* 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.
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).
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.
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 ]
Yield
Reaction Conditions
Operation 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.
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.
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.
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.
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.
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.
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
(S)-4-[(S)-2-Amino-3-(9H-fluoren-9-ylmethoxycarbonyl)-propionylamino]-4-[(S)-1-((S)-1,3-dicarbamoyl-propylcarbamoyl)-5-(9H-fluoren-9-ylmethoxycarbonylamino)-pentylcarbamoyl]-butyric acid 9H-fluoren-9-ylmethyl ester[ No CAS ]
calcium oxide - glutamine type composition[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; for 2h;
64.57 parts of powdered glutamine were added to 100 parts of water with stirring, and then 12.39 parts of powdered calcium oxide were added thereto. As the reaction advanced, the powdered calcium oxide dissolved in the solution of asparagine, the transparency being increased, and an insoluble portion disappeared. After two-hour reaction, a water-soluble antibacterial composition of calcium oxide - glutamine type was obtained. The calcium oxide concentration of this composition was 7.00percent, and its pH was 11.0.
3-nitrophthalic anhydride19.32 g,D, L-isoglutamine 14.62 g,Sodium acetate 8.92 g,Acetic acid 100ml,Reflux reaction,The stirring reaction was maintained for 7 hours,After cooling to room temperature,Washed with water and dried to obtain 29.86 g of a gray solid in a yield of 93.2percent.
In acetic acid;
EXAMPLE 7 2-(4-Nitro-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid A mixture of glutamine (10 mmol) and 3-nitrophthalic anhydride (10 mmol) in 15 ml of acetic acid is heated to reflux. The cooled reaction mixture is concentrated and the residue purified by chromatography to afford 2-(4-nitro-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid.
N-Lauroyl-glutamin (N-dodecanoyl-glutamin)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trimethylamine; In 1,4-dioxane; methanol; water;
N-Lauroyl-glutamin (N-dodecanoyl-glutamin) 9.22 g lauroylchloride dissolved in 46 ml dioxane were slowly added to 6.72 g glutamine and 13.94 g trimethylamine in 92 ml water and 92 ml dioxane, the temperature being 0° C. After stirring at room temperature for 1 hour, the dioxane was evaporated and the remaining solution was acidified to pH 1 with HCl. The crystals were filtered off and recrystallized from acetone and then from methanol: 9.9 g white needles. NMR (DMSO-d6) among others: 8.05 (d,1H), 7.3 (s,1H), 6.78 (s,1H), 4.13 (m,1H), 2.03-2.18 (m,4H).
1. Preparation of Z-Ala-Gln-OH To a solution of 4.80 g of <strong>[3401-36-3]Z-Ala-OSu</strong> in 60 ml of tetrahydrofuran was added a solution of 2.19 g of H-Gln-OH in 40 ml of water and 2.10 ml of triethylamine and the mixture was stirred at a room temperature for 20 hours. Tetrahydrofuran and water were removed by distillation and the residue thus obtained was extracted with n-butanol. The n-butanol extract was washed with a 2%-acetic acid and butanol was removed by distillation. The precipitated substance thus obtained was collected by filtration and reprecipitated with methanol-ethyl acetate to obtain 3.87 g of Z-Ala-Gln-OH.
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
35
[ 56-85-9 ]
[ 50-78-2 ]
aluminum acetylsalicylate bis-glutaminate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With aluminum isopropoxide; In ethanol; water;
EXAMPLE 4 In this example, 14.6 g of glutamine is dissolved in 190 ml of hot water having a temperature of 85° C. To the solution is added 10.2 g of aluminum isopropoxide while stirring. Then, the reaction mixture is cooled quickly. To the mixture is added a solution which is obtained by dissolving 9 g of acetylsalicylic acid in 50 ml of ethanol. After the completion of reaction, the formed precipitates are filtered and are dried to obtain 19 g of aluminum acetylsalicylate bis-glutaminate as a white powder.
II. Synthesis of 2-hydroxy-5-oxoiproline Using Glutamine: The synthesis of 2-hydroxy-5-oxoproline from glutamine as a starting material is similar to that using 2-pyrrolidone-5-carboxylic acid. The relevant reactions are as follows: Fremy's Salt (1.5 mmole) was added to a solution of 0.5 mmole of glutamine in 10 ml of sodium bicarbonate buffer (pH 9.5). The reaction was stirred at room temperature and monitored daily by 13C-NMR for the disappearance of the starting material and the appearance of the desired product. The glutamine was completely converted to the desired product in 4 days.
With trifluoroacetic acid; In water; at 0 - 85℃; for 8.5h;
To a 250 mL round bottom flask equipped with an electromagnetic stirrer, 14.6 g of glutamine, 60 mL of water, and 60 mL of TFA were added. When glutamine fully dissolved, the reaction mixture was cooled on an ice bath to between 0 and 5 C., and 15.4 g of theino(3,4-c)furan-1,3-dione was added. At the above temperature, the reaction mixture was allowed to react for 30 min. The reaction mixture was then allowed to warm to room temperature and allowed to react for additional 4 h. The reaction mixture was stripped of solvent in vacuo at 85 C. over 4 h to obtain a tacky solid (28 g). The solid was dissolved in 140 mL of anhydrous THF, and 20 g of CDI and a catalytic quantity of DMAP were added and allowed to react at a reflux for 6 h until a large amount of white solid precipitated. The white solid was cooled and filtered to yield 18 g of dried title compound. 1H NMR (DMSO-d6): delta 11.10 (s, 1H), 8.26 (s, 2H), 5.03 (dd, 1H, J=3 Hz, J=3 Hz), 2.87-2.82 (m, 1H), 2.66-2.55 (m, 2H), 2.07-2.04 (m, 1H); MS (m/z): 263 (M-1)+.
5-(2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione (Method 1) [Show Image] To a 250 mL round bottom flask equipped with an electromagnetic stirrer, 14.6 g of glutamine, 60 mL of water, and 60 mL of TFA were added. When glutamine fully dissolved, the reaction mixture was cooled on an ice bath to between 0 and 5C, and 15.4 g of theino(3,4-c)furan-1,3-dione was added. At the above temperature, the reaction mixture was allowed to react for 30 min. The reaction mixture was then allowed to warm to room temperature and allowed to react for additional 4h. The reaction mixture was stripped of solvent in vacuo at 85C over 4h to obtain a tacky solid (28 g). The solid was dissolved in 140 mL of anhydrous THF, and 20 g of CDI and a catalytic quantity of DMAP were added and allowed to react at a reflux for 6h untill a large amount of white solid precipitated. The white solid was cooled and filtered to yield 18 g of dried title compound. 1H NMR (DMSO-d6): delta 11.10 (s, 1H), 8.26 (s, 2H), 5.03 (dd, 1H, J = 3Hz, J = 3Hz), 2.87-2.82 (m, 1H), 2.66-2.55 (m, 2H), 2.07-2.04 (m, 1H); MS (m/z): 263 (M-1)+.
bis(4,4'-(naphthylglutamineboryl)phenyl) ether[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
Example 126; Bis(4,4'-(naphthylglutamineboryl)phenyl) ether [Show Image] The entitled compound (46 mg) was obtained by allowing 86 mg of bis(4,4'-(naphthyl-hydroxyboryl)phenyl) ether and 52 mg of glutamine to act in 0.6 mL of ethanol. NMR (DMSO-d6), 2.20 (m, 4H), 3.4 (m, 8H), 4.35 (m, 2H), 6.7-7.8 (m, 24H)
bis(3,3'-(phenyl-glutamineboryl)benzyl) ether[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
Example 153; Bis(3,3'-(phenyl-glutamineboryl)benzyl) ether [Show Image] The entitled compound (52 mg) was obtained by allowing 41 mg of bis(3,3'-(phenylhydroxyboryl)benzyl) ether and 29 mg of glutamine to act in 1 mL of ethanol. NMR (DMSO-d6), 1.8-2.1 (m, 4H), 2.3 (m, 4H), 3.6-4.2 (m, 4H), 6.0-7.6 (m, 18H)
bis(4,4'-(phenyl-glutamineboryl)phenyl) ether[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; at 60℃; for 1h;
Example 70 Bis(4,4'-(phenyl-glutamineboryl)phenyl) ether [Show Image] Bis(4,4'-(phenylhydroxyboryl)phenyl) ether (22 mg) and glutamine (19 mg) were heated in 2 mL of ethanol at 60°C for one hour to give 8 mg of the entitled compound. NMR (DMSO-d6), 2.05 (m, 4H), 2.25 (m, 4H), 2.42 (m, 4H), 3.3 (m, 4H), 4.0 (m, 2H), 6.8-7.8(m, 18H)
With ethanol; at 60℃; for 1h;
Example 273bis(4,4'-(phenyl-glutamineboryl)phenyl)ether (1024)TG 83, x-Fold 0.56, SOC IC50 0.25 muMBis(4,4'-(phenylhydroxyboryl)phenyl)ether (22 mg) and glutamine (19 mg) were heated in ethanol (2 mL) at 60° C. for 1 hr to give the title compound (8 mg).
(4-(phenyl-glutamineboryl)phenyl) (4'-(hydroxymethylphenyl-glutamineboryl)phenyl) ether[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; at 80℃; for 3h;
Example 76; (4-(Phenyl-glutamineboryl)phenyl) (4'-(hydroxymethylphenyl-glutamineboryl)phenyl) ether [Show Image] Bis(4,4'-(phenylhydroxyboryl)phenyl) ether (31 mg) and glutamine (22 mg) were heated in 3 mL of ethanol at 80°C for three hours to give 32 mg of the entitled compound. NMR (DMSO-d6) 2.0 (m, 4H), 2.2 (m, 4H), 2.5 (m, 4H), 3.5 (m, 4H), 4.0 (m, 2H), 6.9-7.0 (m, 17H)
Example 9 Preparation of the Polyamino Acid of Formula (I) in which; and n=13 (Theoretical Index) This polyamino acid is obtained according to the same procedure as that described in Example 5, but replacing the lysine with the corresponding molar amount of glutamine.
With triethylamine; In dimethylsulfoxide-d6;Product distribution / selectivity;
Acid using Compound 8 and Compound 9(1) TestThe optical transformation of amino acid using the binaphthol derivative of the present invention was tested as follows.As the binaphthol derivative, Compound 8 (Examples 1 and 2) and Compound 9 (Examples 3 and 4) were used, and the racemic amino acid was exemplified by six amino acids, including triethylamine (Table 2 below).Into an NMR tube, 0.7 ml of DMSO-d6, 0.022 mmol L-amino acid, 0.08 mmol triethylamine, and 0.02 mmol binaphthol derivative were added, and 1H-NMR was measured.Immediately after the L-amino acid completely reacted with the binaphthol derivative, an imine was formed.Then, 1H-NMR was measured over time, from which the L-amino acid was confirmed to have been transformed into a D-amino acid.FIG. 2 illustrates the 1H NMR showing the transformation of L-phenylalanine into D-phenylalanine using Compound 8.The upper first spectrum of FIG. 2 shows 1H NMR of the imine compound, formed 1 hour after the reaction of the S-binaphthol derivative of Compound 8 and the L-phenylalanine in the presence of 4 equivalents of Et3N, the 1H NMR spectra thereunder sequentially showing states after reaction times of 5 hours, 8 hours, 24 hours, and 48 hours.As shown in these spectra, new peaks appear just after the reaction. These peaks coincide with the peaks of imine formed through the reaction of Compound 8 and D-phenylalanine. After 48 hours, the peaks detected in L-phenylalanine almost disappear, whereas the peaks detected in D-phenylalanine predominate. This means that L-phenylalanine was transformed into D-phenylalanine.In FIG. 2, in the compound formed through the reaction of Compound 8 and L-alanine, about 97.7percent of L-phenylalanine can be seen to have been transformed into D-phenylalanine (L:D=1:42, according to the calculation of the area of the peaks) after about 48 hours. However, almost no D-phenylalanine was transformed into L-phenylalanine. This is because Compound 8 is the S-binaphthol derivative. Thus, if the R-binaphthol derivative is used, D-amino acid can be transformed into L-amino acid.Consequently, using the compound of the present invention, only one isomer of optically pure D-amino acid or L-amino acid from racemic amino acid can be effectively obtained.Other amino acids were tested in the same manner as above, using Compound 8 and Compound 9. As the results, the final ratio of L-amino acid and D-amino acid is summarized in Table 2 below.COMPARATIVE EXAMPLE 2Optical Transformation of L-Amino Acid into D-Amino Acid using Known Binaphthol DerivativeThe optical transformation of amino acid was tested in the same manner as in Example 9, with the exception that the binaphthol derivative of Comparative Example 1 was used. The results are also summarized in Table 2 below. TABLE 2 Ratio of D-Amino Acid/L-Amino Acid in Equilibrium (measured by1H NMR Integration ratio) KR/KS Ex. 8 Amino Alcohol Compound 8 Compound 9 C.Ex. histidine 50/1 - 13.9/1 tyrosine 20/1 25/1 12.3/1 phenylalanine 42/1 11/1 11.1/1 serine 27/1 - 10.6/1 glutamine 18/1 - 14.8/1 asparagines 17/1 - 13.0/1
A fourth implementation is a Glutamine compound of the formula: wherein; R is the Glutamine group identified and defined above; X is the Amino Acid base identified and defined above; and Y is selected from the group consisting of a Nitrate and a Nitrite. Applicants have cost-effectively synthesized Glutamine Nitrate by combining nitric acid and Glutamine, mixing with water, and leaving to crystallize
Example 182di(3-chloro-4-methylphenyl)(glutaminate-O,N)borane (4105)TG 137, x-Fold 1.01Di(3-chloro-4-methylphenyl)borinic acid (32 mg) and glutamine (15 mg) were reacted in ethanol (0.6 mL) at 90° C. for 2 hr to give the title compound (34 mg).
Example 276diphenyl(glutaminate-O,N)borane (854)TG 105, x-Fold 0.8Diphenylborinic acid (39 mg) and glutamine (3.7 mg) were reacted in ethanol (0.6 mL) at 60° C. for 1 hr to give the title compound (10 mg).
Example 4822,8-di(phenylglutamine-O,N borane)dibenzothiophene (8015)TG 114, x-Fold 1.08Compound 8012 (Example 387) (40 mg) and glutamine (31 mg) were reacted at 80° C. to give the title compound (15 mg).NMR (DMSO) 2.2 (m, 2H), 2.5 (m, 4H), 3.3 (m, 10H), 7.0-7.8 (m, 16H)
Example 269diphenyl(glutaminate-O,N)borane (879)TG 95, x-Fold 1.01, SOC IC50 3 muMDiphenyl 2-aminoethylborinate (112 mg) and glutamine (74 mg) were stirred with heating in a mixture of ethanol (0.4 mL), water (1.5 ml) and acetic acid (0.03 ml) at 100° C. for 10 min to give the title compound (21 mg).
Example 3042,8-di(3-thiophenylglutamine-O,N boryl)dibenzothiophene (8020)TG 47, x-Fold 0.90Compound 8013 (Example 406) (24 mg) and glutamine (19 mg) were stirred in ethanol at 80° C. for 12 hr to give the title compound (16 mg).NMR (DMSO) 1.90 (m, 2H), 1.95 (m, 2H), 2.10 (m, 4H), 2.30 (m, 4H), 7.0-8.0 (m, 12H)
Glutamine (36.5g, 0.25mol) was stirred with IM sodium bicarbonate (750ml) and toluene (200ml). Benzyl chloro formate (50ml, 59.75g, 0.35mol, 1.4 equiv.) was added drop- wise over 20 min. and the resulting mixture was stirred under nitrogen at room temperature overnight. Ethyl acetate (400ml) was added and phases were separated. The organic phase was extracted with water (50ml) and discarded. The aqueous phase was acidified with 6N hydrochloric acid and extracted with ethyl acetate (2 x 600ml). The combined extracts were washed with water (100ml) and stripped. The residue was dried in a vacuum oven (500C) to produce (1) (64g, 91.4percent).
5-amino-2-(4-fluoro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide; at 90℃; for 8h;
Step 2: 5-amino-2-(4-fluoro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid A mixture of the above 4-fluoroisobenzofuran-1,3-dione (40 g, crude) and L-glutamine (35 g, 239 mmol) in dry DMF (200 mL) was stirred at 90 °C for 8 h. The solvent was removed under reduced pressure. The residue was re-dissolved in 4N HCl (200 mL) and stirred for additional 8 h. The resulting precipitation was collected by filtration, washed with water, and dried to afford 5-amino-2-(4-fluoro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid (37 g, crude) as an off-white solid. LC-MS: 295.2 [MH]+. 1H NMR (400 MHz, CDCl3): 2.16-2.20 (m. 2H), 2.31-2.43 (m, 2H), 4.79-4.83 (m, 1H), 6.79 (br, 1H), 7.26(br, 1H), 7.77-7.85 (m, 2H), 7.98-8.03 (m, 1H), 13.32(br, 1H).
Glutamine (2.08 g, 4.21 mmol) was dissolved in formic acid (20 mL), was added acetic anhydride (3.0 eq, 4.06 mL) and allowed to stirred at room temperature for 23 hours the reaction. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, recrystallized by adding methanol and ethyl acetate, the corresponding formamide (11a) was obtained (1.61 g, 9.26 mmol, 65percent). Compound 11a (1.60 g, 9.17 mmol), and in DMF (20 mL) in, benzyl bromide (1.5 eq, 1.63 mL) and potassium carbonate (3.0 eq, 3.79 g) and, stirring for 3 hours to react at 60 It was. After completion of the reaction, water is added to inactivate the reaction mixture, acetic acid dAnd extracted with chill. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure, recrystallized by adding ethyl acetate, the corresponding benzyl ester (11b) (453.3 mg, 1.71 mmol, 19percent) a Obtained. Compound 11b (232.2 mg, 0.89 mmol) was added in DCM (10 mL), PhOPOCl2 (1.5 eq, 197 muL) and pyridine (5.0 eq, 609 muL) was added, followed by stirring to react at room temperature for 2.5 hours It was. After completion of the reaction, a saturated saline was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with hydrochloric acid, sodium bicarbonate, and with saturated brine, furtherDried over magnesium sulfate, filtered, subjected to concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to give isonitriles (11) (53.8 Mg, to obtain a 0.22 mmol, 25percent). Yellow oil.
With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 24h;
The <strong>[475-11-6]N-methyl-L-proline</strong> b (1.29 g, 10 mmol) was added to dichloromethane (20 mL),Add DCC (2.47g, 12mmol) and thenL-glutamine (1.46 g, 10 mmol),Reaction at room temperature for 24 hours, filtration,The mother liquor was concentrated to dryness to give a white solid, 1.5 g, yield 58.4%, that is compound B-3.
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