18 h. After 18 hr, all the suspended solid had dissolved to a clear solution. Nitrogen was bubbled through the solution for 10 min, then it was extracted with aqueous NaHCO3 (2*100 mL) and distilled water (100 mL). The organic layer was dried (MgSO4), evaporated, and kept in a dessicator over NaOH pellets for 48 h to afford 15 (6.7 g, 86%) as an oil. 1H-NMR δH: 1.39 (s, 9H, COO-t-Bu), 1.41 (s, 9H, COO-t-Bu), 1.60-1.90 (2 m, 2H, CH2CH(NH2)-), 2.15-2.35 (m, 2H, CH2COO), 2.85 (s, 2H, NH2), 3.20-3.35 (m, 1H, CH(NH2)-). MS (ESI): 260 (M++H, 100), 283 (M++Na, 10).
Stage #1: Glutamic acid With toluene-4-sulfonic acid In benzene at 105℃; for 1h;
Stage #2: 1-octadecanol In benzene at 105℃; for 14h;
Stage #3: With sodium carbonate In chloroform; water; benzene
1.1
1. Synthesis of Glu2C18 Glutamic acid (2.96 g, 20 mmol) and p-toluenesulfonic acid monohydrate (4.56 g, 24 mmol) were dissolved in benzene (150 mL), and the solution was refluxed at 105°C for 1 hr while removing the generated water using a Dean-Stark trap. Stearyl alcohol (11.9 mg, 44 mmol) was added, and the mixture was further refluxed at 105°C for 14 hr while removing the generated water. The solvent was evaporated under reduced pressure, the residue was dissolved in chloroform (150 mL), and the mixture was washed twice with saturated aqueous sodium carbonate solution (150 mL) and twice with water (150 mL). The chloroform layer was recovered, dehydrated with sodium sulfate (5 g), and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (400 mL) at 60°C and the insoluble component, if any, was filtered off, recrystallized at 4°C, filtered and dried to give a white powder Glu2C18 (13.3 g, yield 85%).
Stage #1: Glutamic acid; 1-Hexadecanol With toluene-4-sulfonic acid In benzene at 85℃; for 10h; Heating / reflux;
Stage #2: With sodium carbonate In chloroform; water
1.A
A benzene solution (100 mL) of p-toluenesulfonic acid hydrate (4.56 g, 24 mmol) was subjected to boiling point reflux at 85° C., and water was removed before the reaction using Dean-Stark apparatus. Glutamic acid (2.96 g, 20 mmol) and hexadecylalcohol (10.7 g, 44 mmol) were added to the reaction solution, and subjected to boiling point reflux for 10 hours while the generated water was removed. As the reaction proceeded, the suspension was gradually dissolved to become transparent.After the reaction completed, the solvent was removed at reduced pressure. The resultant solution was dissolved in chloroform, and washed with a saturated aqueous solution of sodium carbonate 3 times. The chloroform layer was dewatered with magnesium sulfate. The resultant substance was filtered, and then the solvent was removed at reduced pressure. The residue was recrystallized with methanol at 4° C. to obtain dialkylglutamic acid derivative (1) (yield: 83%) as white powder. The analysis results of the dialkylglutamic acid derivative (1) were as follows: Thin layer chromatography (silica gel plate, chloroform/methanol (4/1) (volume/volume): Rf: 0.83 (monospot))Infrared absorption spectrum (cm-1): 1737 (νCO, ester)1H-NMR (CDCl3, 500 MHz, δ ppm): 0.89 (t, 6H, -CH3); 1.25 (s, 52H, -CH2-CH2-); 1.62 (m, 4H, -CO-O-C-CH2); 1.84 (m, 1H, glu α-CH2); 2.08 (m, 1H, glu β-CH2); 2.45 (t, 2H, glu γ-CH2); 3.45 (t, 1H, glu α-CH); 4.06, 4.10 (t, 4H, -CO-O-CH2)MS (ESI) Calcd: 595.9. Found: 597.3 (MH)+
Stage #1: Glutamic acid With trifluoroacetic acid In dichloromethane at 40℃; for 1h;
Stage #2: With thionyl chloride In dichloromethane at 0 - 40℃; for 6h;
1.1
1-1) 1 equivalent (1.47 g, 10 mmol) of glutamic acid was added to 5 mL of trifluoroacetic acid and 5 mL of dichloromethane and the resulting mixture was stirred at 40 °C for 1 hour. Then, 3 equivalents (2.18 mL, 30 mmol) of SOCl2 were slowly added dropwise to the reaction solution in an ice bath, followed by reaction at a temperature of 0 to 40 °C for 6 hours. After the reaction was complete, trifluoroacetic acid and dichloromethane were removed by concentration under reduced pressure and the reaction was confirmed by thin layer chromatography (TLC).
Stage #1: Glutamic acid With sodium hydroxide In water at 65℃;
Stage #2: oxiranyl-methanol In water at 65℃; for 6.5h;
Stage #3: With hydrogenchloride; water at 20℃;
14 Synthesis Example 14 : Synthesis of a glyceryl derivative of glutamic acid
To 3 liter three-neck round-bottom flask put with 1060 ml of water, 118 g of glutamic acid was added and dispersed, followed by adjusting the pH of the solution to 9.4 by adding 20 % aqueous sodium hydroxide to dissolve glutamic acid. While being heated at about 65°C and agitated, the aqueous solution was gradually dropped with 58 g of glycidol over 30 minutes. After the dropping finished, the solution was still left at 65°C under agitation for 6 hours to complete reaction. After completion of the reaction, the reaction solution was cooled down to a room temperature and then its pH was adjusted to 6.6 by adding hydrochloric acid, followed by concentration under a reduced pressure to obtain 241g of glyceryl derivative of glutamic acid. 19% of the product can be considered as sodium chloride yielded by the neutralization. Contents of total nitrogen, total carbon and amino nitrogen were measured on the glyceryl derivative of glutamic acid and glutamic acid employed as raw material. The results were as follows. Since glutamic acid is hardly soluble in water, sodium glutamate 1 hydrate was used for analysis instead.According to the above results, it was confirmed that 70 % or more of the amino groups in the glutamic acid were reacted with glyceryl group, and it was understood that the major component of the obtained glyceryl derivative of glutamic acid was sodium N-glycerylglutamate.
2
10 g of glutamic acid was added to a 250 ml round-bottom flask, and 100 ml of water was added and stirred for 30 minutes. Then, a formaldehyde aqueous solution (concentration: 37%, 20 ml) was added to the flask, and the reaction was conducted at 80° C. After performing the reaction for 3 hours, a yellow liquid was obtained. The liquid was concentrated, and azeotroped with 100 ml of toluene to further remove the water. The product was dried under high vacuum to obtain a yellow solid (10.52 g, Yield: 97.22%).
Stage #1: 17-α-hydroxyprogesterone 3-CMO With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In 1,4-dioxane at 20℃; for 4h;
Stage #2: Glutamic acid In 1,4-dioxane at 20℃; for 2h;
13 Synthesis of the 17-α-hydroxyprogesterone Derivative, 14
Example 13 Synthesis of the 17-α-hydroxyprogesterone Derivative, 14 17-α-hydroxyprogesterone-3-CMO (0.10 g, 0.25 mmol) was dissolved in dioxane (4 mL). DCC (56 mg, 0.27 mmol) and N-hydroxysuccinimide (32 mg, 0.27 mmol) were added, and the reaction was allowed to proceed for 4 h at RT. DCU formed was removed by filtration, and the filtrate was concentrated in vacuo. The residue was redissolved in dioxane (7 mL). Glutamic acid (36 mg, 0.25 mmol; predissolved in 0.1 M NaHCO3 (7 mL) was added, and the mixture was stirred for 2 h at RT. The precipitation formed was removed by filtration, and the filtrate was concetrated in vacuo. Purification was performed on a preparative TLC plate (eluent, acetonitrile: water, 2:1, v/v). ESI-TOF MS for C26H35N2O8-(M-H)31 : calcd, 503.24; obsd, 503.28.
Stage #1: 4-nitro-2,3-dihydro-1H-isoindol-1-one With caesium carbonate; triethylamine at 0 - 20℃; Inert atmosphere;
Stage #2: Glutamic acid With triethylamine In tetrahydrofuran at 0℃; Reflux;
18
A mixture of 4-nitro-2,3-dihydro-lH-isoindol-l-one (8Og) and cesium carbonate (219g) in triethylamine (100ml) was stirred for over half an hour. Under nitrogen ethyl chloroformate (68ml) was added by droplet below 0°C and reacted by stirring at room temperature for 3 ~ 5 hours. The resulting mixture was added in ice water (100OmL) and then light yellow solid was precipitated. After filter, the cake was washed by iced water. The aqueous phase was extracted with dichloromethane twice and the combined extracts were dried with anhydrous sodium sulphate. After filtered, the filtrate was concentrated to dry under reduced pressure. The concentrated was diluted with n-hexane (120ml) and stirred to precipitate crystal. Filter and drying under reduced pressure gave light yellow solid.A mixture of D,L-glutamic acid (66.7 g) in tetrahydrofuran (330ml) was stirred with the intermediate prepared above in batches at subzero temperature. Triethylamine (6.5ml) was added in the mixture to react for 20min and then for 16 ~ 24 hours under reflux. The reaction mixture was cooled and filtered. The filtrate was concentrated to dryness under reduced pressure. The concentrate was dissolved in dichloromethane (60ml) and extracted with saturated sodium bicarbonate solution. When pH of the resulting mixture was adjusted to 2 by 2N hydrochloric acid, a number of light yellow solid was precipitated, subsequently extracted with dichloromethane, and washed with distilled water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, finally cystal grew by standing, filtered and dried to give 94.2 g of title product as light yellow solid, yield79%. purity95.81%. FAB(M+1): 309.Element analysis: theoretical data: C 50.65%, H 3.92%, N 9.09%measured data: C 50.54%, H 4.01%, N 9.04%
5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl]-2,3'-bipyridine glutamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In toluene; at 20 - 55℃;
Toluene (5 ml) and <strong>[202409-33-4]etoricoxib</strong> (1 g) were taken into a reaction flask, the mixture was heated at 50-55C, followed by the addition of glutamic acid (0.5 g). The reaction mass was cooled to 20-25C and maintained for 12 hours. The solid obtained was filtered, washed with toluene (5ml) and then dried at 50-55C for 1 hour to yield 1.1 g of crystalline <strong>[202409-33-4]etoricoxib</strong> glutamate (Purity by HPLC: 95.24%).
N-(5-methoxy-1-[(4-methylphenyl)sulfonyl]-1H-indol-3-ylmethyl)glutamic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: Glutamic acid; 5-methoxy-1-(p-methylphenylsulfonyl)-1H-indol-3-carbaldehyde With triethylamine In methanol at 20℃; for 3h;
Stage #2: With sodium tetrahydroborate at -40℃; for 12h;
Stage #3: With hydrogenchloride In water
4.2.4. N-({5-Methoxy-1-[(4-methylphenyl)sulfonyl]-1H-indol-3-ylmethyl)glutamic acid (15e)
5-Methoxy-1-(methylphenylsulfonyl)-1H-indol-3-carbaldehyde (92 g, 280 mmol) was added to a mixture of glutamic acid (90.4 g, 615 mmol) and triethylamine (171 mL, 1.225 mmol) in methanol (300 mL). The solution was stirred at room temperature for 3 h then cooled at -40 °C for 12 h NaBH4 powder (4 g, 105 mmol) was slowly added while keeping the temperature below 0 °C, then the stirred solution was allowed to raise room temperature. Solvents were evaporated and the residue was dissolved in water. The solution was washed with ethyl acetate (3×200 mL) then acidified until pH 3 with 1 M HCl under strong magnetic stirring. The solid obtained was filtered then recrystallized from water to give 90% of acid 15e as a white-gray powder, mp (H2O) 160-162 °C; Rf (EtOAc/MeOH, 7/3) 0.3; IR: ν cm-1 1698, 1609, 1572, 1480; 1H NMR (D2O/NaOD): δ ppm 1.63-1.99 (m, 2H), 2.19 (t, J=8.4 Hz, 2H), 3.16 (dd, J=7.7, 5.9 Hz, 1H), 3.79 (d, J=13.1 Hz, 1H), 3.94 (d, J=13.1 Hz, 1H), 7.18 (t, J=6.7 Hz, 1H), 7.26 (t, J=6.7 Hz, 1H), 7.33 (s, 1H), 7.52 (d, J=7.4 Hz, 1H), 7.94 (d, J=7.4 Hz, 1H); 13C NMR (D2O/NaOD): δ ppm 21.6 (CH3), 29.7 (CH2), 35.0 (CH2), 45.5 (CH2), 55.7 (CH3), 62.9 (CH), 103.3 (CH), 111.9 (CH), 113.7 (C), 116.4 (CH), 117.8 (CH), 126.6 (2 CH), 129.9 (2 CH), 130.6 (C), 132.0 (C), 135.2 (C), 144.9 (C), 155.7 (C), 182.0 (C), 182.5 (C). Anal. Calcd for C22H24N2O7S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.11; H, 5.44; N, 5.87.
Stage #1: 1,3,5-trichloro-2,4,6-triazine; Glutamic acid With sodium hydroxide In water at 0℃; Microwave irradiation;
Stage #2: With hydrogenchloride In water
General procedure for the microwave-assisted synthesis
General procedure: A solution of amino acid (1.94 mmol) and NaOH (0.22 g, 5.40 mmol) in H2O (1 mL) was added dropwise into a 20 mL test tube containing a 1 mL aqueous solution of TCT (0.1 g, 0.54 mmol) at 0 °C. The mixture was allowed to warm to room temperature, boiling chips were added and the reaction vessel was placed on the center of the turn-table in a domestic microwave oven (Samsung GB872, 850 W, 2.54 GHz). The mixture was then irradiated at the specified power for the prescribed time. After the microwave was switched off, the reaction mixture was cooled and acidified with concentrated HCl. The precipitate was collected by filtration, washed successively with H2O and EtOH before drying at 80 °C to afford the pure product. Novel compounds 1b-e and 1j were fully characterized by 1H NMR, 13C NMR, FT-IR, and HRMS analyses. Spectroscopic data for known compounds 1a, 1f-i and 1k were consistent with those reported in the literature.
N,N<SUP>1</SUP>-mono(1-carboxyl-3-methybutyl)-3,4,9,10-perylenetetracarboxylmonoimide[ No CAS ]
C35H26N2O10[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
Stage #1: Glutamic acid; N,N<SUP>1</SUP>-mono(1-carboxyl-3-methybutyl)-3,4,9,10-perylenetetracarboxylmonoimide With 1H-imidazole; nitrogen In water at 120℃; for 0.25h; Schlenk technique; Inert atmosphere;
Stage #2: With hydrogenchloride In water
2.6. Synthesis of unsymmetrical diimide (PDI-3)
Glutamic acid (0.34 g, 2.6 mmol), PMI (0.50 g, 1.3 mmol) and imidazole (1.43 g) were charged in a 25 ml Schlenk flask. The mixture was purged with nitrogen for 15 min. Then the reaction mixture was heated to 120 °C until the reaction mixture was completely soluble in water. Consequently, the reaction mixture was cooled to 90 °C and deionized water was added and filtered to remove any undissolved particles. The filterate was acidified with 2 M HCl up to pH 3-4 and the formed precipitate is filtered under suction, washed with deionized water until the filterate was neutral. The red solid was dried at 75 °C in vacuum oven until constant weight. Yield 84% (0.54 g). FT-IR (KBr, cm-1): 1693, 1649, 1364, 1592, 2963, 2876, 809, 745 cm-1. 1H NMR, δH (ppm) (400 MHz, DMSO-d6): δ = 8.66 (4H, s), 8.46 (4H, s), 5.66 (2H, s), 2.39-2.43 (4H, m), 2.12-2.39 (2H, m), 1.68-1.79 (1H, m), 0.98-1.06 (6H, m) ppm. 13C NMR, δC (ppm) (100 MHz, DMSO-d6): 173.92, 171.18, 170.71, 162.28, 133.50, 130.76, 123.41, 121.72, 119.60, 52.53, 51.48, 37.75, 30.63, 25.04, 23.73, 22.99, 22.04 ppm. MS (EI): m/z: 633.1 [M-1] Calculated 634.16.
1.1; 2.1; 3.1 Step 1: Synthesis of 1-butyl 2-aminoglutarate
Add 233.23mL n-butanol to a 500mL four-neck bottle, drop 12.0g concentrated sulfuric acid,After the dripping is completed, 15.0 g of glutamic acid is added at one time, heated to 45-50° C., and reacted until the raw materials disappear. 24.76g of triethylamine was added dropwise to PH=7-8, and a large amount of white solid was precipitated.The product 1-butyl 2-aminoglutarate was obtained by suction filtration with a yield rate of 80%.
10-ethoxy-6-(methoxymethyl)-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-5(6H)-one[ No CAS ]
10-ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-5(6H)-one glutamic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
In ethanol at 90℃; for 3h;
17
General procedure: In the compound prepared in Step 10 (326.9 g, 0.875 mol), ethanol (2.3 L) and c-hydrochloric acid (230 ml) were added, followed by refluxing and stirring at 90° C. for 3 hours. After securing the completion of the reaction, the reaction mixture was concentrated under a reduced pressure and recrystallized in ethanol (100 ml) and ethyl acetate (900 ml). The solid thus produced was recrystallized using water (1.0 L) and acetone (8.0 L) to obtain the title compound (351 g, yield: 88.7%, moisture content: 8.5%, white solid). The same procedure was performed as described in Example 1, except for using glutamic acid instead of c-hydrochloric acid in Step 10 to obtain the title compound (545 mg, 96%). 1H-NMR (400 MHz, DMSO-d6) δ 10.68 (br s, 1H), 7.36 (br s, 1H), 6.76 (s, 1H), 6.59 (s, 1H), 4.17 (q, J=6.9, 7.2 Hz, 2H), 3.59˜3.52 (m, 4H), 3.41˜3.27 (m, 8H), 2.42˜2.34 (m, 6H), 1.87˜1.81 (m, 1H), 1.75˜1.72 (m, 2H), 1.40 (t, J=6.9 Hz, 3H)
4-((4,6-bischloro-1,3,5-triazin-2-yl)amino)-benzoic acid[ No CAS ]
[ 617-65-2 ]
C20H22N6O10[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With sodium hydroxide In water for 0.333333h; Microwave irradiation;
Compound 3d
General procedure: A solution of amino acid (2.4 mmol) and NaOH (7.2 mmol) in1 mL H2 O was slowly added into a vessel containing a 1 mLaqueous solution of the monosubstituted triazine 1 (1.0 mmol).After completed addition, boiling chips were added and thereaction vessel was microwave irradiated at 180 W for theprescribed time. After cooling down, the reaction mixture wasacidified using concentrated HCl. The precipitate was recoveredby filtration, washed successively with H2O and acetone beforedrying at 80 C to afford pure product.
6-(4’-methoxyphenyl)-2,4-dihydro-1H-thieno[3,2-d][1,3]oxazine-2,4-dione[ No CAS ]
((2-carboxy-5-(4-methoxyphenyl)thiophen-3-yl)carbamoyl)-L-glutamic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: Glutamic acid; 6-(4’-methoxyphenyl)-2,4-dihydro-1H-thieno[3,2-d][1,3]oxazine-2,4-dione With triethylamine In water at 100℃;
Stage #2: With hydrogenchloride In water at 0℃;
Method D, general procedure for the synthesis of 5-Aryl-3-ureidothiophene-2-carboxylic acid (V) [4]:
General procedure: The 5-Aryl-2-thiaisatoic-anhydrid (IV) (0.46 mmol) was suspended in water (7.5 mL) and the appropriate amine (0.92 mmol) was added. After addition of triethylamine (1.84 mmol), the reaction mixture was stirred, heated to 100 °C and then cooled to room temperature. The reaction mixture was poured into a mixture of concentrated HCl and ice (1:1) and extracted with EtOAc/THF (1:1, 60 mL). The organic layer was washed with aqueous HCl (2M), followed by saturated aqueous NaCl (2 x 50 mL),dried (MgSO4) and concentrated. The crude material was suspended in a mixture of n-hexane/EtOAc (2:1, 20 mL) heated to 50 °C and after cooling to room temperature separated via filtration.
4-(3-fluoro-4-nitro-phenyl)-6-methyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one[ No CAS ]
1-(5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-nitrophenyl)-5-oxopyrrolidine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate In water; dimethyl sulfoxide at 20℃; for 2h;
4-(3-fluoro-4-nitro-phenyI)-6-methyI-lH-pyrroIo[2 -c]pyridin-7-one
A mixture of 4-(3-fluoro-4-nitro-phenyl)-6-methyl- 1 -(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7- one (0.059 g, 0.13 mmol), 2-aminopentanedioic acid (0.044 g, 0.27 mmol), and potassium carbonate (0.037 g, 0.27 mmol) in water (0.05 mL) and dimethylsulfoxide (6 mL) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate and filtered over Celite using methanol to rinse. The combined filtrate was concentrated under reduced pressure to yield crude intermediate that was used directly in the next step. (0546) The crude intermediate, l-(5-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-2- nitrophenyl)-5-oxopyrrolidine-2-carboxylic acid (0.053 g, 0.13 mmol) was dissolved in ethanol (5 mL) and acetic acid (0.15 ml, 2.68 mmol). Iron (0.060 g, 1.07 mmol) was added and the suspension was heated at 1 10 °C 1.5 h. After cooling, the mixture was diluted with ethyl acetate and the mixture was filtered through Celite using ethyl acetate to rinse. The combined filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (acetonitrile/water/0.1% trifluoroacetic acid), yield title compound (3.7 mg, 6%) as a white solid. 1H NMR (400 MHz, DMSO-i) δ 12.01 - 12.23 (m, 1H), 10.76 (s, 1H), 8.26 (d, J = 1.87 Hz, 1H), 7.21 - 7.39 (m, 2H), 7.06 (d, J= 8.10 Hz, 1H), 6.41 - 6.58 (m, 1H), 4.53 (s, 1H), 3.50 - 3.61 (m, 3H), 2.54 - 2.72 (m, 1H), 2.10 - 2.48 (m, 3H). LCMS M/Z (M+H) 349. (0547) The following compounds were prepared in a similar fashion to Example 9: Examples 10-17
1,5-dimethyl 2-[(t-butoxycarbonyl)amino]pentanedioate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95.2%
Stage #1: methanol With acetyl chloride at 0℃; for 0.0833333h;
Stage #2: Glutamic acid for 2h; Reflux;
Stage #3: di-<i>tert</i>-butyl dicarbonate With triethylamine In tetrahydrofuran at 0 - 20℃; for 2.58333h;
I-1 Step I-1 Preparation of compound N-Boc-glutamic acid dimethyl ester (1-2)
Acetyl chloride (5.0 mL) was slowly added dropwise to methanol (100.0 mL) at 0° C., stirred for 5 minutes, then glutamic acid (10.0 g, 67.9 mmol) was added, stirring continued and heating to reflux, maintaining reflux temperature Reaction for 2 hours.The reaction was stopped and the solvent was distilled off under reduced pressure.The resulting oil was dissolved in THF and TEA (28.54 mL, 203.7 mmol) was added dropwise at 0°C and stirred at 0°C for 5 minutes.Di-tert-butyl dicarbonate (17.78 g, 81.5 mmol) dissolved in THF (30.0 mL) was further added dropwise and stirred for 2.5 hours at room temperature.After the reaction was completed, the solvent was removed under reduced pressure, the residue was dissolved in water (200.0 mL), acidified with citric acid solution to pH=4, extracted with DCM (2×100.0 mL), and the organic phases were combined.The organic phase was washed with saturated brine and the organic phase was dried over anhydrous sodium sulfate, then concentrated. The resulting crude product was purified by flash chromatography (PE:EA = 5:1) to give the title compound (1-2) (17.8 g). , Yield 95.2%).
85%
Stage #1: methanol; Glutamic acid With thionyl chloride at 0 - 20℃; Inert atmosphere;
Stage #2: di-<i>tert</i>-butyl dicarbonate With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;
1 Example 1 Synthesis of γ-(2-(2-methoxyethoxy)ethoxy)-L-glutamic acid (L-EG2-Glu)
To the flask was added 25 mL of diethylene glycol monomethyl ether. 5 g of glutamic acid was added with stirring forming a white suspension. 3 mL of concentrated sulfuric acid was slowly added dropwise to the ice bath at 0°C. After the dropwise addition, the temperature was gradually raised to room temperature. Stir overnight at room temperature. After the reaction, the solution became clear. This solution was slowly added dropwise to a solution of triethylamine in isopropanol (a mixture of 12 mL of triethylamine and 48 mL of isopropanol) resulting in a white precipitate. After the separation by centrifugal method to obtain a white solid. And washed twice with excess isopropanol. The product was obtained. The final product after vacuum drying was L-EG2-Glu in 48% yield, as shown in Fig. 1.
Stage #1: formaldehyd; Glutamic acid With sodium hydrogencarbonate In water at 20℃; for 2h;
Stage #2: curcumin In methanol; water at 20℃; for 4h;
13 Preparation of curcumin-glutamate conjugate
1.33 g (9.0 mmol) of glutamic acid and 1.52 g of sodium bicarbonate (18.0 mmol) were dissolved in 10 mL of deionized water, A solution of 1.5 mL of formaldehyde (37%, 18.0 mmol) was added and the reaction was stirred at room temperature for 2 hours and 50 mL of methanol was added. And then add 1.1 lg (3. Ommol) curcumin, stirring at room temperature for 4 hours, TLC monitoring to curcumin reaction is complete, An appropriate amount of 0.5 M dilute hydrochloric acid was added to neutralize the sodium bicarbonate. The reaction product was separated by silica gel column chromatography, and dichloromethane / methanol / ice Acid mixed solvent elution, curcumin - glutamate conjugate 1.23g, yield 45.2% (synthetic route shown in Figure 22).
N-(4-methoxycinnamoyl)glycylglutamic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With sodium carbonate In tetrahydrofuran; water at 10 - 20℃; for 24h;
4 Preparation of N- (4-methoxycinnamoyl) glycylglutarmicacid
To a solution of Na2CO3 (3.18 g, 30 mmol) and glutamic acid (4.41 g, 30 mmol) in water (50 mL) was added 4-methoxycinnamic acid-L-glycine N-hydroxysuccinimide ester Tetrahydrofuran (70 mL) solution of N- (4-methoxycinnamoyl) glycine N-hydroxysuccinimide ester (6.64 g, 20 mmol) was added thereto while maintaining the temperature at about 10 ° C. The reaction solution is stirred at about 20 ° C for 24 hours. The filtrate was concentrated under reduced pressure to remove tetrahydrofuran in the reaction solution, and the remaining water layer was washed twice with ethyl acetate (30 mL). It is acidified to pH 1-2 with concentrated HCl and then stirred for a further 5 hours while maintaining 0-5oC. The resulting precipitate was filtered and recrystallized from ethanol to give 5.32 g (73%) of N- (4-methoxycinnamoyl) glycylglutaric acid as a precipitate.
With phosphoric acid; ruthenium-carbon composite; hydrogen; In water; at 180℃; under 60006.0 Torr; for 24h;
as a metal-supported catalyst, ruthenium carbon having a dispersity of 17.46percent, a metal surface area of 63.78 (m 2 / g), a particle diameter of 7.73 (nm), and a metal loading of 5percent A catalyst was prepared.In a pressure vessel, 100 g of water, 3.2 g of glutamic acid, 2.86 g of phosphoric acid and 0.16 g of ruthenium carbon catalyst were mixed. The mixture was stirred for 16 hours while pressurizing at 180 ° C. to a hydrogen pressure of 8 MPa. After completion of the reaction, the reaction mixture was filtered. When the components contained in the filtrate were analyzed by LC (liquid chromatography), prolinol was obtained in a yield of 35percent. Prolinol was synthesized under the same conditions as in Example 1. However, the reaction time was 24 hours. The yield of prolinol was 36percent.
With sulfuric acid; sodium nitrite In water at 30℃; for 10h;
A solution of sodium nitrate (10.0 g, 144.0 mmol) in 140 mL of water and a solution of concentrated sulfur acid (7.2 g, 73.0 mmol) in 140 mL of water were added dropwise simultaneously to suspension of compound 1 (18.0 g, 122.0 mmol) at the temperature of the reaction mixture of not higher than 30° C., and the mixture was stirred for 10 hours at room temperature. The solvent was removed under vacuum, and the residue was extracted with hot acetate (3×100 mL). The solvent was removed under vacuum, and the residue was extracted with hot methylene chloride (2×100 mL). The solvent was removed under vacuum, and the yield of product 2 in the form of colorless syrup was 8 g (51%).
With triethylamine In N,N-dimethyl-formamide at 45℃;
9
From palmitoyl chloride and glutamic acid reaction synthesis, the specific reaction conditions are as follows: 10 mmol of glutamic acid was suspended in 10 ml of DMF, and the mixture was stirred in an oil bath at 45 ° C. 12 mmol of palmitoyl chloride was added dropwise until glutamic acid was completely dissolved. After adding 200 ul of triethylamine for 1-2 h, 100 ml of distilled water was added, The pH was adjusted to 1-2 with 1 M HCl, filtered under reduced pressure and washed with water. The washed material was dried in an oven at 50 ° C and removed. The mixture was washed three times with a mixed solvent of petroleum ether: ethyl acetate (100: 1: 1), centrifuged, taken out and dried under reduced pressure.
With dmap; ammonium chloride; at 150℃; for 0.166667h;Microwave irradiation; Sealed tube; Green chemistry;
General procedure: 2-(2,6-Dioxopiperidin-3-yl)isoindole-1,3-dione. (1): phthalicanhydride (0.10 g, 0.68mmol), glutamic acid (0.10 g,0.68mmol), DMAP (0.02 g, 0.16mmol), and NH4Cl (0.04 g,0.75mmol) were mixed thoroughly in a CEM-sealed vialwith a magnetic stirrer.The sample was heated for 10min at150?C in a CEM Discover microwave powered at 150W. Itwas then cooled rapidly to 50?C.When at room temperatureit was dissolved in 15mL of (1 : 1) ethyl acetate : acetone. Theorganic layer was washed with 2x (10 mL) distilled water andthen dried over sodium sulfate (anhydrous). The organiclayer was concentrated under vacuum. The residue wastreated with hexanes (30mL) affording a white solid (0.14 g,80%)
With dmap; ammonium chloride at 150℃; for 0.166667h; Microwave irradiation; Sealed tube; Green chemistry;
Thalidomide Synthesis
General procedure: 2-(2,6-Dioxopiperidin-3-yl)isoindole-1,3-dione. (1): phthalicanhydride (0.10 g, 0.68mmol), glutamic acid (0.10 g,0.68mmol), DMAP (0.02 g, 0.16mmol), and NH4Cl (0.04 g,0.75mmol) were mixed thoroughly in a CEM-sealed vialwith a magnetic stirrer.The sample was heated for 10min at150∘C in a CEM Discover microwave powered at 150W. Itwas then cooled rapidly to 50∘C.When at room temperatureit was dissolved in 15mL of (1 : 1) ethyl acetate : acetone. Theorganic layer was washed with 2x (10 mL) distilled water andthen dried over sodium sulfate (anhydrous). The organiclayer was concentrated under vacuum. The residue wastreated with hexanes (30mL) affording a white solid (0.14 g,80%)
3-(2,6-dioxopiperidin-3-yl)-3-aza-bicyclo[3.2.0]heptane-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With dmap; ammonium chloride at 150℃; for 0.166667h; Microwave irradiation; Sealed tube; Green chemistry;
Thalidomide Synthesis
General procedure: 2-(2,6-Dioxopiperidin-3-yl)isoindole-1,3-dione. (1): phthalicanhydride (0.10 g, 0.68mmol), glutamic acid (0.10 g,0.68mmol), DMAP (0.02 g, 0.16mmol), and NH4Cl (0.04 g,0.75mmol) were mixed thoroughly in a CEM-sealed vialwith a magnetic stirrer.The sample was heated for 10min at150∘C in a CEM Discover microwave powered at 150W. Itwas then cooled rapidly to 50∘C.When at room temperatureit was dissolved in 15mL of (1 : 1) ethyl acetate : acetone. Theorganic layer was washed with 2x (10 mL) distilled water andthen dried over sodium sulfate (anhydrous). The organiclayer was concentrated under vacuum. The residue wastreated with hexanes (30mL) affording a white solid (0.14 g,80%)
bicyclo[2.2.2]oct-2-ene-2,3-dicarboxylic anhydride[ No CAS ]
[ 617-65-2 ]
[ 14170-53-7 ]
Yield
Reaction Conditions
Operation in experiment
62%
With dmap; ammonium chloride at 150℃; for 0.166667h; Microwave irradiation; Sealed tube; Green chemistry;
Thalidomide Synthesis
General procedure: 2-(2,6-Dioxopiperidin-3-yl)isoindole-1,3-dione. (1): phthalicanhydride (0.10 g, 0.68mmol), glutamic acid (0.10 g,0.68mmol), DMAP (0.02 g, 0.16mmol), and NH4Cl (0.04 g,0.75mmol) were mixed thoroughly in a CEM-sealed vialwith a magnetic stirrer.The sample was heated for 10min at150∘C in a CEM Discover microwave powered at 150W. Itwas then cooled rapidly to 50∘C.When at room temperatureit was dissolved in 15mL of (1 : 1) ethyl acetate : acetone. Theorganic layer was washed with 2x (10 mL) distilled water andthen dried over sodium sulfate (anhydrous). The organiclayer was concentrated under vacuum. The residue wastreated with hexanes (30mL) affording a white solid (0.14 g,80%)
With dmap; ammonium chloride; at 150℃; for 0.166667h;Microwave irradiation; Sealed tube; Green chemistry;
2-(2,6-Dioxopiperidin-3-yl)isoindole-1,3-dione. (1): phthalicanhydride (0.10 g, 0.68mmol), glutamic acid (0.10 g,0.68mmol), DMAP (0.02 g, 0.16mmol), and NH4Cl (0.04 g,0.75mmol) were mixed thoroughly in a CEM-sealed vialwith a magnetic stirrer.The sample was heated for 10min at150?C in a CEM Discover microwave powered at 150W. Itwas then cooled rapidly to 50?C.When at room temperatureit was dissolved in 15mL of (1 : 1) ethyl acetate : acetone. Theorganic layer was washed with 2x (10 mL) distilled water andthen dried over sodium sulfate (anhydrous). The organiclayer was concentrated under vacuum. The residue wastreated with hexanes (30mL) affording a white solid (0.14 g,80%). mp 268-270?C. 1H NMR (400MHz, DMSO-d6) delta 11.14 (s, 1 H, NH), 7.94 (m, 4 H, Ar), 5.17 (dd, 1H, 12.5, 5.5Hz),2.92 (m, 1 H), 2.57 (m, 2), 2.09 (m, 1H); 13C NMR (100MHz,DMSO-d6) 172.7, 169.8, 167.1, 134.9, 131.2,123.4, 49.0, 30.9,22.0; MS m/z 258 (M+); 230, 213, 202, 173, 148, 111, 76,50.
(1) Weigh 5 g of alpha-glutamic acid and <strong>[2035-75-8]adipic anhydride</strong> in a mass ratio of 1:1, mix and melt with heat, then add 10 ml of acetic anhydride, and reflux at 125 C. for 30 minutes. After the reaction, let stand, cool to room temperature, and precipitate. The crystals were filtered and the crystals were washed three times with ethyl acetate and dried in vacuo at 60C to give alpha-amino protected glutamic anhydride.
Copper acetate monohydrate (41.2 parts by mass) and glutamic acid (29.4 parts by mass) were dissolved in 750 parts by volume of water, respectively.Under the condition of 70 C, the aqueous solution of copper acetate was added dropwise to the aqueous solution of glutamic acid, and the reaction was carried out for 48 hours at room temperature after completion of the dropwise addition.The precipitate was filtered off with suction and washed with an appropriate amount of water and ethanol, respectively.Drying at 70 C for 24 h under vacuum gave glutamic acid chelated copper with a yield of 90%.Separating glutamic acid (5.5 parts by mass) and copper glutamate chelate copper (3.38 parts by mass) in a mixed solution of DMF (2 parts by volume) and 4 parts by volume of water,Further, 1,1,3,3-tetramethylguanidine (5.8 parts by volume) was added dropwise.The mixture was stirred at 40 C for 2 h until all the compounds dissolved.At this time, DMF (16 parts by volume) and ethyl 5-(chloromethyl)-2-furancarboxylate (11.5 parts by mass) were slowly added to the reaction mixture, and stirred at room temperature for 48 h.At this time, acetone (200 parts by volume) was added and stirred overnight, a solid was precipitated, and the crude product was filtered off with suction and washed with a small amount of acetone 2-3 times.The solid was suspended in an aqueous solution of ethylenediaminetetraacetic acid disodium salt (0.45 M) for 1 hour, filtered, and the solid was washed three times with a small amount of distilled water.A solid product was obtained after drying in vacuo for 24 h, yield 64%
With hydrogenchloride; sodium hydroxide; potassium hexacyanoferrate(III) In water; water-d2 at 20℃; for 0.333333h; chemoselective reaction;
Oxidative coupling of Ac-Gly-SH with α-amino acids or α-amino amides.
General procedure: AA or α-amino amide (AA-NH2) (150 mM) was dissolved in degassed H2O/D2O (98:2; 1 ml) and the solution was adjusted to pH 9.5 with HCl/NaOH. Ac-Gly-SH (50 mM) was added and the total volume was adjusted to 2 ml with H2O/D2O (98:2). Potassium hexacyanoferrate(iii) (K3[Fe(CN)6], 150 mM) was added and the solution was stirred at room temperature for 20 min while maintaining the solution at pH 9.5 with NaOH. The resulting suspension was centrifuged and the supernatant was analysed by one- and two-dimensional NMR spectroscopy (1H-1H correlated spectroscopy (COSY), 1H-13C heteronuclear single quantum coherence spectroscopy (HSQC) and 1H-13C HMBC in H2O/D2O (98:2). The yield was quantified using MSM as an internal standard. The ligation product (Ac-Gly-AA-X; X = OH or NH2) was confirmed by 1H-13C HMBC NMR spectral analysis and high-resolution mass spectrometry (HRMS). Reaction mixtures were lyophilized and dissolved in DMSO-d6 or CD3OD for further NMR spectral analysis if 1H-13C HMBC cross-correlation peaks were obscured by the HOD resonance during the original NMR analysis in H2O/D2O (98:2). Yields and HRMS data are given in Table 3, Supplementary Table 8 (Ac-Gly-AA-OH), Extended Data Table 4 and Supplementary Table 9 (Ac-Gly-AA-NH2), and characterization data are provided in Supplementary Information.
With ammonia In methanol; diethyl ether at 0 - 5℃;
2.4.1. Synthesis of Ammonium (4-(trifluoromethyl)phenyl)Carbamodithioate
General procedure: In a 100 mL round bottom flask, 20 mL of methanol, 20ml of diethyl ether, 9 mL of the concentrated ammonia solution(d 0.88) and 5.4 g (4.3 mL, 0.71 mole) of carbondisulphide were taken. The mixture was cooled on an icebath to maintain the temperature about to 0°C. Then 9.66 g(7.53 mL, 0.60 mole) of 4-(trifluoromethyl) aniline was added from the separatory funnel during 20 minutes understirring. The mixture was stirred for 2 hours and allowed tostand at room temperature for 24 hours. A heavy precipitateof respective ammonium dithiocarbamate was separated out,filtered and washed with diethyl ether. During preparation ofsome substituted derivatives, no precipitates of dithiocarbamateproducts were formed and in such cases, the liquid reactionmixture was used in the next step.
2-hydroxy-3-allyloxyglutamic acid disodium salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30.2 kg
Stage #1: Glutamic acid With sodium hydroxide In water Large scale;
Stage #2: Allyl glycidyl ether In water at 20℃; for 22h; Large scale;
1.1; 2.1; 3.1; 4.1 (1) Preparation of 2-hydroxy-3-allyloxyglutamic acid disodium salt
Add 14.7Kg (100mol) of glutamic acid, 40Kg (200mol) of 20% concentration sodium hydroxide solution and 30kg of deionized water to the reaction kettle, stir and neutralize to form the disodium glutamate, then weigh allyl Glycidyl ether 11.4Kg (100mol), and dropwise added to the reaction kettle at 20 ° C for 2h, after the end of the dropwise addition, continue the reaction for 20h, after the reaction is completed, the water is distilled off under reduced pressure to obtain 2-hydroxy-3- Allyloxyglutamic acid disodium salt30.2kg (99mol).
N-[(9,10-dihydro-1-nitro-9,10-dioxo-2-anthracenyl)carbonylglutamic acid][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃;
General synthesis of anthraquinone-amino acid compounds (8)8a-8i
About 7.5 mmol of each amino acid was weighed into a 100 mL three-necked flask. 25 mL of an aqueous solution containing about 0.3 g of NaOH was added, the mixture was stirred and cooled to 0 °C with ice water, and 1.6 g of 1-nitro-2-benzoyl anthraquinone (4) (5 mmol) in THF was added along with a 5 mL of an NaOH solution after 20 min. A dropping funnel was used to maintain a pH of 8-10 in the vigorously stirred solution. After completion of the dropwise addition, the reaction continued under ice water for 1 hour, and the reaction was allowed to proceed overnight at room temperature. The following day, the reaction mixture was poured into 200 mL of ice water, acidified with dilute hydrochloric acid (pH 1-2), stirred, vacuum-filtered, and the filtrate was washed with a small amount of water several times to obtain a solid product. This product was then separated and purified by column chromatography.
With sodium hydroxide In water; acetone at 0 - 10℃;
General procedure: 0.5 mol fatty acid and 150 ml benzene were added into a 500 mlthree-necked flask, stirred and dissolved in a water bath to 30 °C. 1 molthionyl dichloride was slowly added in by a constant pressure funnel in30 min, then the condensation reflux reaction was carried out at70- 90 °C for 3- 4 h. Then a vacuum distillation process was used to removethe excess thionyl dichloride and benzene to obtain the fatty acylchloride. Add 1mol amino acid to 500 ml flask, add 50ml 20% sodium hydroxidesolution, then add 100 ml anhydrous acetone, stirred thoroughlyuntil the mixture was homogeneous. Then slowly adding fatty acyl chlorideto a container. During the process, the constant pressure funnel wasused to add 20% sodium hydroxidewater solution to control the pH valueof the system in the range of 8- 10. The system temperature was set at0- 10 °C by an ice-water bath. After the reaction, the acetone was removedby spin-evaporation. A large number of white crystalline solidwas precipitated after the pH value of the system was adjusted to 1- 2using a hydrochloric acid solution. Add the white crystal to the flask, dissolvein ethanol, heat to 40 °C, and then add 20% sodium hydroxide. Theprecipitated crystal was dried to obtain the final product.
With sodium hydroxide In water; acetone at 0 - 10℃;
General procedure: 0.5 mol fatty acid and 150 ml benzene were added into a 500 mlthree-necked flask, stirred and dissolved in a water bath to 30 °C. 1 molthionyl dichloride was slowly added in by a constant pressure funnel in30 min, then the condensation reflux reaction was carried out at70- 90 °C for 3- 4 h. Then a vacuum distillation process was used to removethe excess thionyl dichloride and benzene to obtain the fatty acylchloride. Add 1mol amino acid to 500 ml flask, add 50ml 20% sodium hydroxidesolution, then add 100 ml anhydrous acetone, stirred thoroughlyuntil the mixture was homogeneous. Then slowly adding fatty acyl chlorideto a container. During the process, the constant pressure funnel wasused to add 20% sodium hydroxidewater solution to control the pH valueof the system in the range of 8- 10. The system temperature was set at0- 10 °C by an ice-water bath. After the reaction, the acetone was removedby spin-evaporation. A large number of white crystalline solidwas precipitated after the pH value of the system was adjusted to 1- 2using a hydrochloric acid solution. Add the white crystal to the flask, dissolvein ethanol, heat to 40 °C, and then add 20% sodium hydroxide. Theprecipitated crystal was dried to obtain the final product.
With sodium hydroxide In water; acetone at 0 - 10℃;
General procedure: 0.5 mol fatty acid and 150 ml benzene were added into a 500 mlthree-necked flask, stirred and dissolved in a water bath to 30 °C. 1 molthionyl dichloride was slowly added in by a constant pressure funnel in30 min, then the condensation reflux reaction was carried out at70- 90 °C for 3- 4 h. Then a vacuum distillation process was used to removethe excess thionyl dichloride and benzene to obtain the fatty acylchloride. Add 1mol amino acid to 500 ml flask, add 50ml 20% sodium hydroxidesolution, then add 100 ml anhydrous acetone, stirred thoroughlyuntil the mixture was homogeneous. Then slowly adding fatty acyl chlorideto a container. During the process, the constant pressure funnel wasused to add 20% sodium hydroxidewater solution to control the pH valueof the system in the range of 8- 10. The system temperature was set at0- 10 °C by an ice-water bath. After the reaction, the acetone was removedby spin-evaporation. A large number of white crystalline solidwas precipitated after the pH value of the system was adjusted to 1- 2using a hydrochloric acid solution. Add the white crystal to the flask, dissolvein ethanol, heat to 40 °C, and then add 20% sodium hydroxide. Theprecipitated crystal was dried to obtain the final product.
Stage #1: Glutamic acid With ammonium hydroxide In water at 15℃; for 0.5h;
Stage #2: In water at 60℃; for 2h;
Stage #3: With hydrogenchloride In ethanol at 30℃;
1-4 Example 3
(1) 29.4g L-glutamic acid is stirred and dispersed in 294g water,Slowly add 8.75g ammonia water dropwise,The temperature is controlled to be less than 15°C, and the temperature is kept for 0.5h after being dissolved.The diammonium salt of L-glutamic acid is produced.(2) Heat to 60 and react for 2h,The diammonium salt of L-glutamic acid removes one molecule of ammonia and cyclizes to 3-aminopiperidine-2,6-dione, which is precipitated in water.(3) Filter and dry at 105 degrees Celsius for 3 hours,21.3g of 3-aminopiperidine-2,6-dione was obtained, 21.3g of 3-aminopiperidine-2,6-dione dissolved in 213g of ethanol,And pass hydrochloric acid gas into the system, control the temperature at 30,Until no more solid precipitation.(4) Filter and dry at 70°C for 3 hours to obtain 27.2 g of 3-aminopiperidine-2,6-dione hydrochloride, with a total yield of 82.6% and a purity of 98.92%.
With phosphoric acid In 5,5-dimethyl-1,3-cyclohexadiene at 130℃; for 8h;
2 to 48 [Examples 2 to 48] Production of Compound (E-2) to Compound (E-48)
General procedure: With the exceptions of adding the raw material 1, the raw material 2 and the solvent in the combinations shown below in Tables 1 to 8, and setting the reaction temperature, pressure and time as shown below in Tables 1 to 8, the same method as Example 1 was used to produce compounds (E-2) to (E-48).
4.1. General Procedure
General procedure: A four-dram vial was charged with palladium(II) acetate and 3.0 mL of 50/50 (v/v)acetone/water. The mixture was stirred until completely dissolved. To this was added theappropriate amino acid and left to stir overnight. All reaction solutions turned from a darkred orange to a clear yellow with a pale yellow-white precipitate on overnight stirring. Anodor of acetic acid was noted when the vial was opened. The supernatant was transferredvia pipette to a clean vial and allowed to evaporate to give clear yellow needles sometimessuitable for X-ray crystallography. The pale-yellow precipitate was washed with cold waterand dried under vacuum. The original reaction precipitate and the material obtainedfrom evaporation were combined and weighed to determine a final yield.
Stage #1: Glutamic acid With toluene-4-sulfonic acid In toluene at 25℃; for 1h;
Stage #2: (8Z)-heptadec-8-en-1-ol In toluene at 24℃; for 25h;
5.1 (1) Synthesis of GA-C18
Weigh 11.8g glutamic acid and 18.3g 4-methylbenzenesulfonic acid (p-Tos) in a 500mL round-bottom flask, add 350mL of toluene to dissolve, stir at 25 °C for 1h. After adding 47.8 g cis-9-octadecenol, the reaction was stirred for 24 h at 25 °C. After the end of the reaction, the organic solvent was removed by rotary steaming, 100mL of dichloromethane was added to dissolve, extracted three times with an equal volume of 5% sodium bicarbonate solution, the organic layer was dried overnight with anhydrous sodium sulfate, filtered, rotated to remove the organic solvent, and continued to dry the residual organic solvent in 40 °C vacuum overnight, that is, GA-C18 was obtained, with a yield of 65.7%.
With di-tert-butyl peroxide In toluene at 140℃; for 12h;
9 Example 9
0.2 mmol of benzofuranone derivative I (R=9-heptadecenyl), 0.2 mmol of glutamic acid, 0.1 mmol of di-tert-butyl peroxide, and 2 mL of toluene were added to a 10 mL reaction tube, and the reaction was stirred at 140°C The reaction was carried out for 12h. After the reaction was completed, the target compound IIA (R=9-heptaenyl) was obtained by column chromatography to obtain a white powder with a yield of 93%.
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