* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry, 1947, vol. 12, p. 43,45
[2] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1933, vol. 218, p. 129,138
4
[ 77287-34-4 ]
[ 156-81-0 ]
[ 849585-22-4 ]
[ 617-48-1 ]
[ 2491-15-8 ]
[ 110-15-6 ]
[ 108-53-2 ]
[ 71-30-7 ]
[ 113-00-8 ]
[ 127-17-3 ]
[ 66-22-8 ]
[ 66224-66-6 ]
[ 56-40-6 ]
[ 302-72-7 ]
[ 18514-52-8 ]
Yield
Reaction Conditions
Operation in experiment
0.18 mg
With ferric sulfate nonahydrate In water at 80℃; for 24 h;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
With ferric sulfate nonahydrate In water at 80℃; for 24 h;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
General procedure: Drop-wise SOCl2 (1.6 mL, 22 mmol) wasadded to a cooled (0 C) suspension of L-phenylalanine (3.3 g, 20 mmol) in dryMeOH (30 mL) about 30 min. The clear solution was stirred in an ice-bath for30 min. Then the mixture was still stirred for 12 h at room temperature andsubsequently heated to 50 C and reacted for 2 h, and the solvent wasevaporated under reduced pressure. The residue was dried in vacuum to give 1as a white solid.25 This material was pure enough to be used in the next stepwithout further purification. To a cooled suspension of 1 (2.157 g, 10 mmol)and triethylamine (1.5 mL, 11 mmol) in dry toluene (20 mL) at 0 C was addeddrop-wise a solution of triphosgene (1.48 g, 5 mmol) in 10 mL of dry tolueneover 30 min. The reaction mixture was stirred at 0 C for 15 min and thenrefluxed for 3 h. Upon cooling to room temperature, vacuum filtered, thesolvent was evaporated under reduced pressure to give the product 2 ascolorless oil. This material was also used in the next step without furtherpurification, assuming a quantitative yield. To a solution of 2-aminopyridine(0.94 g, 10 mmol) in dry CH2Cl2 (10 mL) at room temperature was added dropwisea solution of 2 in 10 mL of dry CH2Cl2. The mixture was stirred for 12 h atroom temperature and the solvent was evaporated under reduced pressure togive brown oil, which was subsequently diluted with 1% acetic acid solution(20 mL) and extracted with ethyl acetate (3 15 mL). The organic fractionswere washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4,filtered and concentrated under reduced pressure. The crude product waswashed thoroughly with hexane, dried in vacuum and recrystallized fromethanol which afforded a white crystalline product of 3a.
With bis(trichloromethyl) carbonate; triethylamine; In chloroform; at -10 - 55℃;
In a stirrer, thermometer, constant pressure drip funnel, in a 500ml three-necked bottle with a condenser tube and an exhaust gas absorption device, 15g (0.17mol) of alanine, 17.04g (0.17mol) of triethylamine, 50 ml of chloroform was stirred at -10 C to 0 C; 16.66 g (0.056 mol) of triphosgene was dissolved in 50 ml of chloroform and transferred to a constant pressure dropping funnel. Slowly drip into the three-necked bottle at a speed of 1ml/min, and then increase the temperature to 55 C after the dropwise addition; After the system was clarified, 55 ml of methanol was added and stirring was continued for 1 h; The reaction solution was cooled to room temperature and transferred to a constant pressure dropping funnel. Add 59.65 g (0.51 mol) of dimethyl oxalate and 17.89 g (0.18 mol) of triethylamine to the original three-necked bottle, the above reaction solution was slowly added dropwise at a rate of 1 ml / min at 50 C; After the dropwise addition, the temperature was maintained for 0.5h, and the temperature was raised to 60 C. Continue stirring for 2 hours to end the reaction; remove excess solvent from the reaction solution by distillation, adjust the pH to 7 with 0.5% sodium hydroxide solution; 80 ml of ethyl acetate were extracted three times, and the organic phases were combined. Dry over anhydrous sodium sulfate; remove the solvent by distillation under reduced pressure and recover dimethyl oxalate, that is, 30.51 g of N-methoxyoxalyl alanine methyl ester is obtained, the gas phase content was 97.0%, and the yield was 93.0%.
S1. Dissolve alanine (A) in glacial acetic acid. The mass ratio of alanine to glacial acetic acid (g/mL) is 1:7.Acetylic anhydride was added dropwise, the mass ratio of alanine to acetic anhydride was 10:20, and the temperature was raised to reflux for 1 hour, followed by cooling and quenching.Spin-drying the solvent, ethyl acetate was added to stir the crystals to give 2-acetylaminopropionic acid (B);
With acetic acid; at 70℃;
General procedure: Amino acid (10 g) was mixed with glacial acetic acid (50 mL). Acetic anhydride (1.1 equiv.) was added to the reaction vessel and the mixture was kept at 70 C for 10-30 min, until total dissolution of the initial product. Acetic acid was then removed under vacuum and the N-acetylamino acid was recrystallized from ethyl acetate. The final compound was obtained in 95-99% yield and dried in high vacuum overnight andhigh purity was confirmed by NMR experiments.
General procedure: Phenylglycine (1.0 equiv, 6.60 mmol, 1.0 g) was added to2.0 M NaOH (20 mL) in a 100 mL round-bottomed flask.The solution was cooled to 0 C in an ice bath, and then 4-fluorobenzoylchloride (9, 1.0 equiv, 6.60 mmol, 0.78 mL)was added dropwise over 20 min. The reaction was allowedto warm to r.t. and stirred for 2 h. The solution was thenmade slightly acidic (pH 5-6) by dropwise addition of 2.0 MHCl and was extracted with EtOAc (5 × 75 mL). The organicphase was dried over MgSO4 and concentrated in vacuo toyield 8d as white solid.
A solution of commercial D,L-alanine (5.00 g, 56.12 mmol) in 150 mL absolute ethanol and 5 mL HCl 37% was refluxed for 5 h. The solvent was then evaporated and the uncoloured oily residue was dried under vacuum; Yield 92%; 1H NMR (CDCl3): delta 1.05 (t, 3H, J = 7.07 Hz, -OCH2CH3), 1.45 (d, 3H, J = 7.25 Hz, -CHCH3), 3.48 (q, 2H, J = 7.07Hz, -OCH2CH3), 4.02 ppm (q, 1H, J = 7.25Hz, -CHCH3); HRMS (ESI, 140 eV): m/z [M+H+] calcd for C5H12NO2: 118.0868 found: 118.0794.
With bis(trichloromethyl) carbonate; triethylamine; In chloroform; at -10 - 55℃;
In a stirrer, thermometer, constant pressure drip funnel,In a 500-ml three-necked bottle of a condenser and an exhaust gas absorption device, 15 g (0.17 mol) of alanine, 17.04 g (0.17 mol) of triethylamine, and 50 ml of chloroform were charged. Stir at -10-0 C ; take 16.66g (0.056mol) of triphosgene and dissolve it in 50ml chloroform, transfer it to the constant pressure dropping funnel slowly drip into the three-necked bottle at a speed of 1ml/min, and then increase the temperature to 55 C after the dropwise addition; After the system is clarified, add 76 ml of ethanol and continue stirring for 1 hour; The reaction solution was cooled to room temperature and transferred to a constant pressure dropping funnel. In an original three-necked flask, 73.82 g (0.51 mol) of diethyl oxalate and 17.89 g (0.18 mol) of triethylamine were added. The above reaction solution was slowly added dropwise at a rate of 1 ml / min at 50 C; After the dropwise addition, the temperature was maintained for 0.5h, the temperature was raised to 70 C, and the reaction was continued for 2h to end the reaction; The excess solvent in the reaction solution was distilled off, and adjusted to pH ? 7 with 0.5% sodium hydroxide solution; 80 ml of ethyl acetate was extracted three times. Combine the organic phases and dry over anhydrous sodium sulfate; The solvent was distilled off under reduced pressure, and diethyl oxalate was recovered. That is, 34.79 g of N-ethoxyoxalyl alanine ethyl ester was obtained, the gas phase content was 96.3%, and the yield was 91.7%.
With potassium carbonate; In dimethyl sulfoxide; at 150℃;
INTERMEDIATE: (3,7-Dimethyl-quinoxalin-2-yl)-hydrazine (Ilj). 4-Chloro-3-nitrotoluene (19 mL) was dissolved in DMSO (300 mL). Racemic alanine (45 g) and K2C03 (20 g) were added, and the mixture was stirred overnight at 150 C. The crude mixture was poured into water (300 mL) and acidified with 37% aq HC1. The product was extracted into EtOAc. The organic layer was washed with brine and concentrated in vacuo. The residue was refluxed for 0.5h in a mixture of methanol (300 mL) and 96% sulfuric acid (20 mL). The volatiles were removed in vacuo. The residue was partitioned between water and EtOAc after basification with NaOH. The organic layer was washed with brine, dried over MgSO i, filtered, and concentrated in vacuo. The residue was dissolved in a mixture of ethanol (500 mL), THF (100 mL) and 2M aq sulfuric acid (35 mL). The mixture was degassed with Ar. 10% Palladium on charcoal (1 g) was added, and the mixture was treated with hydrogen gas (3 bar) using a Parr shaker for 3 h. More 10% palladium on charcoal (1 g) was added and the mixture was treated with hydrogen gas (3 bar) using a Parr shaker overnight. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was partitioned between water and EtOAc. The aq layer was basified with 28% aq NaOH and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO i, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica (eluent: heptanes? EtOAc) to afford 3,7-dimethyl-3,4-dihydro-lH-quinoxalin-2-one (6.12 g) as a pale brown solid that was used directly in the next step. A suspension of this material (5.98 g) and 10% palladium on charcoal (0.60 g) in 1,2-dimethylbenzene (200 mL) refluxed overnight. The crude mixture was cooled to 50 C and diluted with THF (200 mL) before it was filtered through a plug of celite. The filtrate was concentrated in vacuo to yield 3,7-dimethylquinoxalin-2(lH)-one (5.9 g) as a brown solid that was used in the next step. A portion of this material (1.08 g) was added to an ice-cold mixture of phosphoryl chloride (20 mL) and DIPEA (2.16 mL). The mixture was heated at 100 C for 2h. The volatiles were removed in vacuo. The residue was diluted with DCM (50 mL) and poured carefully onto ice (200 mL) to quench excess phosphoryl chloride. The aq layer was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO i, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica (eluent: heptanes? EtOAc) to afford 3-chloro-2,6-dimethyl-quinoxaline (879 mg) sufficiently pure for the next step. A larger portion of this material (3.31 g) prepared in a similar manner was dissolved in ethanol (100 mL). Hydrazine hydrate (3.2 mL) was added, and the mixture was refluxed for 8h before the heat was turned off and the mixture was allowed to stand at ambient temperature overnight. Next morning, hydrazine hydrate (1 mL) added and the mixture was refluxed for 8h. The mixture was allowed to cool to ambient temperature. The volatiles were removed in vacuo. The residual solid was washed with water and heptanes before it was dried to afford Ilj (2.57 g) as a slightly red solid sufficiently pure for the next step.
1,3-Dimethyl-5-(2-nitro-propenyl)-1,3-dihydro-benzoimidazol-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In butan-1-ol;
1,3-Dimethyl-5-(2-nitro-propenyl)-1,3-dihydro-benzoimidazol-2-one <strong>[55241-49-1]1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde</strong> (2.48 g, 13.1 mmol, obtained using the same procedure used for 1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde) in n-butanol (25 mL) was treated with -alanine (298.0 mg) and nitroethane (1.85 mL). The mixture was heated to 115 C. for 4 hours, more nitroethane (0.5 mL) was added and the heating was continued for 2 hours. The reaction was allowed to cool, was filtered and washed with ether then dried to give 1,3-Dimethyl-5-(2-nitro-propenyl)-1,3-dihydro-benzoimidazol-2-one (2.229 g).
EXAMPLE 1A N-Acetylalanine 134 g (1.50 mol) of DL-alanine are introduced into acetic acid and treated dropwise with 230 g (2.25 mol) of acetic anhydride. The mixture is additionally stirred at 100 C. for 2 h to complete the reaction and the solvent is then stripped off in vacuo. The solid obtained is suspended in ethyl acetate and filtered off with suction. For purification, the solid is washed several times with diethyl ether. Yield: 162 g (82.6% of th.) 1H-NMR (methanol-d4): delta/ppm 1.38 (d, 3 H), 1.97 (s, 3 H), 4.37 (q, 1 H).
Amino acid analysis (acid hydrolysis over 24 hours using a solution of 6N HCl containing 1percent phenol at 130° C.) gave Ala 5.82, Val 0.98, Asp 1.19. Fmoc-Pip-OH was obtained by an analogous method to that described in E. Atherton and R. C. Sheppard ("Solid phase peptide synthesis: a practical approach", IRL press, 1989, page 51) for N-Fmoc-L-methionine: Fmoc-Pip-OH: NMR (DMSO-d6) 1.3 (m, 2H), 1.7 (m, 2H), 2.5 (m, 2H), 2.9 (t, 2H), 3.7 (m, 1H), 4.2 (t, 1H), 4.4 (d, 2H), 7.4 (m, 4H), 7.7 (d, 2H), 7.9 (d, 2H); mass spectrometry m/e (ES+) 352.2 (MH+)
43
[ 27527-05-5 ]
[ 40056-18-6 ]
N-[N-(3,4-dichlorophenyl)-D,L-alanyl]-β-cyclohexylalanine methyl ester[ No CAS ]
[ 302-72-7 ]
Yield
Reaction Conditions
Operation in experiment
Synthesis of N-[N-(3,4-dichlorophenyl)-D,L-alanyl]-beta-cyclohexylalanine methyl ester Following General Procedure D and using beta-cyclohexylalanine methyl ester (prepared from beta-cyclohexylalanine (Bachem) using General Procedure K) and N-(3,4-dichlorophenyl)-D,L-alanine, the title compound, as a mixture of diastereomers about alanine, was prepared as an oil.
N-Chloroacetyl alanine ethyl ester The procedure of C. S. Marvel and W. A. Noyes, J. Amer. Chem. Soc., 42, 2265 (1920) was followed. Thirty grams (0.34 mole) of alanine was suspended in 150 ml of ethyl alcohol in a reaction flask and anhydrous hydrogen chloride gas was passed into the mixture at an initial temperature of 25 C. Addition was continued until 50 g (1.4 moles) of gas had been added. The temperature rose to 65 C. over the course of the addition. After addition was complete, the mixture was heated at reflux for 3.5 hours. During this time there was formation of a solid. Upon cooling, the solid separated and was removed by filtration to give 47.5 g of alanine ethyl ester hydrochloride (91% yield).
With sodium hydroxide; In water; ethyl acetate; at 70 - 80℃; for 7.0h;Product distribution / selectivity;
Into a 100 L glass reactor, ethyl acetate (37L, MC<0.01%), powdered and vacuum dried alanine (500g,particle size < 200 micron, MC < 0.01%) are added. The out let of reactor is connected to a scrubber. The reservoir of the scrubber is filled with 10% sodium hydroxide solution and inert atmosphere is created by applying nitrogen. Triphosgene (500g) is dissolved in ethyl acetate (5L) and charged into the addition tank. Reaction mixture is heated to 70-800C, and then triphosgene solution is added in portions during 4- 6h. After the addition of about 4.2L triphosgene solution, the reaction is clear solution. Then, the remaining triphosgene solution is added and reaction maintained 70-800C for further Ih. The reaction mixture is cooled to 600C, the filtered through a hyflow bed under nitrogen atmosphere. The filtered reaction mixture is charged to the reactor and solvent removed to 1/3 volume, then hexane (30L, MCO.01%,) is added and stirred for Ih at 0-50C. Separated crystalline product is filtered and dried under nitrogen atmosphere and stored at -200C. Yield: 50Og (87.7%), assay = 99.7% (non-aqueous titration), Chlorides = 0.01% (argentometry), free alanine < 0.01 % (TLC).
44.8%
In acetonitrile;Heating / reflux;Product distribution / selectivity;
Powdered and vacuum dried alanine (1Og, particle size < 200 micron, MC < 0.01%) is added to acetonitrile (50OmL, MC <0.1) and heated to reflux temperature. A solution of triphosgene (1Og) in acetonitrile is added during course of 4h. Reaction mixture is heated a till clear solution is obtained, filtered and solvent distilled to obtain a concentrate. To the concentrate, hexane (500 mL, MCO.1%) is added and cooled to 0-5 C. The separated crystalline material is filtered under nitrogen, and packed under nitrogen atmosphere and stored at -20 C. Yield: 5.1g (44.8%), assay = 99.4%, Chlorides = 0.01%, free alanine < 0.01%.
32.5%
In tetrahydrofuran;Heating / reflux;Product distribution / selectivity;
Powdered and vacuum dried alanine (1Og, particle size < 200 micron, MC < 0.01%) is added to tetrahydrofuran (50OmL, MC <0.1) and heated to reflux temperature. A solution of triphosgene (1Og) in tetrahydrofuran is added during course of 6h. Reaction mixture is heated till clear solution is obtained, filtered and solvent distilled to obtain a concentrate.To the concentrate, hexane (400 mL, MCO.1%) is added and cooled to 0-5 C. The separated crystalline material is filtered under nitrogen, and packed under nitrogen atmosphere and stored at -20 C.Yield: 3.7 (32.5%), assay = 99.1%, Chlorides <0.01%, free alanine < 0.01% (TLC).
1-a: 2- (4-bromophthalimide) propionic acid 3.00 g (13.2 mmol) of <strong>[86-90-8]4-bromo-phthalic anhydride</strong>,(13.5 mmol) of alanine,glacial acetic acid20 mL,Put into 50mL reaction flask, reflux to the remaining raw materials, let cool, pour 50mL of cold water, precipitate a white solid, filter, washed and dried to obtain 2.89g white solid, yield 73.4% by weight.
INTERMEDIATE: (5-Methoxy-3-methyl-quinoxalin-2-yl)-hydrazine (lie). 2-Methoxy-6-nitro- phenylamine (25.0 g) was dissolved in 37% aq HC1, and the mixture ws cooled on an ice/water bath. A solution of NaN02 (11.8 g) in water (3 mL) was added, and the resulting mixture was stirred at 0 C for 15 min. The reaction mixture was added to a solution of cuprous monochloride (14.7 g) in 37% aq HC1 (10 mL) under stirring at 45-50 C. The resulting mixture was stirred at 50 C for 15 min, cooled at 5 C for 15 min. The solid was filtered off and dried to give 2-chloro-l-methoxy-3- nitrobenzene (16.5 g). A mixture of 16 g of this material, racemic alanine (17 g), and K2CO3 (12 g) was heated in DMSO (180 mL) at 100 C for 24h. The volatiles were removed using a freeze dryer. The residue was acidified with 2M aq HC1 (50 mL) and extracted into EtOAc. The organic extract was extracted with 2M aq Na2C03 and water. The combined aq extracts were acidified with 2M aq HC1 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO i, filtered, and concentrated in vacuo to afford 2-(2-methoxy-6-nitro-phenylamino)-propionic acid. This material was dissolved in ethanol (600 mL) and 96%> sulphuric acid (6 mL) was added. The mixture was heated at 80 C overnight. The volatiles were removed in vacuo and the residue was dissolved in EtOAc and washed with 2M aq Na2C03. The organic layer was dried over MgSO i, filtered, and concentrated in vacuo to afford 2-(2-methoxy-6-nitro-phenylamino)-propionic acid ethyl ester (8.0 g). This material was dissolved in ethanol (300 mL) and 5% palladium on carbon was added. The mixture was treated with 3 bars of hydrogen pressure on a Parr shaker for 3h. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica (eluent: heptanes? EtOAc) to afford 5-methoxy-3-methyl-3,4-dihydro- lH-quinoxalin-2-one (3.0 g). This material was dissolved in ethanol (300 mL) and treated with 30% aq hydrogen peroxide at 80 C overnight. Most of the volatiles were removed in vacuo. The residue was suspended in ethanol (10 mL) and cooled on an ice/water bath before the solid was filtered off, washed with ice-cold ethanol, and dried to afford 5-methoxy-3-methyl-lH-quinoxalin-2-one (2.2 g). This material was dissolved in phosphoryl chloride (24 mL) and heated at 130 C for 2h. The volatiles were removed in vacuo. The residue was partitioned between chloroform and ice + 2M aq NaOH. The organic layer was dried over MgSO i, filtered, and concentrated in vacuo to afford 2- chloro-5-methoxy-3-methyl-quinoxaline (2.5 g). This material was dissolved in ethanol (22 mL), hydrazine hydrate (2.9 mL) was added, and the mixture was refluxed for 2h. The volatiles were removed in vacuo, and water was added. The solid was filtered off, washed with water and heptanes and dried to afford lie (1.70 g) sufficiently pure for the next step.
A mixture of 2-fluoro-3-nitro- pyridine (12 g), Et3N (30 mL), and racemic alanine (11.87 g) was refluxed in methanol (200 mL) overnight. The mixture was cooled to ambient temperature and the filtrate was concentrated in vacuo. The residue was partitioned between DCM and water. The organic layer was dried over Na2C03, filtered, and concentrated in vacuo to afford 2-(3-nitro- pyridin-2-ylamino)-propionic acid (7.8 g). This material was dissolved in AcOH (50 mL) and iron (8.2 g) was added. The mixture was refluxed for 1.5h. After cooling to ambient temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was washed with water and dried to afford 3-methyl-3,4-dihydro-lH-pyrido[2,3- b]pyrazin-2-one (1.4 g). This material was mixed with 5% aq NaOH (92 mL) and water (18 mL) before 30% aq hydrogen peroxide (9.2 mL) was added. The mixture was stirred at 60 C for l Oh. After cooling to ambient temperature the pH was adjusted to neutral to precipitate 3-methyl-lH-pyrido[2,3-b]pyrazin-2-one (1.2 g). This material was dissolved in DMF (10 mL) and treated with PyBroP (4.6 g) and DIPEA (1.6 mL) at ambient temperature of 16h. The precipitated white solid was filtered off, washed with ethanol and dried to afford 2-(benzotriazol-l -yloxy)-3-methyl-pyrido[2,3-b]pyrazine (0.4 g). This material (0.4 g) and hydrazine hydrate (0.5 mL) were refluxed in ethanol (5mL) for 10 min. After cooling to ambient temperature, the precipitated white solid was filtered off, washed with ethanol and dried to afford give Ila (0.2 g) sufficiently pure for the next step.
INTERMEDIATE 3-Hydrazinyl-5-methoxy-2-methylquinoxaline (Ila). To a solution of 3- fluoro-2-nitroanisole (5 g) in DMSO (60 mL) were added racemic alanine (5.8 g,) and K2C03 (4.0 g). The reaction mixture was heated at 90 C for 3h and then at 110 C for 20h. The reaction mixture was then cooled to ambient temperature. The crude mixture was poured onto 100 mL ice and the acidified with 37% aq HC1. EtOAc was added, and the organic layer was washed with brine, dried over MgSO i, filtered, and concentrated in vacuo. The residue was dissolved in a mixture of THF (20 mL), ethanol (100 mL), and 2M aq sulfuric acid (7 mL). A stream of argon was bubbled through the mixture for 5 min after which 10% palladium on charcoal (600 mg) was added and mixture was treated with hydrogen gas (3 bar) for 23h using a Parr shaker. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was partitioned between DCM and a 1 : 1 mixture of sat. aq K2CO3 and water. The aq layer was extracted with DCM. The combined organic layers were washed with brine, dried over MgS04, filtered, and concentrated in vacuo to afford 8-methoxy-3-methyl-3,4-dihydro-lH-quinoxalin-2-one (4.9 g) as a black oil. This material was dissolved in 1,3-xylene (200 mL). 10% palladium on charcoal (600 mg) was added and the mixture was refluxed for 12h. The reaction was allowed to cool to ambient temperature and THF (200 mL) was added. The mixture was filtered through a plug of celite and the filtrate was concentrated in vacuo to afford 8-methoxy-3-methyl-lH-quinoxalin-2-one (3.91 g). This material was added to ice-cold phosphoryl chloride (60 mL). The reaction was then heated at 100 C for 140 min. After cooling to ambient temperature the volatiles were removed in vacuo. The residue was diluted with DCM (100 mL) and poured carefully onto ice (150 mL). The pH was adjusted to neutral using K2CO3. The aq layer was extracted with DCM. The combined organic layers were washed with brine, dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica (eluent: heptanes? EtOAc) to afford 3-chloro- 5-methoxy-2-methyl-quinoxaline (2.8 g). This material was added to a mixture of ethanol (90 mL) and hydrazine hydrate (3.3 mL) and refluxed for 25h before it was cooled to ambient temperature. The volatiles were removed in vacuo. The resulting solid was washed with water and heptanes and dried to afford Ila (2.7 g) sufficiently pure for next step.
With caesium carbonate; In ethanol; water; for 5h;Reflux;
INTERMEDIATE (8-Bromo-3-methyl-quinoxalin-2-yl)-hydrazine (lid). A mixture of l-bromo-3- fluoro-2-nitro-benzene (99 g), racemic alanine (120 g) and CS2CO3 (440 g) in ethanol (1.2 L) and water (400 niL) was refluxed for 5h. After cooling to ambient temperature, the mixture was diluted with water (600 mL) and acidified to pH 3. The precipitate solid was collected and dried to afford racemic 2-(3-bromo-2-nitro-phenylamino)-propionic acid (110 g) as a yellow solid. lOg of this material in acetic acid (35 mL) and treated with iron powder (5.8 g) at 90 C for 2h, cooled and filtered then most of the acetic acid was removed in vacuo. The remaining slurry was extracted with DCM, dried over Na2S04, filtered, and concentrated in vacuo to afford 8-bromo-3- methyl-3,4-dihydro-lH-quinoxalin-2-one (6.4 g) as a yellow solid. A larger portion of this material prepared in a similar manner (29.2 g) was dissolved in 5% aq NaOH and treated with 30% aq hydrogen peroxide (140 mL) and water (180 mL). The mixture was stirred at 60 C for 6h before it was cooled. The precipitate solid was filtered off, washed with water, and dried to afford 8-bromo-3 -methyl- lH-quinoxalin-2-one (28.0 g). 21 g of this material was stirred in PI1POCI2 (80 mL) at 150 C for 4h. After cooling, water was added to quench excess PI1POCI2 and pH was subsequently adjusted to 7 with aq ammonia. The precipitated solid was filtered off, washed with water, and dried to afford 5-bromo-3-chloro-2-methyl-quinoxaline (17.7 g) as a yellow solid. This material was dissolved in ethanol (250 mL) was treated with hydrazine hydrate (160 mL) at reflux for 3h. Most of the volatiles were removed in vacuo. The precipitated solid was filtered off, washed with water, and dried to afford lid (14.8 g) as a yellow solid sufficiently pure for the next step.
General procedure: 3-Chlorophenylglycine (5.41 mmol, 1.0 g) was added toTFAA (3 mL) in a 25 mL round-bottomed flask. The mixture was stirred for 2 h at r.t. and excess TFAA was removed invacuo by means of azeotroping with toluene (5 × 10 mL) togive 1.32 g (93percent yield) of a yellow solid product.
With thionyl chloride; sodium hydrogencarbonate; In methanol;
Step 1. Synthesis of methyl alanine (#E1). Thionyl chloride (18.4 mL, 252.8 mmol) was added to a solution of alanine (15.0 g, 168.5 mmol) in methanol at 0 C. Then, the reaction mixture was stirred at room temperature for 3 h. After the depletion of the starting material, the reaction was cooled to 0 C. and treated with solid NaHCO3. The slurry was filtered through Celite pad, and rinsed with MeOH (100 mL). The filtrate was concentrated under reduced pressure to provide a residue that was diluted with DCM, washed with water, brine, dried and concentrated to give #E1 (19.0 g, crude). This was used for the next step without further purification. Rf: 0.6 (20% methanol in DCM). 1H NMR (400 MHz, d6-DMSO): delta 1.36 (d, J=7.2 Hz, 3H), 3.11 (s, 1H), 3.68 (s, 3H), 3.90 (q, J=7.2 Hz, 1H), 6.50 (br s, 3H).
Synthesis of Tridecyl 2-aminopropanoate (90) To a stirred solution of DL-alanine 1 (15 g, 168.5 mmol) in toluene (300 mL) was added <strong>[112-70-9]1-tridecanol</strong> 89 (30.39 g, 151.68 mmol) in one lot, followed by pTSA (35.26 g, 185.38 mmol). After the addition, the temperature of the reaction mixture was slowly raised to reflux temperature, the water was separated azeotropically and the reaction mixture was monitored by TLC. The reaction mixture was concentrated under vacuum, the obtained residue was taken in ethyl acetate (200 mL) and washed with aqueous 5% Na2CO3 (3*50 mL) followed by brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford 90 (38 g, yield: 83.15%) as a liquid.
With ferric sulfate nonahydrate; In water; at 80℃; for 24h;pH 7.57;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 muL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0% w/w) at 80 C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 muL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0% w/w ofthe corresponding salt?s pellet) at 80 C for 24 h. For the innerenvironment, NH2CHO (200 muL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0% w/w) at80 C for 24 h. The reaction of NH2CHO (10% v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 muL) at 60C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 C, detector temperature 280 C, gradient 100 C for 2min, and 10 C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98% compared to that of the reference standards.The analysis was limited to products of ?1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
With magnesium sulfate; In water; at 80℃; for 24h;pH 7.57;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 muL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0% w/w) at 80 C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 muL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0% w/w ofthe corresponding salt?s pellet) at 80 C for 24 h. For the innerenvironment, NH2CHO (200 muL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0% w/w) at80 C for 24 h. The reaction of NH2CHO (10% v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 muL) at 60C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 C, detector temperature 280 C, gradient 100 C for 2min, and 10 C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98% compared to that of the reference standards.The analysis was limited to products of ?1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
With palladium; In toluene; at 140℃; for 24h;Inert atmosphere; Schlenk technique;
In a clean dry 10 ml Schlenk reaction tube, the mass fraction of sequentially adding 10% Pd/C4 . 5 mg, ortho-nitro acetophenone 40 mg, c gly 67 mg, 1 ml of toluene as a solvent, is condensed on the return is, under the protection of nitrogen 140 o C reaction 24 hours. After the reaction, through the filter, the catalyst can be directly used in the next cycle, the filtrate after direct turns on lathe does a small amount of petroleum ether and ethyl acetate (volume ratio of 3:1) dissolving, through a short silica gel column of column separation, to obtain 24 mg white solid, yield 62%.
2-aminopropionic acid lactic acid 2-methylpiperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In a constant temperature stirring reaction system, 80 g of methylpiperazine and 776 g of water were added to the three containers; 72 g of lactic acid Placed in the dropping funnel, the water bath to the reaction temperature of 30 C, and constant temperature; start the mixer, control the stirring speed 1200r / min; start dropping funnel switch, lactic acid dropwise into the piperazine solution, dropping rate 100 drops / min, after the drip continued to respond 2h. 71g of the gas-based propionic acid by spoon on the step into the liquid, in 30min plus finished, plus after the reaction to continue for 2h, to terminate the reaction. After the completion of the reaction is the product of aminopropionic acid lactic acid methyl piperazine compound ionic liquid solution, the concentration of 0.8 mol / kg, the product without dehydration purification, directly as CO2,SO2 collector.
With sodium hydroxide; In ethanol; water; at 60℃; for 0.333333h;
The 1mmol (0.089g) alanine and 1mmol (0.04g) NaOH dissolved in 1mL of distilled water, placed in 100mL conical flask and stir until dissolved, document.write(""); (2) Weigh 1mmol (0.482g) was dissolved <strong>[22888-70-6]silibinin</strong> containing 50mL of anhydrous ethanol was slowly added dropwise conical flask, 60 stirring, the reaction was gradually appear yellow solid at room temperature after 20min reflux color Burn turns brown, document.write(""); (3) a thin layer of tracking, MgSO 4Dehydration, the solution pH = 8.5,55 water bath and stirred for 0.5h, TLC tracking, stop the reaction mixture was suction filtered, recrystallized from ethanol and dried under vacuum synthesized product is a yellow-brown solid in 42% yield, m.p. 228 ~ 229
((S)-2-N-(N-benzylprolyl)aminobenzophenone)(alanine) Ni(II) complex[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In methanol; at 40 - 50℃; for 2.16667h;Inert atmosphere;
To a round bottomed flask containing MeOH (70 mL) under N2 was added 9 (7.68 g, 20.0 mmol, 1 equiv.), DL-Alanine (3.60 g, 40.0 mmol, 2 equiv) and Ni(NO3)2*6H2O (11.6 g, 40.0 mmol, 2 equiv.) and the contents heated to 40 C. A solution of KOH (7.84 g, 140 mmol, 7 equiv.) in MeOH (30 mL) was added dropwise to the reaction vessel over 10 min. Once addition was complete, the reaction mixture was heated to 50 C and left to react for 2 h. The reaction was cooled to room temperature and neutralised with conc. acetic acid. Water (400 mL) and DCM (200 mL) were added to the reaction vessel and left to stir overnight. The mixture was then separated with DCM (3 300 mL) and the organic layers combined, dried and concentrated in vacuo to give the crude product as a red oil. The crude material was then purified by silica chromatography (0-100% EtOAc in Pet. Ether 40-60, 0-5% MeOH in EtOAc) to give the title compound as a bright red solid (7.55 g, 74%). numax (neat): 2976, 2872, 1678, 1622, 1591, 1440 cm-1. 1H NMR (400 MHz, CDCl3): delta 8.12-8.06 (m, 3H), 7.54-7.44 (m, 3H), 7.39 (t, 2H, J = 8.4 Hz), 7.27-7. 12 (m, 3H), 6.96 (d, 1H, J = 7.6 Hz), 6.68-6.61 (m, 2H), 4.43-4.40 (m, 1H), 3.91 (q, 1H, J = 7.2 Hz), 3.75-3.69 (m, 1H), 3.56 (d, 1H, J = 12.8 Hz), 3.53-3.47 (m, 1H), 2.77-2.72 (m, 1H), 2.59-2.51 (m, 1H), 2.25-2.18 (m, 1H), 2.11-2.04 (m, 1H), 1.61-1.59 (m, 3H). 13C NMR (101 MHz, CDCl3): 180.3, 170.1, 170.1, 142.0, 133.4, 133.3, 133.0, 131.9, 131.4, 129.6, 128.8, 128.7, 127.4, 127.1, 126.3, 123.8, 120.7, 70.1, 66.4, 63.0, 57.2, 30.7, 24.0, 21.7. 1C not observed. HRMS: (C28H28O3N3Ni) [M+H]+ requires 512.1479, found [M+H]+ 512.1467. [alpha]D20 = +2669 (c = 0.03, MeOH).
(7S)-2-chloro-7-methyl-7,8-dihydropteridine-6(5H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In ethanol; at 128℃; for 14h;
A-21. (7S)-2-Chloro-7-methyl-7,8-dihydropteridin-6(5H)-one 2,4-Dichloropyrimidin-5-amine (11 g, 67.08 mmol), (2S)-2-aminopropanoic acid (7.172 g, 80.5 mmol) and N,N-diisopropylethylamine (46 mL, 268 mmol) in ethanol (100 mL) was heated at 128 C. for 14 h. The reaction was evaporated in vacuo to half volume. Water (100 ml) was added to the mixture at room temperature and stirred for 1 hour. The resulting precipitate was collected by vacuum filtration, washed well with water and dried to provide the desired product wt. 9.56 g; Analytical SFC (column: cellulose 2 (40% ethanol, 60% CO2, isocratic): Rt 0.983 mins.) showed a S:R mixture 2:1; ESMS(M+1)=199.03.
Using the <strong>[66107-29-7]4-methoxyphenyl trifluoromethanesulfonate</strong> prepared in step S1 of Example 1, the "one-pot method" was used to construct C(sp3)-C(sp2) bonds and prepare β-aryl amino acids. The steps are as follows: Argon Under air protection, add racemic alanine (45mg, 0.5mmol), NiCl2 (65mg, 0.5mmol), ligand L1 (244mg, 0.5mmol), potassium carbonate (530mg, 2.5mmol), and dry molecular sieve into the reaction Into the tube, add anhydrous DMSO (10 mL). React at 65C for 3 hours, add palladium acetate (11mg) or tris(dibenzylideneacetone) dipalladium (45mg)/Xantphos (57mg), <strong>[66107-29-7]4-methoxyphenyl trifluoromethanesulfonate</strong> (384mg, 3eq), The temperature was raised to 110C and reacted for 36 hours. After the reaction is complete, cool to room temperature, add 50 mL of water, extract with ethyl acetate (20 mL×3), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product, which is subjected to column chromatography (dichloromethane/acetone=8:1 ) To obtain the product, the palladium acetate catalyzed reaction yield was 71%, dr>99:1; the tris(dibenzylideneacetone)dipalladium/Xantphos catalyzed reaction yield was 69%, dr>99:1. The reaction formula is as follows:Using this product, the β-aryl amino acid was prepared by the method of step S4 in Example 1.
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