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Product Citations

Aprajita Tripathi ; Debolina Dasgupta ; Anil Pant , et al. DOI:

Abstract: Upon antigenic stimulation, CD4+T-cells undergo clonal expansion, elevating their bioenergetic demands and utilization of nutrients like glucose and glutamine. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known regulator of oxidative stress, but its involvement in modulating the metabolism of CD4+T-cells remains unexplored. Here, we elucidate the role of Nrf2 beyond the traditional antioxidation, in modulating activation-driven expansion of CD4+T-cells by influencing their nutrient metabolism. T-cell-specific activation of Nrf2 enhances early activation and IL-2 secretion, upregulates TCR-signaling, and increases activation-driven proliferation of CD4+T-cells. Mechanistically, high Nrf2 inhibits glucose metabolism through glycolysis but promotes glutamine metabolism via glutaminolysis to support increased T-cell proliferation. Further, Nrf2 expression is temporally regulated in activated CD4+T-cells with elevated expression during the early activation, but decreased expression thereafter. Overall, our findings uncover a novel role of Nrf2 as a metabolic modulator of CD4+T-cells, thus providing a framework for improving Nrf2-targeting therapies and T-cell immunotherapies.

Keywords: T-cell metabolism ; antioxidation ; adaptive immune cells ; T-cell activation

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Product Details of [ 56-85-9 ]

CAS No. :56-85-9 MDL No. :MFCD00008044
Formula : C5H10N2O3 Boiling Point : -
Linear Structure Formula :- InChI Key :ZDXPYRJPNDTMRX-VKHMYHEASA-N
M.W : 146.14 Pubchem ID :5961
Synonyms :
NSC 27421;(S)-2,5-Diamino-5-Oxopentanoic Acid;Glavamin;Glumin;Glutamine;(+)-Glutamine;L-Gln;L-Glutamic acid 5-amide
Chemical Name :(S)-2,5-Diamino-5-oxopentanoic acid

Calculated chemistry of [ 56-85-9 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.6
Num. rotatable bonds : 4
Num. H-bond acceptors : 4.0
Num. H-bond donors : 3.0
Molar Refractivity : 33.54
TPSA : 106.41 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -9.43 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.38
Log Po/w (XLOGP3) : -3.15
Log Po/w (WLOGP) : -1.34
Log Po/w (MLOGP) : -3.58
Log Po/w (SILICOS-IT) : -1.42
Consensus Log Po/w : -1.82

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : 1.5
Solubility : 4650.0 mg/ml ; 31.8 mol/l
Class : Highly soluble
Log S (Ali) : 1.48
Solubility : 4440.0 mg/ml ; 30.4 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : 0.68
Solubility : 698.0 mg/ml ; 4.78 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.76

Safety of [ 56-85-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 56-85-9 ]

* 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.

  • Upstream synthesis route of [ 56-85-9 ]
  • Downstream synthetic route of [ 56-85-9 ]

[ 56-85-9 ] Synthesis Path-Upstream   1~33

  • 1
  • [ 85-44-9 ]
  • [ 56-85-9 ]
  • [ 50-35-1 ]
YieldReaction ConditionsOperation in experiment
71%
Stage #1: at 20 - 80℃; for 6 h;
Stage #2: With 1,1'-carbonyldiimidazole In ISOPROPYLAMIDE at 20 - 90℃; for 4 h;
Example 6; 10 g (68.42 mmoles) of L-glutamine are suspended in 50 ml of dimethyl-acetamide in a 250 ml 5-neck round-bottom flask at room temperature, followed by 10 g (67.6 mmoles) of phthalic anhydride and the mixture is heated to T=80° C. After 6 h the solution is cooled to 30° C. and dropped in a round-bottom flask containing 12 g (74 mmoles) of carbonyl-diimidazole dissolved in 20 ml of dimethyl-acetamide at room temperature. The resulting solution is heated to 85-90° C. and kept under stirring at this temperature for 4 h, then the solution is poured into a conical flask containing 500 ml of cold water. The precipitated solid is filtered, washed twice with 250 ml of water and taken up in 100 ml of (4/1) water/ethanol. After filtering and drying overnight under vacuum at 40° C. a crystalline white solid is obtained (12.5 g; Y=71percent).
65%
Stage #1: at 20 - 80℃; for 6 h;
Stage #2: With 1,1'-carbonyldiimidazole In 1-methyl-pyrrolidin-2-one at 20 - 90℃; for 4 h;
Example 5; 10 g (68.42 mmoles) of L-glutamine are suspended in 50 ml of N-methyl-2-pyrrolidone in a 250 ml 5-neck round-bottom flask at room temperature, followed by 10 g (67.60 mmoles) of phthalic anhydride and heated to T=80° C. After 6 h the solution is cooled to 30° C. and poured into a round-bottom flask containing 12 g (74 mmoles) of carbonyl-diimidazole dissolved in 30 ml of N-methyl-2-pyrrolidone at room temperature. The solution is heated at 85-90° C. and kept under stirring at this temperature for 4 h. The solution is then poured into a conical flask containing 500 ml of cold water. The precipitated solid is filtered, washed twice with 250 ml of water and taken up in 100 ml of (4/1) water/ethanol. After filtration and drying overnight under vacuum at 40° C. a crystalline white solid is obtained (11.5 g; 24 mmoles; Y=65percent).
63%
Stage #1: at 20 - 80℃; for 6 h;
Stage #2: With 1,1'-carbonyldiimidazole In DMF (N,N-dimethyl-formamide) at 20 - 90℃; for 4 h;
Example 7; Following the procedure of example 6 using dimethyl-formamide instead of dimethyl-acetamide thalidomide is obtained in 63percent yield.
62%
Stage #1: at 20 - 80℃; for 6 h;
Stage #2: With 1,1'-carbonyldiimidazole In dimethyl sulfoxide at 20 - 90℃; for 4 h;
Example 4; 10 g (68.42 mmoles) of L-glutamine are suspended in 50 ml of DMSO in a 250 ml 5-neck round-bottom flask at room temperature, added with 10 g (67.60 mmoles) of phthalic anhydride and heated to T=80° C. After 6 h the solution is cooled to 20° C., filtered and poured into a round-bottom flask containing 12 g (74 mmoles) of carbonyl-diimidazole in 20 ml of DMSO at 20° C. The resulting solution is heated to 85-90° C. and stirred at this temperature for 4 h. The solution is then poured into a conical flask containing 500 ml of cold water (about 5° C.) and left under stirring for 2 h at room temperature. The precipitated solid is filtered and washed twice with 250 ml of water. The filtered solid is then suspended in 200 ml of (4/1) water/methanol at 60° C., filtered and dried overnight under vacuum at 40° C., to give a crystalline white product (10.9 g, yield 62percent).
60%
Stage #1: at 20 - 85℃; for 6 h;
Stage #2: at 40℃; for 2 h;
Stage #3: With hydrogenchloride In ethanol; water at 5 - 25℃; for 4 h;
EXAMPLES; Example 1; L-glutamine (10 g; 68.42 mmoles) is suspended in pyridine (50 ml) at room temperature. Phthalic anhydride (14 g, 94.5 mmoles) is added and the mixture is gradually heated to T=80-85° C. After 6 h, an aliquot of the reaction mixture is distilled off under vacuum and the mixture is cooled to 40° C. Carbonyl-diimidazole (12 g, 74 mmoles) is added in portions, keeping under stirring for 2 h, thereafter the mixture is concentrated under vacuum to about one fifth of the starting volume, cooled to 25° C., then diluted with a cold (approx. 5° C.) 4:1 water-ethanol mixture (100 ml). Aqueous hydrochloric acid (37percent) is dropped to adjust the pH to 7.0+/-0.5. The mixture is left under stirring for 4 h until it warms up to room temperature, then the precipitated solid is filtered by suction and washed twice with 25 ml of water. The resulting solid is then dried overnight under vacuum at 40° C., to give a white crystalline product (10.6 g; yield: 60percent on glutamine).
45%
Stage #1: at 20 - 85℃; for 6 h;
Stage #2: at 40℃;
Example 2; 5 g (34.21 mmoles) of L-glutamine are suspended in 25 ml of pyridine in a 100 ml 5-neck round-bottom flask at room temperature, followed by addition of 5 g (33.80 mmoles) of phthalic anhydride and the mixture is heated to T=80-85° C. 6 hrs later an aliquot of the reaction mixture is distilled under vacuum, then cooled to 40° C. 3.1 g (45.5 mmoles) of imidazole are loaded in the flask, which is then cooled to 5-10° C., then 1.6 ml (22 mmoles) of thionyl chloride are dropped in with caution. The mixture is stirred at room temperature for 1 h, heated to 85° C. and kept under stirring at this temperature for 3 h, then distilled to one fifth of the starting volume. The residue is cooled to 25° C. and 100 ml of a cold (ca. 5° C.) (4/1) water/absolute ethanol mixture are added. The mixture is acidified with 37percent HCl to pH=7.0-0.5 and left under stirring for 4 h until room temperature, then the precipitated solid is filtered by suction and washed twice with 25 ml of water. The resulting solid is then dried overnight under vacuum at 40° C. to give a white crystalline product (3.9 g, yield 45percent).
41%
Stage #1: at 20 - 80℃; for 6 h;
Stage #2: at 5 - 20℃; for 3 h;
Stage #3: With hydrogenchloride In ethanol; water at 8 - 35℃; for 4 h;
Example 3; 5 g (34.21 mmoles) of L-glutamine are suspended in 25 ml of pyridine in a 100 ml 5-neck round-bottom flask at room temperature, followed by 5 g (33.80 mmoles) of phthalic anhydride. The mixture is heated to T=80° C. for 6 hrs, then the solution is cooled to 5-10° C. 2.60 ml (4.2 g; 35.3 mmoles) of thionyl chloride are dropped with caution in the reaction flask, then the mixture is cooled to room temperature. After 3 h a pyridine volume of about 80-85percent of the starting volume is distilled off and the residue is cooled to 30-35° C., then 100 ml of a (4/1) water/absolute ethanol mixture are added. The mixture is cooled to 8-10° C. with an ice bath and acidified with 37percent HCl 37percent to pH=7-5. The mixture is left under stirring for 4 h until room temperature; the precipitated solid is filtered by suction and washed twice with 25 ml of water. The resulting solid is then dried overnight under vacuum at 40° C. to give a crystalline white solid (3.6 g, yield 41percent).

Reference: [1] Patent: US2005/272934, 2005, A1, . Location in patent: Page/Page column 3
[2] Patent: US2005/272934, 2005, A1, . Location in patent: Page/Page column 3
[3] Patent: US2005/272934, 2005, A1, . Location in patent: Page/Page column 3
[4] Patent: US2005/272934, 2005, A1, . Location in patent: Page/Page column 3
[5] Patent: US2005/272934, 2005, A1, . Location in patent: Page/Page column 2-3
[6] Patent: US2005/272934, 2005, A1, . Location in patent: Page/Page column 3
[7] Patent: US2005/272934, 2005, A1, . Location in patent: Page/Page column 3
[8] , 2018, vol. 19, # 10,
  • 2
  • [ 56-85-9 ]
  • [ 131-11-3 ]
  • [ 50-35-1 ]
YieldReaction ConditionsOperation in experiment
72%
Stage #1: at 20 - 85℃; for 6 h;
Stage #2: at 40℃; for 2 h;
Stage #3: With hydrogenchloride In ethanol; water at 5 - 25℃; for 4 h;
Example 8; Following the procedure of example 1 using dimethyl-phthalate instead of phthalic anhydride thalidomide is obtained in 72percent yield.
Reference: [1] Patent: US2005/272934, 2005, A1, . Location in patent: Page/Page column 3
  • 3
  • [ 56-85-9 ]
  • [ 88-95-9 ]
  • [ 50-35-1 ]
YieldReaction ConditionsOperation in experiment
58%
Stage #1: at 10 - 15℃; for 4 h;
Stage #2: at 20℃; for 4 h;
Stage #3: With hydrogenchloride In water at 5 - 20℃; for 4 h;
Example 9; L-glutamine (10 g; 68.42 mmoles) is suspended in pyridine (50 ml) at 10° C. and added with phthaloyl-dichloride (27.8 g; 136.84 mmoles), keeping the temperature below 15° C. After 4 h carbonyl-diimidazole (12 g) is added in portions, keeping under stirring for 4 h at room temperature, then the mixture is concentrated under vacuum and poured in cold water (100 ml; 5° C). (37percent) Aqueous hydrochloric acid is dropped adjusting the pH to 7.0+/-0.5 and the mixture is left under stirring for 4 h, until room temperature. The precipitate is filtered by suction, washed twice with 25 ml of water and dried overnight under vacuum at 40° C. to give thalidomide in 58percent yield.
Reference: [1] Patent: US2005/272934, 2005, A1, . Location in patent: Page/Page column 3
  • 4
  • [ 85-44-9 ]
  • [ 56-85-9 ]
  • [ 50-35-1 ]
  • [ 149-87-1 ]
Reference: [1] Synthesis, 2001, # 7, p. 999 - 1000
  • 5
  • [ 56-85-9 ]
  • [ 4344-84-7 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1989, # 1, p. 88 - 94
  • 6
  • [ 56-85-9 ]
  • [ 4344-84-7 ]
Reference: [1] Chemische Berichte, 1961, vol. 94, p. 2106 - 2114
[2] Chemistry and Industry (London, United Kingdom), 1959, p. 1413
  • 7
  • [ 56-84-8 ]
  • [ 56-85-9 ]
  • [ 70-47-3 ]
  • [ 56-86-0 ]
Reference: [1] Bioorganic Chemistry, 2004, vol. 32, # 2, p. 63 - 75
  • 8
  • [ 27372-38-9 ]
  • [ 56-85-9 ]
Reference: [1] Patent: US2873294, 1958, ,
[2] Patent: US2873294, 1958, ,
  • 9
  • [ 77935-68-3 ]
  • [ 56-41-7 ]
  • [ 56-85-9 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1980, vol. 28, # 12, p. 3549 - 3554
  • 10
  • [ 56-86-0 ]
  • [ 7664-41-7 ]
  • [ 56-85-9 ]
Reference: [1] Biochemical Journal, 1959, vol. 71, p. 400,403, 404
  • 11
  • [ 7664-41-7 ]
  • [ 98-79-3 ]
  • [ 56-85-9 ]
Reference: [1] Enzymol., 1940, vol. 9, p. 185
  • 12
  • [ 56-85-9 ]
  • [ 108-24-7 ]
  • [ 2490-97-3 ]
Reference: [1] Synthetic Communications, 1992, vol. 22, # 2, p. 257 - 264
[2] Biochemical Journal, 1939, vol. 33, p. 674
  • 13
  • [ 56-85-9 ]
  • [ 24424-99-5 ]
  • [ 13726-85-7 ]
YieldReaction ConditionsOperation in experiment
89% With sodium hydroxide In tetrahydrofuran; water at 10 - 25℃; for 20 h; EXAMPLE 1: N (Boc)-L-Glutamine (1): L-Glutamine (25g, 0.l7lmol) (Procured fromSpectrochem chemicals) was dissolved in (300 mL) of aqueous solution of NaOH (21.9,0.547 mol).The solution was cooled and a solution of Boc anhydride (0.205) in THF (150 mL) was added at <10°C (Exothermic reaction).Then the reaction mixture was stirred at 25°C for 20 h. TLC control: MeOH, CH2C12 (1:1) with 0.1percent AcOH. The organic phase was separated off, the water phase was extracted with hexane (100 mL), and acidified by 2N HCLto pH 2, and extracted with ethyl acetate (2x250 mE). Combined organic phase was dried over Na2SO4, then evaporated by vacuum, diluted with methylene chloride, and evaporated again. The product is obtained as a sticky oil, which could be crystallized by hexanc to after standing for 2-3 days to yield N-(Boc)-L-glutamine (1) (37.5g,89percent)as colorless solid.1H NMR (DMSO, 300 MHz) 7.27 (111, s, OH), 6.97 (2H, d, J=7.92Hz, NH), 3.83 (1H, m, J=4.29 Hz, H-3), 2.09 (211, t, J=9.54 Hz, H-5), 1.9082-1.6856 (2H, m,H-4), 1.3687 (9H, s, H-6) ESI-MS (m/z):269(M+Na)
1.3 kg With sodium carbonate In acetone at 20℃; Large scale Glutamine 2KG, 10percent sodium carbonate solution 40 liters, stirred to dissolve, add acetone 20 liters, and then at room temperature was added dropwise a mixture of di-tert-butyl dicarbonate 5KG and 4 liters of acetone, while constantly adjusted with sodium carbonate PH = 8 -9, at room temperature overnight.The mixture was adjusted to pH 2 with 3N hydrochloric acid and extracted five times with ethyl acetate. The combined ethyl acetate was washed three times with saturated brine and the ethyl acetate was distilled off to obtain 1.3 kg of tert-butoxycarbonyl-L-glutamine.
Reference: [1] Journal of the American Chemical Society, 1997, vol. 119, # 17, p. 4086 - 4087
[2] Patent: WO2015/189856, 2015, A1, . Location in patent: Page/Page column 14
[3] Synthetic Communications, 2008, vol. 38, # 2, p. 162 - 169
[4] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 8, p. 2777 - 2780
[5] Organic Syntheses, 1985, vol. 63, p. 160 - 160
[6] European Journal of Medicinal Chemistry, 1992, vol. 27, # 8, p. 825 - 833
[7] Acta chemica Scandinavica. Series B: Organic chemistry and biochemistry, 1986, vol. 40, # 4, p. 235 - 241
[8] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 15, p. 2057 - 2060
[9] Patent: US5925339, 1999, A,
[10] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 23, p. 9984 - 9990
[11] Chinese Chemical Letters, 2012, vol. 23, # 3, p. 297 - 300
[12] Patent: CN106916111, 2017, A, . Location in patent: Paragraph 0047; 0048; 0049; 0075; 0076
  • 14
  • [ 1070-19-5 ]
  • [ 56-85-9 ]
  • [ 13726-85-7 ]
Reference: [1] Monatshefte fuer Chemie, 1974, vol. 105, p. 1110 - 1135
[2] Synthesis, 1974, p. 661 - 662
[3] Journal of the American Chemical Society, 1965, vol. 87, p. 620 - 631
[4] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1977, vol. 15, p. 80 - 81
  • 15
  • [ 56-85-9 ]
  • [ 18595-34-1 ]
  • [ 13726-85-7 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1968, vol. 716, p. 175 - 185
[2] Justus Liebigs Annalen der Chemie, 1971, vol. 743, p. 57 - 68
  • 16
  • [ 56-85-9 ]
  • [ 16965-08-5 ]
  • [ 13726-85-7 ]
Reference: [1] Journal of the Chemical Society [Section] C: Organic, 1967, p. 2632 - 2636
  • 17
  • [ 56-85-9 ]
  • [ 59279-60-6 ]
Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 15, p. 2057 - 2060
  • 18
  • [ 56-85-9 ]
  • [ 1142-20-7 ]
  • [ 39537-23-0 ]
YieldReaction ConditionsOperation in experiment
65%
Stage #1: With hexachloroethane; triphenylphosphine In tetrahydrofuran at 0℃; for 1.5 h;
Stage #2: With potassium hydroxide In tetrahydrofuran; dichloromethane; water at 0℃; for 2 h;
Dissolve 15 mmol of triphenylphosphine with 10 ml of tetrahydrofuran, drop it into a mixed system composed of 10 mmol of carbobenzoxy-alanine (Z-Ala), 20 mmol of hexachloroethane and 10 ml of tetrahydrofuran. After reacting at 0° C. for 1.5 hours, drop it into a liquid mixture containing 18 mmol of glutamine, 20 ml of water and 40 ml of dichloromethane. While reacting, regulate pH to 13 with potassium hydroxide, the reaction temperature is 0° C., the reaction time after dropping is 2 hours. And then acidify it to regulate pH=2.0 with dilute sulfuric acid. The aqueous phase, after concentrated, reacts with hydrogen in methanol at room temperature for 15 hours. The product L-Ala-L-Gln with a yield of 65percent is obtained.
48%
Stage #1: With hexachloroethane; triphenylphosphine In toluene at 0℃; for 3 h;
Stage #2: With sodium hydroxide In water; toluene at 15℃; for 1.5 h;
In a round bottom flask, add in 10 mmol each of carbobenzoxy-alanine (Z-Ala), triphenylphosphine and hexachloroethane respectively, and then 30 ml of toluene. After reacting at 0° C. for 3 h., drop it into a liquid mixture containing 25 mmol of glutamine and 20 ml of water. While reacting, regulate pH to 12 with sodium hydroxide, the reaction temperature is 15° C., the reaction time after dropping is 1.5 hours. And then acidify it to pH=2.5 with dilute hydrochloric acid. The aqueous phase, after concentrated, reacts with hydrogen gas in methanol at room temperature for 15 hours. The product L-Ala-L-Gln with a yield of 48percent is obtained.
45%
Stage #1: With hexachloroethane; triphenylphosphine In acetonitrile at 5℃; for 1 h;
Stage #2: With sodium hydroxide; potassium carbonate In water; acetonitrile at 5℃; for 2 h;
Dissolve 30 mmol of hexachloroethane with 10 ml of acetonitrile, drop it into a mixed system composed of 10 mmol of carbobenzoxy alanine (Z-Ala), 20 ml of triphenylphosphine and 10 ml of acetonitrile.
After reacting at 5° C. for 1.0 h., drop it into 20 ml of water containing 10 mmol of glutamine.
While reacting, regulate pH to 10 with 20 mmol of sodium hydroxide and then potassium carbonate successively, the reaction temperature is 5° C., and the reaction time after dropping is 2 hours.
And then acidify it to regulate pH to 3.0 with concentrated hydrochloric acid.
The aqueous phase, after concentrated, reacts with trifluoroacetic acid at room temperature for 40 hours.
After the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln is obtained with a yield of 45percent by recrystallizing the solids with 1,4-dioxane-water.
Reference: [1] Patent: US2005/233977, 2005, A1, . Location in patent: Page/Page column 4-5
[2] Patent: US2005/233977, 2005, A1, . Location in patent: Page/Page column 4
[3] Patent: US2005/233977, 2005, A1, . Location in patent: Page/Page column 5
  • 19
  • [ 56-85-9 ]
  • [ 5872-22-0 ]
  • [ 39537-23-0 ]
YieldReaction ConditionsOperation in experiment
52%
Stage #1: With hexachloroethane; triphenylphosphine In toluene at 5℃; for 2 h;
Stage #2: With sodium hydroxide In water; toluene; Petroleum ether at 10℃; for 1.5 h;
Dissolve 10 mmol of triphenylphosphine with 10 ml of toluene, drop it into a mixed system composed of 10 mmol of tert-butylcarbonylalanine (Boc-Ala), 10 mmol of hexachloroethane and 20 ml of toluene. After reacting at 5° C. for 2 hours, drop it into a liquid mixture containing 15 mmol of glutamine, 20 ml of water and 60 ml of petrolium ether. While reacting, regulate pH to 12 with sodium hydroxide, the reaction temperature is 10° C., the reaction time after dropping is 1.5 hours. And then acidify it to regulate pH=1.5 with dilute sulfuric acid. The aqueous phase, after concentrated, reacts with hydrogen chloride/1,4-dioxane at room temperature for 5 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln with a yield of 52percent is obtained by recrystallizing the solids with 1,4-dioxane-water.
45%
Stage #1: With hexachloroethane; triphenylphosphine In tetrahydrofuran at 0℃; for 1.5 h;
Stage #2: With potassium hydroxide; sodium carbonate In tetrahydrofuran; dichloromethane; water at 8℃; for 2 h;
Dissolve 20 mmol of hexachloroethane with 10 ml of tetrahydrofuran, drop it into a mixed system composed of 10 mmol of tert-butylcarbonylalnine (Boc-Ala), mmol of triphenylphosphine and 20 ml of tetrahydrofuran. After reacting at 0° C. for 1.5 hours, drop it into a liquid mixture containing 20 mmol of glutamine, 20 ml of water and 15 ml of dichloromethane. While reacting, regulate pH to 10 with 20 mmol of potassium hydroxide and then with sodium carbonate successively, the reaction temperature is 8° C., the reaction time after dropping is 2 hours. And then acidify it to regulate pH=2.0 with concentrated hydrochloric acid. The aqueous phase, after concentrated, reacts with methylsulfonic acid at room temperature for 20 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln with a yield of 45percent is obtained by recrystallizing the solids with methanol-water.
40%
Stage #1: With hexachloroethane; triphenylphosphine In 1,2-dichloro-ethane at 10℃; for 0.333333 h;
Stage #2: With potassium hydroxide In cyclohexane; water; 1,2-dichloro-ethane at 20℃; for 0.5 h;
In a round bottom flask, add in 10 mmol of tert-butylcarbonylalanine (Boc-Ala), 15 mmol of triphenyl phosphine and 20 mmol of hexachloroethane, and then add in 20 ml of 1,2-dichloroethane. After reacting at 10° C. for 20 min, drop it into a liquid mixture containing 30 mmol glutamine, 20 ml of water and 20 ml of cyclohexane. While reacting, regulate pH to 11 with potassium hydroxide, the reaction temperature is 20° C., the reaction time after dropping is 30 min. And then acidify it to regulate pH=1.5 with dilute nitric acid. The aqueous phase, after concentrated, reacts with trifluoroacetic acid at room temperature for 15 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln with a yield of 40percent is obtained by recrystallizing the solids with tetrahydrofuran-water.
Reference: [1] Patent: US2005/233977, 2005, A1, . Location in patent: Page/Page column 4
[2] Patent: US2005/233977, 2005, A1, . Location in patent: Page/Page column 4
[3] Patent: US2005/233977, 2005, A1, . Location in patent: Page/Page column 4
  • 20
  • [ 56-85-9 ]
  • [ 39537-23-0 ]
YieldReaction ConditionsOperation in experiment
50%
Stage #1: With hexachloroethane; triphenylphosphine In tetrahydrofuran at 10℃; for 0.333333 h;
Stage #2: With sodium hydroxide In tetrahydrofuran; cyclohexane; water at 25℃; for 0.5 h;
Dissolve 30 mmol of triphenylphosphine with 30 ml of tetrafuran, drop it into a mixed system composed of 10 mmol of N-(O,O-dimethyl) phosphoalanine, 30 mmol of hexaethane and 10 ml of tetrahydrofuran.
After reacting at 10° C. for 20 min., drop it into a liquid mixture containing 30 mmol of glutamine, 20 ml of water and 20 ml of cyclohexane.
While reacting, regulates pH to 12 with sodium hydroxide, the reaction temperature is 25° C., the reaction time after dropping is 30 min.
And then regulate pH to 1.5 by acidifying it with dilute nitric acid.
The aqueous phase, after concentrated, reacts with 20percent hydrogen bromide/glacial acetic acid at room temperature for 5 hours.
As the reaction is finished, drop in 50 ml of ether, solids deposit, the product L-Ala-L-Gln is obtained with a yield of 50percent by recrystallizing with methanol-water.
45%
Stage #1: With hexachloroethane; triphenylphosphine In dichloromethane; toluene at 0℃; for 3 h;
Stage #2: With potassium hydroxide; potassium hydrogencarbonate In dichloromethane; water; toluene; Petroleum ether at 0℃; for 1.5 h;
EXAMPLE 1 Dissolve 20 mmol of hexachloroethane with 10 mmol of dichloromethane, drop it into a mixed system composed of 10 mmol of N-(O,O-dimethyl) phosphoalanine, 20 mmol of triphenylphosphine and 20 mmol of toluene. After reacting at 0° C. for 3 hours, drop the reaction mixture into a stirring mixture containing 25 mmol of glutamine, 20 ml of water and 60 ml of petrolium ether, regulate pH to 10 with 20 mmol of potassium hydroxide and then potassium bicarbonate successively, reaction temperature is 0° C., the reaction time after dropping is 1.5 hours, stirring and the condition of pH=10 are maintained during the course of the reaction, and then it is acidified to pH=2.5 with concentrated hydrochloric acid. The aqueous phase, after concentrated, reacts with methylsulfonic acid at room temperature for 20 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln with a yield of 65percent is obtained by recrystallizing the solids with isopropanol-water. [α]D=10.55, C=2, m.p.=214-215.5. EXAMPLE 2 Dissolve 20 mmol of hexachloroethane with 10 ml of dichlormethane, drop it into a mixed system composed of 10 mmol of N-(O,O-dimethyl) phosphoalanine, 20 mmol of triohenylphosphine and 20 ml of toluene. After reacting at 0° C. for 3 hours, drop it into a liquid mixture containing 25 mmol of glutamine, 20 ml of water and 60 ml of petrolium ether. While reacting, regulate pH to 10 with 20 mmol of potassium hydroxide and then with potassium carbonate successively, the reaction temperature is 0° C. the reaction time after dropping is 1.5 hours. Then acidify it to regulate pH=2.5 with concentrated hydrochloric acid. The aqueous phase, after concentrated, reacts with methylsulfonic acid at room temperature for 20 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln is obtained with a yield of 45percent by recrystallizing the solids with isopropanol-water.
40%
Stage #1: With hexachloroethane; triphenylphosphine In toluene at 5℃; for 1 h;
Stage #2: With sodium carbonate In ethanol; water; toluene at 5℃; for 0.166667 h;
In a round bottom flask, add in 10 mmol of N-(O,O-dimethyl) phosphoalanine, 20 mmol of triphenylphosphine and 30 mmol of hexachloroethane respectively, and then add in 20 ml of toluene. After reacting at 5° C. for 1 hour, add it into a liquid mixture containing 10 mmol of glutamine, 20 ml of water and 5 ml of ethanol. While reacting, regulate pH to 9.5 with sodium carbonate, the reaction temperature is 5° C., the reaction time is 10 min. And then regulate pH to 1.0 by acidifying it with phosphoric acid. The aqueous phase, after concentrated, reacts with trifluoroacetic acid at room temperature for 15 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln with a yield of 40percent is obtained by recrystallizing the solids with methanol-water.
Reference: [1] Patent: US2005/233977, 2005, A1, . Location in patent: Page/Page column 3
[2] Patent: US2005/233977, 2005, A1, . Location in patent: Page/Page column 3
[3] Patent: US2005/233977, 2005, A1, . Location in patent: Page/Page column 4
  • 21
  • [ 56-85-9 ]
  • [ 39537-23-0 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: With hexachloroethane; triphenylphosphine In dichloromethane at 0℃; for 0.666667 h;
Stage #2: With potassium hydroxide In dichloromethane; cyclohexane; water at 20℃; for 0.5 h;
Dissolve 30 mmol of hexaethane with 20 ml of dichloromethane, drop it into a mixed system composed of 10 mmol of N-(O,O-diethyl) phosphoalanine, 30 mmol of triphenylphosphine and 10 ml of dichloromethane.
After reacting at 0° C. for 40 min., drop it into a liquid mixture containing 30 mmol of glutamine, 20 ml of water and 10 ml of cyclohexane.
While reacting, regulate pH to 13 with potassium hydroxide, the reaction temperature is 20° C., the reaction time after dropping is 30 min.
And then acidify it to regulate pH=1.5 with dilute nitric acid.
The aqueous phase, after concentrated, react with trifluoroacetic acid at room temperature for 10 hours.
As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln is obtained with a yield of 60percent by recrystallizing the solids with 1,4-dioxane-water.
40%
Stage #1: With hexachloroethane; triphenylphosphine In acetonitrile at 15℃; for 2.5 h;
Stage #2: With sodium carbonate In water; toluene; acetonitrile at 30℃; for 1 h;
In a round bottom flask, add in 10 mmol of N-(O,O-diethyl) phosphoalanine, 10 mmol of triphenylphosphine and 15 mmol of hexachloroethane respectively, and then add in 20 ml of acetonitrile. After reacting at 15° C. for 2.5 hour, drop it into a liquid mixture composed of 30 mmol of glutamine, 20 ml of water and 30 ml of toluene. While reacting, regulate pH to 8.5 with sodium carbonate, the reaction temperature is 30° C., the reaction time after dropping is 1 hour. And then acidify it to regulate pH=2 with dilute sulfuric acid. The aqueous phase, after concentrated, reacts with saturated hydrogen bromide/1,4-dioxane at room temperature for 5 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln is obtained with a yield of 40percent by recrystallizing the solids with tetrahydrofuran-water.
Reference: [1] Patent: US2005/233977, 2005, A1, . Location in patent: Page/Page column 3
[2] Patent: US2005/233977, 2005, A1, . Location in patent: Page/Page column 3
  • 22
  • [ 56-85-9 ]
  • [ 39537-23-0 ]
YieldReaction ConditionsOperation in experiment
52%
Stage #1: With hexachloroethane; triphenylphosphine In 1,2-dichloro-ethane at 20℃; for 1.5 h;
Stage #2: With potassium hydroxide In water; 1,2-dichloro-ethane at 10℃; for 2 h;
Dissolve 15 mmol of hexachloroethane with 10 ml of 1,2-dichloroethane, add it into a mixed system composed of 10 mmol of N-(O,O-diisopropyl) phosphoalanine, 15 mmol of triphenylphosphine, and 10 ml of 1,2-dichloroethane. After reacting at 20° C. for 1.5 hours, drop it into 20 ml of water containing 20 mmol of glutamine. While reacting, regulate pH to 13 with potassium hydroxide, the reaction temperature is 10° C., the reaction time after dropping is 2 hours. And then regulate pH to 1.5 by acidifying it with dilute nitric acid. The Aqueous phase, after concentrated, reacts with trifluoroacetic acid at room temperature for 10 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln with a yield of 52percent is obtained by recrystallizing the solids with isopropanol-water.
45%
Stage #1: With hexachloroethane; triphenylphosphine In dichloromethane at 10℃; for 3 h;
Stage #2: With sodium hydroxide; sodium carbonate In dichloromethane; water; ethyl acetate at 10℃; for 1 h;
Dissolve 15 mmol of triphenylphosphine with 20 ml of dichloromethane, drop it into a mixed system composed of 10 mmol of N-(O,O-diisopropyl) phosphoalanine, 20 mmol of hexachloroethane and 10 mmol of dichloromethane.
After reacting at 10° C. for 3 hours, add it into a liquid mixture containing 10 mmol of glutamine, 20 ml of water and 20 ml of ethylacetate.
While reacting, regulate pH to 9 with 10 mmol of sodium hydroxide and then with sodium carbonate successively, the reaction temperature is 10° C., and the reaction time after dropping is 1 hour.
And then acidify it to regulate pH=2.0 with dilute sulfuric acid.
The aqueous phase, after concentrated, reacts with 20percent hydrogen bromide/glacial acetic acid at room temperature for 5 hours.
As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln is obtained with a yield of 45percent by recrystallizing the solids with methyl alcohol-water.
Reference: [1] Patent: US2005/233977, 2005, A1, . Location in patent: Page/Page column 4
[2] Patent: US2005/233977, 2005, A1, . Location in patent: Page/Page column 4
  • 23
  • [ 56-85-9 ]
  • [ 101-41-7 ]
  • [ 5959-95-5 ]
  • [ 28047-15-6 ]
Reference: [1] Tetrahedron Asymmetry, 2006, vol. 17, # 2, p. 245 - 251
  • 24
  • [ 76-84-6 ]
  • [ 56-85-9 ]
  • [ 102747-84-2 ]
Reference: [1] Tetrahedron Letters, 1991, vol. 32, # 6, p. 739 - 742
  • 25
  • [ 56-85-9 ]
  • [ 132388-69-3 ]
Reference: [1] Tetrahedron Letters, 1991, vol. 32, # 6, p. 739 - 742
  • 26
  • [ 56-85-9 ]
  • [ 132388-60-4 ]
Reference: [1] Synthetic Communications, 2017, vol. 47, # 12, p. 1136 - 1141
  • 27
  • [ 56-85-9 ]
  • [ 132327-80-1 ]
Reference: [1] Tetrahedron Letters, 1991, vol. 32, # 6, p. 739 - 742
  • 28
  • [ 56-85-9 ]
  • [ 71989-20-3 ]
YieldReaction ConditionsOperation in experiment
85% With potassium carbonate In acetonitrile at 20℃; for 2 h; General procedure: To a solution of H-Phe-OH (100 mg, 60.5 mmol) in 50 percent MeCN (6.1 mL)were added Fmoc-OPhth (233 mg, 60.5 mmol) and K2CO3 (167 mg, 121 mmol) and stirred at room temperature. After 2 h of stirring saturated sodium bicarbonate solution and H2O were added and the resulting solution was washed with diethyl ether. The aqueous phase is acidified to pH 1 with 1M HCl and extracted with diethyl ether. The organic phase was washed with 1 M HCl, H2O, brine, dried over MgSO4. The filtrate was evaporatedevaporated under reduced pressure to give yellow solid as crude product.
Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 16, p. 1600 - 1603
  • 29
  • [ 56-85-9 ]
  • [ 82911-69-1 ]
  • [ 71989-20-3 ]
YieldReaction ConditionsOperation in experiment
84% With sodium carbonate In tetrahydrofuran; water To a stirred solution of L-glutamine (1.75 g, 12 mmole) and sodium carbonate (1.27 g, 12 mmole) in 30 ml of water, was added a solution of Fmoc-OSu (3.0 g, 8.9 mmole) in 60 ml of THF. After stirring overnight the mixture was concentrated under reduced pressure to remove the THF. The residue was diluted with 100 ml of 1 N hydrochloric acid . The white solid was collected by filtration and recrystallized in DMF-0.1 N hydrochloric acid aqueous solution to afford a white powder (38, 2.76 g). Yield: 84percent. 1H-NMR (90 MHz, DMSO-d6) ppm: 12.47 (1H, s), 7.89-7.20 (10 H, m), 6.68 (1H, s, br), 4.22-3.90 (4H, m), and 2.25-1.86 (4H, m).
Reference: [1] Journal of Peptide Science, 2017, vol. 23, # 3, p. 202 - 214
[2] Patent: US2006/161007, 2006, A1, . Location in patent: Page/Page column 12
[3] Synthetic Communications, 2009, vol. 39, # 11, p. 2022 - 2031
  • 30
  • [ 56-85-9 ]
  • [ 71989-20-3 ]
Reference: [1] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 10, p. 3103 - 3108
  • 31
  • [ 56-85-9 ]
  • [ 88744-04-1 ]
  • [ 71989-20-3 ]
Reference: [1] Synthesis, 1986, # 4, p. 303 - 305
  • 32
  • [ 56-85-9 ]
  • [ 28920-44-7 ]
  • [ 71989-20-3 ]
Reference: [1] Organic Process Research and Development, 2004, vol. 8, # 6, p. 920 - 924
  • 33
  • [ 56-85-9 ]
  • [ 28920-43-6 ]
  • [ 71989-20-3 ]
Reference: [1] Journal of the Chinese Chemical Society, 2011, vol. 58, # 4, p. 509 - 515
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