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CAS No. : | 2835-06-5 | MDL No. : | MFCD00064402 |
Formula : | C8H9NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 151.16 | Pubchem ID : | - |
Synonyms : |
DL-α-Phenylglycine
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 40.69 |
TPSA : | 63.32 Ų |
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) : | -8.43 cm/s |
Log Po/w (iLOGP) : | 0.9 |
Log Po/w (XLOGP3) : | -1.7 |
Log Po/w (WLOGP) : | 0.45 |
Log Po/w (MLOGP) : | -1.43 |
Log Po/w (SILICOS-IT) : | 0.52 |
Consensus Log Po/w : | -0.25 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.02 |
Solubility : | 159.0 mg/ml ; 1.05 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 0.88 |
Solubility : | 1160.0 mg/ml ; 7.64 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -1.44 |
Solubility : | 5.46 mg/ml ; 0.0361 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.44 |
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: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium hydroxide; acetic anhydride In water-are; water | (a) D-α-Acetamido-α-phenylacetic acid (2a) 500 g (3.31 mol) of D-α-amino-α-phenylacetic acid are suspended in 6 liters of water, and the suspension is cooled to 10° C. and 132 g (3.31 mol) of NaOH dissolved in 1,000 ml of water are added. After 15 minutes, 675 g (6.62 mol) of acetic anhydride and then 397 g (9.93 mol) of NaOH--dissolved in 1,000 ml of water--are poured into the clear solution at 0° C., stirring rapidly. The temperature increases from 0° C. to 30° C. during this. The solution is stirred for a further 20 minutes at pH 9 to 10 in an ice/sodium chloride bath and is then acidified to pH 1 with concentrated hydrochloric acid (about 1 liter). The suspension is then stirred for 10 minutes, cooled to 10° C., filtered with suction and washed with 10 liters of water. The product is dried over KOH in vacuo. Yield: 553 g (87percent). C10 H11 NO3 (193.2). Melting point 190°-191° C. [α]58920° =-218.6° (C=1, C2 H5 OH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | at 0 - 20℃; for 1.5 h; | Amino(phenyl)acetic acid (33 mmol, 5 g) was cooled at 0 °C and added to a mixture of concentrated H2SO4 (98percent w/w,5 mL) and fuming HNO3 (90percent w/w, 5 mL). The mixturewas stirred for 1 h at 0 °C then 30 min at r.t. After this, thereaction was hydrolyzed with cold water (60 mL). The pHwas adjusted by addition of 10M NH4OH. The resultingmixture was stirred at 4 °C for 10 h, 3-nitrophenylglycinewas isolated by filtration. After washing with cold water,the compound was isolated as a yellow powder. Scheme S1.Yield: 64percent. 1H-NMR (DMSO, 200 MHz): δ = 8.27 (s, H-4,1H), 8.10 (d, J = 8.1 Hz, H-6, 1H), 7.83 (d, J = 7.9 Hz, H-8,1H), 7.64 (t, J = 7.9 Hz, H-7, 1H), 4.51 (s, H-2, 1H). Anal.calcd. for C8H8N2O4: C, 48.98; H, 4.11; N, 14.28. Found:C, 48.92; H, 4.19; N, 14.31. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at 0℃; for 6 h; | A solution of 151 grams (1 mol) Compound 1 in 1.5 methanol was mixed with 2 molar equivalents (146 mE) of thionyl chloride (50C12) at 0° C. under stirring. Afier 6 hours, the solvent was evaporated by vacuum to give Compound 2 in a quantitative yield. |
94.3% | at 18 - 22℃; for 18 h; | DL-α-phenylglycine (394.7 g, 2.611 mol) and a solution of methanol/HCl 4.3 N (3940 mL, 16.942 mol) were placed in a 5 L glass reactor and the granulate suspension was stirred at room temperature (20° +/- 2° C) for 18 hours, with its conversion into a clear solution being observed after approximately 4 hours and its conversion into a cloudy solution (fine suspension) after 8-10 hours. The mixture was concentrated at reduced pressure to an approximate volume of 1,0 L, with approximately 3.3L having been distilled. In this way, a thick, white suspension was obtained which was cooled to 20° +/- 1° C and was filtered, with the filter being washed with methanol (300 mL). The resulting solid was dried at 60° C and atmospheric pressure to constant weight (455,8 g). The filtrate was concentrated again under reduced pressure to an approximate volume of 135 mL, with approximately 600 mL having been distilled. The thick, natural coloured suspension was cooled to 20° +/- 1° C and was filtered, with the filter being washed with methanol (50 mL). The resulting solid was dried at 60° C and atmospheric pressure to constant weight (40.4 g). Both solids contained the title product (IV) (496.2 g, 94.3percent yield).1H NMR (200 MHz, CD3OD)δ:4.01 (s, 3 H, CH3), 5.11 (s, 3 H, NH3+), 5.44 (s, 1 H, CH), 7.66 (s, 5 H, Ar-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.9% | With sulfur trioxide at 20℃; | 2 Example 2: To a 1000 ml four-necked flask equipped with a stirrer, a condenser, and a thermometer, 500 ml of methanol and 151.2 g of phenylglycine were added, and stirring was started, and 96.1 g of sulfur trioxide was added dropwise. After completion of the dropwise addition, the mixture was naturally warmed to room temperature to carry out a reaction, and the mixture was controlled by HPLC. After the reaction was completed, the mixture was concentrated under reduced pressure, and the obtained solid was dissolved in water (800 g, 5° C). After the system is dissolved, the ammonia water is added dropwise, the dropping temperature is ≤20 °C, and the neutralization is carried out until the pH value is 8-9. After the end of the neutralization, the mixture was cooled by centrifugation, rinsed with pure water, and dried to obtain 158.5 g of solid phenylglycine methyl ester, and the molar yield was 95.9%. |
With hydrogenchloride | ||
With hydrogenchloride |
With thionyl chloride; triethylamine 1.) reflux, overnight, 2.) water, RT, 2 h; Multistep reaction; | ||
53 g | With thionyl chloride for 12h; | 1 Methyl 2-amino-2-phenylacetate To a cooled solution of phenylglycine (40.3 g, 266.3 mmol) in MeOH (250 ml), was added thionyl chloride (29.0 mL, 399.5 mmol) dropwise and stirred for 12 h until a colorless solution was obtained. The solvents were evaporated to give a pale yellow solid, more methanol was added to dissolve the solid and the solution was evaporated to dryness. The solid was placed on ahigh vacuum pump for 24 h. (53.0 g). ‘H NMR (300 MHz, CD3OD) ö 7.51 (d, J 1.2 Hz, 5H),5.22 (s, 1H), 3.8 (s, 3H). |
53 g | With thionyl chloride for 12h; Cooling; | 1 SCHEME 1, STEP 1: Methyl 2-amino-2-phenylacetate To a cooled solution of phenylglycine (40.3 g, 266.3 mmol) in MeOH (250 ml), was added thionyl chloride (29.0 mL, 399.5 mmol) dropwise and stirred for 12 h until a colorless solution was obtained. The solvents were evaporated to give a pale yellow solid, more methanol was added to dissolve the solid and the solution was evaporated to dryness. The solid was placed on a high vacuum pump for 24 h. (53.0 g). lH NMR (300 MHz, CD3OD) δ 7.51 (d, J= 1.2 Hz, 5H), 5.22 (s, 1H), 3.8 (s, 3H). |
With chloro-trimethyl-silane | 3.1.2. General Procedure for Esterication of Amino Acids Methyl esters of d-Ile and O-benzyl-Ser derivatives were prepared as described in Li and Sha [38]using 2 mmol of amino acid, 0.5 mL of trimethylsilyl chloride (TMSCl), and 10 mL of methanol. Thereaction mixture was evaporated to dryness and stored in a desiccator. | |
With sulfuric acid Reflux; | ||
With thionyl chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With porcine kidney D-amino acid oxidase (EC 1.4.3.3.); sodium cyanoborohydride; flavin adenine dinucleotide In phosphate buffer at 37℃; | |
With <(1R)-(endo,anti)>-(+)-3-bromocamphor-8-sulfonic acid | ||
With (1S)-10-camphorsulfonic acid |
Multi-step reaction with 2 steps 1: alkaline aq. solution / 0.5 h / 4 °C / pH 11 2: aminoacylase I from Aspergillus melleus; Tris buffer / H2O / 25 °C / pH 7.5 | ||
Multi-step reaction with 2 steps 2: enzyme-substance from soil-bacteria <pseudomonas> | ||
Multi-step reaction with 2 steps 1: ω-transaminase 2: L-2-aminobutyric acid; branched-chain transaminase from Escherichiacoli; S-selective ω-transaminase from Ochrobactrum anthropi; (3-hydroxy-5-hydroxymethyl)-2-methylisonicotinic acid 5-phosphate; isopropylamine / aq. phosphate buffer / 12 h / pH 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sulfuric acid; nitric acid; at 0 - 20℃; for 1.5h; | Amino(phenyl)acetic acid (33 mmol, 5 g) was cooled at 0 C and added to a mixture of concentrated H2SO4 (98% w/w,5 mL) and fuming HNO3 (90% w/w, 5 mL). The mixturewas stirred for 1 h at 0 C then 30 min at r.t. After this, thereaction was hydrolyzed with cold water (60 mL). The pHwas adjusted by addition of 10M NH4OH. The resultingmixture was stirred at 4 C for 10 h, 3-nitrophenylglycinewas isolated by filtration. After washing with cold water,the compound was isolated as a yellow powder. Scheme S1.Yield: 64%. 1H-NMR (DMSO, 200 MHz): delta = 8.27 (s, H-4,1H), 8.10 (d, J = 8.1 Hz, H-6, 1H), 7.83 (d, J = 7.9 Hz, H-8,1H), 7.64 (t, J = 7.9 Hz, H-7, 1H), 4.51 (s, H-2, 1H). Anal.calcd. for C8H8N2O4: C, 48.98; H, 4.11; N, 14.28. Found:C, 48.92; H, 4.19; N, 14.31. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: benzyl chloroformate; phenylglycin With sodium hydroxide In water at 0 - 20℃; for 0.75h; Stage #2: With hydrogenchloride In water | 8 To a solution of 2-amino-2-phenylacetic acid (500 mg, 3.31 mmol) in2N sodium hydroxide (1.65 ml, 3.31 mmol) stirred at 0°C, benzyl carbonochloridate (512 μ, 3.64 mmol) and 2N sodium hydroxide (1.82 ml,3.64 mmol) were simultaneously added dropwise from two different syringes.The reaction was stirred at RT for 45 minutes and a precipitate appeared.Water was added and the solution was extracted with Et2O. The aqueous phase was acidified with IN HCl and the desired product was extracted again with Et2O. The combined organic phases were dried over Na2SO4, filtered and evaporated to obtain 2-(benzyloxycarbonylamino)-2-phenylacetic acid(855 mg; 91% yield). |
91% | With sodium hydroxide at 0 - 20℃; | 8 To a solution of 2-amino-2-phenylacetic acid (500 mg, 3.31 mmol) in 2N sodium hydroxide (1.65 ml, 3.31 mmol) stirred at 0° C., benzyl carbonochloridate (512 μl, 3.64 mmol) and 2N sodium hydroxide (1.82 ml, 3.64 mmol) were simultaneously added dropwise from two different syringes. The reaction was stirred at RT for 45 minutes, and a precipitate appeared. Water was added, and the solution was extracted with Et2O. The aqueous phase was acidified with 1N HCl and the desired product was extracted again with Et2O. The combined organic phases were dried over Na2SO4, filtered and evaporated to obtain 2-(benzyloxycarbonylamino)-2-phenylacetic acid (855 mg; 91% yield). |
88% | With sodium hydroxide for 0.166667h; |
61% | With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 51h; | (R,S)-2-N-(Benzyloxycarbonyl)amino-2-phenylacetic Acid (28). The previously reported procedure2 was modified as follows: NaOH (1.32 g, 33.1 mmol) was added to a suspension of D,L-phenylglycine (5.00 g, 33.1 mmol) in THF/H2O (100:100 mL) at 0 °C. After the suspension dissolved, benzylchloroformate (4.64 mL, 33.1 mmol) in THF (15 mL) was added drop wise. The reaction was maintained at 0 °C (3 h) and then a second equivalent of NaOH (1.32 g, 33.1 mmol), followed by benzylchloroformate (4.64 mL, 33.1 mmol) in THF (15 mL), were added and then the reaction was allowed to warm to room temperature (48 h). The mixture was filtered and the filtrate was concentrated to half of its volume in vacuo and the remaining aqueous layer was basified to pH ~12 with aqueous 10 M NaOH and extracted with CH2Cl2 (3 x 100 mL). The aqueous layer was acidified (pH 1) with aqueous concentrated HCl and extracted with EtOAc (3 x 100 mL). The EtOAc layers were combined, dried (MgSO4), and concentrated in vacuo. The crude product was recrystallized from hot EtOAc/hexanes to give the desired product (5.73 g, 61%) as a light yellow solid. Mp 130-131 °C (lit.1 mp 128-130 °C). Rf 0.31 (1:10 MeOH/CHCl3). 1H NMR (300 MHz, DMSO-d6) δ 5.06 (s, CH2Ph), 5.18 (d, J = 8.1 Hz, CH), 7.30-7.43 (m, 2 PhH), 8.14 (d, J = 8.1 Hz, NH); 13C NMR (75 MHz, DMSO-d6) δ 58.0 (CH), 65.6 (OCH2Ph), 127.7, 127.8, 127.9, 128.3, 128.4, 136.9, 137.1 (2 C6H5), 155.8 (NC(O)O), 172.0 (CHC(O)), one aromatic peak was not detected and is believed to overlap with nearby signals. |
35% | With sodium hydroxide at 0 - 20℃; for 14h; | |
With sodium hydroxide | ||
With sodium hydroxide In tetrahydrofuran; water Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With ammonium formate In methanol at 60℃; for 1.5h; Inert atmosphere; Schlenk tube; | 28 Synthesis of DL-2-phenylglycine Examples 28 Synthesis of DL-2-phenylglycine 751 mg (5.0 mmol) of benzoyl formate (MW: 150.13), 946 mg (15.0 mmol) of ammonium formate (MW: 63.06), and 5.90 mg (0.01 mmol, S/C=500) of the iridium catalyst Ir-7 (MW: 590.13) were introduced in a 20-mL Schlenk tube and subjected to argon-gas replacement. 5 mL of dehydrated methanol was added and the mixture was stirred while heating at 60° C. for 1.5 hr. After distillation of the solvent, a crystal was collected by filtration, washed with methanol, dried under reduced pressure to give 718 mg of DL-2-phenylglycine (95% yield). |
95% | Stage #1: Benzoylformic acid With ammonium formate In methanol at 80℃; for 0.166667h; Inert atmosphere; Stage #2: With formic acid; C29H32ClIrNO; triethylamine In methanol at 80℃; | 3 Example 3 - General procedure for the transfer hydroqenative reductive amination using ammonium formate Example 3 - General procedure for the transfer hydroqenative reductive amination using ammonium formate Ketone (0.5 mmol) and HCOONH4 (5 mmol) were dissolved in MeOH (2ml) in a carousel reaction tube. The mixture was than degassed and stirred for 10 minutes at 80 °C under nitrogen. HCOOH/NEt3 azeotrope (0.5 ml) and catalyst solution (1 ml) (prepared by dissolving catalyst (0.5 μηιοΙ) in MeOH (1 ml)) were then introduced. The resulting mixture was stirred at 80 °C for the time indicated. The reaction was quenched with water, basified with aqueous KOH solution and extracted with DCM. The solvent was then removed under vacuum. The crude product was dissolved in ethanol (10 ml) and 6 N HCI solution (5 ml) was than added. The mixture was refluxed for 6 hrs. Ethanol was then removed under vacuum and the resultant aqueous layer was washed with ethyl acetate to remove impurities. The aqueous layer was basified with a KOH solution and extracted with DCM. The organic layers were combined and dried over sodium sulphate. The final product was obtained after the evaporation of solvent under vacuum. |
95% | With 4-methoxy-N-(1-(naphthalen-2-yl)ethylidene)aniline; ammonium formate In methanol at 80℃; for 12h; Inert atmosphere; chemoselective reaction; |
95% | Stage #1: Benzoylformic acid With ammonium formate In methanol at 80℃; for 0.166667h; Inert atmosphere; Stage #2: With formic acid; 4-methoxy-N-(1-(naphthalen-2-yl)ethylidene)aniline; triethylamine In methanol at 80℃; Inert atmosphere; | 3 General procedure: Ketone (0.5 mmol) and HCOONH4 (5 mmol) were dissolved in MeOH (2 ml) in a carousel reaction tube. The mixture was than degassed and stirred for 10 minutes at 80° C. under nitrogen. HCOOH/NEt3 azeotrope (0.5 ml) and catalyst solution (1 ml) (prepared by dissolving catalyst (0.5 μmol) in MeOH (1 ml)) were then introduced. The resulting mixture was stirred at 80° C. for the time indicated. The reaction was quenched with water, basified with aqueous KOH solution and extracted with DCM. The solvent was then removed under vacuum. The crude product was dissolved in ethanol (10 ml) and 6 N HCl solution (5 ml) was than added. The mixture was refluxed for 6 hrs. Ethanol was then removed under vacuum and the resultant aqueous layer was washed with ethyl acetate to remove impurities. The aqueous layer was basified with a KOH solution and extracted with DCM. The organic layers were combined and dried over sodium sulphate. This general reaction procedure was then applied to the following reductive amination reactions using catalyst 2c in methanol, the results for which are presented in Table 4D below. |
85% | With formic acid; C26H34ClIrN4O; ammonium formate In methanol at 80℃; for 4h; Inert atmosphere; Schlenk technique; | |
81% | With ammonium formate In methanol at 50℃; for 1.5h; | |
74% | With formic acid; ammonium formate; C21H24ClIrN2O In methanol for 8h; Inert atmosphere; Schlenk technique; Reflux; | |
69% | With (S)-2-amino-(2-chlorophenyl)ethanoic acid In water; acetonitrile at 50℃; for 36h; Reflux; Inert atmosphere; | |
29% | With iron sulfide; ammonium carbonate In water at 100℃; for 144h; | |
With ammonia; iron(II) sulfate | ||
With rac-cysteine; ammonia | ||
With ammonium hydroxide; palladium Hydrogenation; | ||
Multi-step reaction with 2 steps 1: ammonium formate / 3,7-dimethyl-10-p-tolyl-5-deazaflavin / 25 h / 120 °C 2: 6 M aq. HCl / Heating | ||
Multi-step reaction with 3 steps 1: NH3 / methanol / Heating 2: HCl / methanol / hygroscopic 3: 55 percent / Bz1QH / methanol / 24 h / Heating; Biomimetic reduction,use of Bz1NH no product | ||
With α-transaminase |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: phenylglycin With sodium tetrahydroborate; iodine In tetrahydrofuran; methanol for 18h; Reflux; Stage #2: With potassium hydroxide In dichloromethane; water at 20℃; for 4h; | 4.2.1 Synthesis of (R,S)4-phenyloxazolidin-2-one 13 To a solution of 2.5g (66.0mmol) of NaBH4 in 125ml of THF at 0°C, 8.4g of I2 (33.0mmol) dissolved in the minimum amount of THF, were slowly added. When the solution turns white, 5.0g of (R,S)-phenylglycine were added. The mixture was heated under reflux for 18h under TLC monitoring (CH2Cl2/EtOH 9:1). The solution was allowed to cool then added of 4ml of MeOH until it turns clear. The solvents were removed under reduced pressure. (0031) The solid residue has been taken with 60ml of a KOH 20% acq. solution and allowed to stir for 4h at room temperature. CH2Cl2 was added and the organic phase was separated, washed with water, dried with Na2SO4 and concentrated in vacuum to afford 4.3g (95%) of (R,S)-phenylglycinol 12 as a light-yellow oil. (0032) 1H NMR (CDCl3-TMS) ppm (δ): 2.84 (broad s., 3H, NH2+OH); 3.46 (m, 1Ha, CH2); 3.56 (m, 1Hb, CH2); 3.87 (m, 1H, CH); 7.20 (m, 5H, arom.). MS: m/z 138 [MH+]. |
87% | With lithium borohydride; sulfuric acid In tetrahydrofuran for 24h; Ambient temperature; | |
With lithium aluminium tetrahydride |
Multi-step reaction with 2 steps 1: 92 percent 2: 72 percent / LiAlH4 | ||
With sodium tetrahydroborate; iodine In tetrahydrofuran Reflux; | ||
11 g | With sodium tetrahydroborate; sulfuric acid In tetrahydrofuran at 0℃; for 15h; Inert atmosphere; Reflux; | |
Multi-step reaction with 2 steps 1: thionyl chloride / Cooling with ice; Reflux 2: sodium tetrahydroborate / methanol / 5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: phenylglycin With sulfuric acid In 1,4-dioxane at -78℃; Stage #2: isobutene In 1,4-dioxane at 20℃; for 48h; Sealed tube; | Intermediate 21tert-Butyl 2-amino-2-phenylacetate (1-21) A stirred suspension of phenylglycine (2.0 g, 13.2 mmol) and concentrated sulphuric acid (2.0 mL) in dioxane (15 mL) was cooled to -78°C. iso-B utylene was gently bubbled through the suspension, until the volume of solution was doubled, after which the reaction vessel was sealed and allowed to warm to ambient temperature. The reaction was allowed to stir for 48 hours and subsequently concentrated under reduced pressure; the resulting crude was partitioned between diethyl ether (2 x 30 mL) and 2 N aqueous solution of sodium hydroxide (60 mL). The resulting organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure to yield the titlecompound as a clear oil which crystallised on standing (2.63 g, 96%).‘H NMR (400 MHz, CDC13): ö 7.39-7.24 (m, 5 H), 4.48 (s, 1 H), 1.39 (s, 9 H). |
96% | With sulfuric acid In 1,4-dioxane at -78 - 20℃; for 48h; Sealed tube; | Intermediate 21. tert-Butyl 2-amino-2-phenylacetate (I-21) Intermediate 21. tert-Butyl 2-amino-2-phenylacetate (I-21) A stirring suspension of phenylglycine (2.0 g, 13.2 mmol) and concentrated sulfuric acid (2.0 mL) in dioxane (15 mL) was cooled to -78° C. iso-Butylene was gently bubbled through the suspension, until the volume of solution was doubled, after which the reaction vessel was sealed and allowed to warm to ambient temperature. The reaction was allowed to stir for 48 hours and subsequently concentrated under reduced pressure; the resulting crude was partitioned between diethyl ether (2*30 mL) and 2 N aqueous solution of sodium hydroxide (60 mL). The resulting organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure to yield the title compound as a clear oil which crystallised on standing (2.63 g, 96%). 1H NMR (400 MHz, CDCl3): δ 7.39-7.24 (m, 5H), 4.48 (s, 1H), 1.39 (s, 9H). |
96% | With sulfuric acid In 1,4-dioxane at -78 - 20℃; for 48h; Sealed tube; |
With sulfuric acid In 1,4-dioxane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In acetic acid at 100℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In water; N,N-dimethyl-formamide; at 20℃; | General procedure: To a solution of amino acid (50 mmol) in a 50 mL solution (25 mL DMF and 25 mL H2O), 52 mmol of acetic anhydride and triethylamine (60 mmol, 6.06 g) were added. The solution was stirred at room temperature overnight. After reaction, the solution was evacuated at reduced pressure to remove DMF. The residue was added to 30 mL of H2O, stirred at rt for 40 min, after which the pH value of the solution was changed to 7.0 with a solution of sodium carbonate and extracted with 20 mL of ethyl acetate three times. The combined organic solution was washed with saturated brine and then dried over anhydrous magnesium sulfate. The organic solution was evacuated to remove the organic solvent, and the residue was chromatographed to afford pure amino acid amides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride; at 0℃; for 6h; | A solution of 151 grams (1 mol) Compound 1 in 1.5 methanol was mixed with 2 molar equivalents (146 mE) of thionyl chloride (50C12) at 0 C. under stirring. Afier 6 hours, the solvent was evaporated by vacuum to give Compound 2 in a quantitative yield. |
94.3% | With hydrogenchloride; at 18 - 22℃; for 18h; | DL-alpha-phenylglycine (394.7 g, 2.611 mol) and a solution of methanol/HCl 4.3 N (3940 mL, 16.942 mol) were placed in a 5 L glass reactor and the granulate suspension was stirred at room temperature (20 +/- 2 C) for 18 hours, with its conversion into a clear solution being observed after approximately 4 hours and its conversion into a cloudy solution (fine suspension) after 8-10 hours. The mixture was concentrated at reduced pressure to an approximate volume of 1,0 L, with approximately 3.3L having been distilled. In this way, a thick, white suspension was obtained which was cooled to 20 +/- 1 C and was filtered, with the filter being washed with methanol (300 mL). The resulting solid was dried at 60 C and atmospheric pressure to constant weight (455,8 g). The filtrate was concentrated again under reduced pressure to an approximate volume of 135 mL, with approximately 600 mL having been distilled. The thick, natural coloured suspension was cooled to 20 +/- 1 C and was filtered, with the filter being washed with methanol (50 mL). The resulting solid was dried at 60 C and atmospheric pressure to constant weight (40.4 g). Both solids contained the title product (IV) (496.2 g, 94.3% yield).1H NMR (200 MHz, CD3OD)delta:4.01 (s, 3 H, CH3), 5.11 (s, 3 H, NH3+), 5.44 (s, 1 H, CH), 7.66 (s, 5 H, Ar-H). |
With thionyl chloride;Inert atmosphere; Cooling; Reflux; | INTERMEDIATE 103-phenyl- 1.4-diazaspirof 4.5]dec-3-en-2-oneStep A. 2-amino-2-phenylacetamide hydrochloride.To ice-chilled methanol (300 mL) under argon, thionyl chloride (50 mL, 660 mmol) was carefully added dropwise over 30min. Then, phenylglycine (50 g, 330 mmol) was added. The ice-bath was removed and the reaction mixture was heated to reflux for 16h. The reaction was then evaporated under reduced pressure. Diethyl ether (200 mL) was added followed by filtration to give the product provided as the hydrochloride salt. ^H NMR (DMSO- d6, 400 MHz) delta: 9.24 (s, 3H), 7.49-7.51 (m, 2H), 7.40-7.41 (m, 3H), 5.20 (s, IH), 3.65 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium hydroxide In dichloromethane at 5 - 20℃; for 0.833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydroxide; sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; | |
97% | With sodium hydroxide | 2 The synthesis of azido-PG01 derivative M1 .5 began with EDC coupling of 4-azidoaniline with Boc-Me-aminophenylglycine M1 .1 . N-Boc deprotection of M1 .2 gave amine M1 .3 which was coupled to 3- indole acetic acid M1 .4 with EDC (Scheme 2) to give the targeted photoaffinity labeled derivative M1 .5. Care was taken to avoid heat and light exposure to prevent decomposition of the azide. |
92% | With sodium hydroxide; triethylamine In water; acetonitrile at 0 - 20℃; for 1h; | 1.B1 Experiment 1: B1 N-Tert-butoxvcarbonv [DL-PHENVL] glycine [N-TERT-BUTOXYCARBONYL DL-PHENYL GLYCINE] was isolated as a white solid (7. 61 g, 92%) from DL-2-phenylglycine (5. 0g, 33. [1MMOL), 1N NAOH (132.] 4mL, 132. [4MMOL)] and (BOC) 20 (19. [0ML,] 82. [7MMOL).] |
92% | With sodium hydroxide In water | 4.B4 Example 4; B4; N-Tert-butoxycarbonyl-DL-phenylglycine [N-TERT-BUTOXYCARBONYL DL-PHENYL GLYCINE] was isolated as a white solid (7.61g, 92%) from DL-2-phenylglycine (5. 0g, 33. [1 MMOL), 1 N NAOH] (132.4mL, 132. [4MMOL)] and (BOC) 20 (19. 0mL, 82. [7MMOL).] |
90.4% | Stage #1: di-<i>tert</i>-butyl dicarbonate; phenylglycin With sodium hydroxide In tert-butyl methyl ether; water at 20 - 40℃; for 6h; Stage #2: With hydrogenchloride In tert-butyl methyl ether; water | |
72% | With sodium hydrogencarbonate; sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 24.1667h; | Intermediate 41. 2-((tert-Butoxycarbonyl)amino)-2-phenylacetic acid (I-41) Intermediate 41. 2-((tert-Butoxycarbonyl)amino)-2-phenylacetic acid (I-41) Phenylglycine (1.51 g, 10 mmol) was dissolved in a mixture of dioxane and water (2:1, 30 mL) and 1.0 N aqueous sodium hydroxide, and the resulting mixture was cooled to 0° C. Di-tert-butyl dicarbonate (3.27 g, 15 mmol) and sodium hydrogen carbonate (0.84 g, 10 mmol) were added in one portion and the mixture was stirred at 0° C. for 10 minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for 24 h. After this time, the reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The aqueous layer was acidified with 1.0 N aqueous potassium hydrogen sulfate solution (pH 2.5) and washed with ethyl acetate (2*40 mL). The combined organic fractions were dried over magnesium sulfate and the solvent was removed in vacuo to yield the title compound (1.8 g, 72%) as a clear oil, which solidified on standing. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.47-7.27 (m, 5H), 5.48* or † (dd, J=72.0 Hz, 6.5 Hz, 1H), 5.13*or † (d, J=5.6 Hz, 1H), 3.71 (s, 1H), 1.43 (s, 3H), 1.21 (s, 6H). * and † refer to different isomers. |
72% | With sodium hydrogencarbonate; sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 24.1667h; | 2-((tert-Butoxycarbonyl)amino)-2-phenylacetic acid (1-41) Phenyiglycine (1.51 g, 10 mmo 1) was dissolved in a mixture of dioxane and water (2:1, 30 mL) and 1.0 N aqueous sodium hydroxide, and the resulting mixture was cooled to 0°C. Di-tert-butyl dicarbonate (3.27 g, 15 mmol) and sodium hydrogen carbonate (0.84 g, 10 mmol) were added in one portion and the mixture was stirred at 0°C for 10 minutes.The ice bath was removed and the reaction mixture was stirred at room temperature for 24h. After this time, the reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The aqueous layer was acidified with 1.0 N aqueous potassium hydrogen sulfate solution (pH 2.5) and washed with ethyl acetate (2 x 40 mL). The combined organic fractions were dried over magnesium sulfate and thesolvent was removed in vacuo to yield the title compound (1.8 g, 72%) as a clear oil,which solidified on standing.‘H NMR (400 MHz, CDC13): ö 8.08 (s, 1 H), 7.47-7.27 (m, 5 H), 5.48* or (dd, J= 72.0 Hz, 6.5 Hz, 1 H), 5•13* ort (d, J = 5.6 Hz, 1 H), 3.71 (s, 1 H), 1.43 (s, 3 H), 1.21 (s, 6 H). * and refer to different isomers. |
72% | With sodium hydrogencarbonate; sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 24h; | |
67% | With sodium hydroxide In 1,4-dioxane at 20℃; for 12h; | |
43% | Stage #1: di-<i>tert</i>-butyl dicarbonate; phenylglycin With sodium hydroxide In water; acetone at 20℃; for 1h; Stage #2: With hydrogenchloride In water | 2 A mixture of 2-amino-2-phenylacetic acid (2.00 g, 13.2 mmol) and di-tert-butyl dicarbonate (3.47 g, 15.9 mmol) in sodium hydroxide (50 ml, 100 mmol) and acetone (50 ml) was stirred at RT for 1 hr. Acetone was removed under reduced pressure, the aqueous phase was acidified to pH about 5 with HCl and extracted twice with EtOAc. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to provide 2-(tert-butoxycarbonylamino)-2-phenylacetic acid (1.42 g; 43% yield). The compound was used in the next step without any further purification. |
43% | With sodium hydroxide In acetone at 20℃; for 1h; | 2 A mixture of 2-amino-2-phenylacetic acid (2.00 g, 13.2 mmol) and di-tert-butyl dicarbonate (3.47 g, 15.9 mmol) in sodium hydroxide (50 ml, 100 mmol) and acetone (50 ml) was stirred at RT for 1 hour. Acetone was removed under reduced pressure, the aqueous phase was acidified to pH about 5 with HCl and extracted twice with EtOAc. The organic phase was dried over Na2SO4, filtered, and evaporated to dryness to provide 2-(tert-butoxycarbonylamino)-2-phenylacetic acid (1.42 g; 43% yield). The compound was used in the next step without any further purification. |
30 Alpha-[(tert-Butoxycarbonyl)amino]phenylacetic Acid PREPARATION 30 Alpha-[(tert-Butoxycarbonyl)amino]phenylacetic Acid The title compound was prepared by a similar method to Preparation 1 from alpha-aminophenylacetic acid and di-t-butyldicarbonate to afford alpha-[(tert-butoxycarbonyl)amino]phenylacetic acid as a white solid. 1H-NMR (CDCl3) δ: 7.40 (5H, m), 5.40-5.10 (1H, bs), 1.50-1.20 (9H, bs). | ||
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; | ||
With triethylamine In 1,4-dioxane; water | ||
With sodium hydrogencarbonate In 1,4-dioxane; water | ||
With sodium hydrogencarbonate | 5 General procedure: N-Boc-Phenylglycine (compound 2, Figure 9) was prepared according to the literature,1 | |
With triethylamine In tetrahydrofuran; water at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 82 percent / K2CO3, TEBA / acetonitrile / 24 h / 25 - 80 °C 2: 20percent aq. KOH, TEBA / CH2Cl2 / 168 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; at 20℃; | Commercially available racemic phenylglycine (lg) was stirred overnight at room temperature in dry methanol (3ml) containing trimethylsilyl chloride (Me3SiCl) (3-5 equivalents). The solvent was removed in vacuo to obtain the corresponding amino acid methyl ester hydrochloride as a white solid with no need for further purification. | |
In methanol; at 20℃; | Commercially available racemic phenylglycine [(LG)] was stirred overnight at room temperature in dry methanol (3ml) containing trimethylsilyl chloride [(ME3SICL)] (3-5 equivalents). The solvent was removed in vacuo to obtain the corresponding amino acid methyl ester hydrochloride as a white solid with no need for further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; trichlorophosphate; at 0℃; for 3h; | B. N-[4-(dimethylaminoimino)-2-fluorophenyl]-2-phenyl-2-(4- chlorophenylaminocarbonylamino)-acetamide; [0347] To a solution of DL-phenylglycine (2.51 g, 10.0 mmol) and 4-amino-3-fluoro- benzonitrile (1.36 g, 10.0 mmol) in pyridine (25 mL) cooled in an ice-bath, POCl3 (2.30 mL, 25.0 mmol) was added. The mixture was stirred for 3h. EtOAc and H2O were added. The organic layer was separated, washed with brine, dried over MgSO4, concentrated in vacuo to give a solid (3.15 g), which was pure enough for the next step.[0348] To a solution of the solid (1.50 g, 4.06 mmol) in CH2Cl2 (10 mL), TFA (6 mL) was added. After it was stirred for 30 min, it was then concentrated in vacuo. The residue was dissolved in THF (15 mL). To the solution, TEA (1.09 mL, 7.84 mmol) was added, followed by addition of 4-chlorophenylisocyanate (0.626 g, 4.07 mmol). After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by HPLC to give a powder (0.842 g). MS 423.1 (M+H) and 445.1 (M+Na).[0349] To a solution of the powder (0.842 g, 1.99 mmol) in pyridine (10 mL) and TEA (1.0 mL), H2S gas was bubbled until saturation was reached. The solution was then stirred at room temperature overnight. It was concentrated in vacuo. The residue was dissolved in acetone (10 mL). Iodomethane (0.620 mL, 9.95 mmol) was added. It was heated at reflux for 30 min, EPO <DP n="70"/>then concentrated in vacuo. The residue was dissolved in MeOH (28 mL).To a seventh of the solution (4 mL, 0.284 mmol), a pre-mixed dimethylamine (2M in THF, 0.713 niL, 1.42 mmol) and HOAc (0.122 mL, 2.14 mmol) were added. The mixture was then stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give white powder (15 mg). MS 468.2 and 470.1 (M+H, Cl pattern). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With hydrogenchloride; sodium hydroxide In tetrahydrofuran; water | R.13 N-(tert-butoxycarbonyl)-D-2-phenylglycine REFERENCE EXAMPLE 13 N-(tert-butoxycarbonyl)-D-2-phenylglycine To a cooled (ice bath) solution of D-2-phenylglycine (15 g, 99.2 mmol) in water (104 mL) and tetrahydrofuran (104 mL), was added 1N NaOH (104 mL). Keeping the flask in the ice bath, di-tert-butyl dicarbonate was added (22.75 g) and the reaction mixture was stirred at room temperature for 2 h. Tetrahydrofuran was evaporated and the resulting solution was extracted with chloroform at basic pH. After acidifying with 5N HCl and filtering the solid precipitated, 17.77 g of the title product was obtained as a white solid (yield: 71%). IR (film) ν: 3200-2300, 1699, 1591, 1485, 1320, 1285, 1268, 1234, 1218, 1202, 1073, 831, 770, 752 cm-1; 1 H NMR (80 MHz, DMSO-d6) δ (TMS): 7.33 (s, 5H, Ar), 5.06 (d, J =8.2 Hz, 1H, CH), 1.37 (s, 9H, CH3 (BOC)). |
With sodium hydroxide In 1,4-dioxane; water | 2.1 N-tert.-Butoxycarbonyl-D-2-phenylglycine Stage 1 N-tert.-Butoxycarbonyl-D-2-phenylglycine 75.6 g=0.5 mol of D-2-phenylglycine, melting point: 302° C. (decomposition), [α]D20 =-154.4° (c=1/1N HCl) are dissolved in a solution of 20 g (=0.5 mol) of NaOH in 500 ml of water, the solution is cooled to +4° C. in an ice-water bath and a solution of 120.1 g (=0.55 mol) of di-tert.-butyl dicarbonate in 1,000 ml of dioxane is added, with stirring. When the addition of the di-tert.-butyl dicarbonate has ended, the mixture is subsequently stirred at room temperature for a further 10 hours, until the evolution of CO2, monitored by a bubble counter, has ended. After the contents of the flask have been acidified to pH 2 with dilute hydrochloric acid, the N-tert.-butoxycarbonyl-D-2-phenylglycine is extracted with ethyl acetate and the ethyl acetate phase is extracted 3 times by shaking with 100 ml of water. The organic phase is then dried over Na2 SO4 and filtered, and the filtrate is concentrated in vacuo. An oil remains, a small sample of which is induced to crystallise with petroleum ether (40°-60° C.). Petroleum ether and the seed crystals are now added to the main portion, and the mixture is stirred vigorously. Crystallisation is complete after a short time. The crystals are filtered off with suction and dried in vacuo to give 112.4 g (=89.5% of theory) of N-tert.-butoxycarbonyl-D-2-phenylglycine, melting point: 90°-91° C., [α]D20 =-129.2° (c=1/DMF), C13 H17 NO4 [251.3]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
553 g (87%) | With sodium hydroxide; acetic anhydride; In water-are; water; | (a) D-alpha-Acetamido-alpha-phenylacetic acid (2a) 500 g (3.31 mol) of D-alpha-amino-alpha-phenylacetic acid are suspended in 6 liters of water, and the suspension is cooled to 10 C. and 132 g (3.31 mol) of NaOH dissolved in 1,000 ml of water are added. After 15 minutes, 675 g (6.62 mol) of acetic anhydride and then 397 g (9.93 mol) of NaOH--dissolved in 1,000 ml of water--are poured into the clear solution at 0 C., stirring rapidly. The temperature increases from 0 C. to 30 C. during this. The solution is stirred for a further 20 minutes at pH 9 to 10 in an ice/sodium chloride bath and is then acidified to pH 1 with concentrated hydrochloric acid (about 1 liter). The suspension is then stirred for 10 minutes, cooled to 10 C., filtered with suction and washed with 10 liters of water. The product is dried over KOH in vacuo. Yield: 553 g (87%). C10 H11 NO3 (193.2). Melting point 190-191 C. [alpha]58920 =-218.6 (C=1, C2 H5 OH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In tetrahydrofuran; ethanol; water dropwise addn. of 1 M soln. of (+)(C10H17)2BOCH3 in THF to phenylglycine in ethanol/H2O (1:1), stirring at 80-100°C; control of completion of the reaction by (11)B-NMR, removing of solvent under vacuum (1-2.0 mm), treating with methanol, filtration, washing with hexane or ether; | |
87% | In tetrahydrofuran; dimethyl sulfoxide dropwise addn. of 1 M soln. of (+)(C10H17)2BOCH3 in THF to phenylglycine in DMSO, stirring at 80-100°C; control of completion of the reaction by (11)B-NMR, removing of solvent under vacuum (1-2.0 mm), treating with methanol, filtration, washing with hexane or ether; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 4-phenylnaphthalene-1,2-dione In water; acetonitrile at 50℃; for 60h; | |
85% | With ammonium peroxydisulfate In water; 1,2-dichloro-ethane at 80℃; for 10h; Sealed tube; | |
83% | With iodine; trifluoroacetic acid In dimethyl sulfoxide at 120℃; for 10h; |
57% | With phosphotungstic acid 44-hydrate; alloxan monohydrate In N,N-dimethyl-formamide at 110℃; | |
49% | With copper(I) 2-hydroxy-3-methylbenzoate; oxygen; ascorbic acid In N,N-dimethyl acetamide at 55℃; for 20h; chemoselective reaction; | |
30% | With oxone; iodine In dimethyl sulfoxide at 95℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tert.-butylhydroperoxide; iodine In ISOPROPYLAMIDE; water at 80℃; for 18h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With pyridine; iodine at 120℃; for 12h; chemoselective reaction; | |
80% | With oxygen; copper(II) bis(trifluoromethanesulfonate) at 100℃; for 20h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 1-(4-methoxyphenyl)ethanone With iodine; dimethyl sulfoxide at 110℃; for 0.75h; Stage #2: phenylglycin at 110℃; for 0.333333h; | 16 General procedure: A mixture of 1-(1H-indol-3-yl)ethanone1(0.5mmol), I2(1.0mmol) in DMSO (3.0mL) was stirred at 110°C for 45min till almost full conversion of the substrates was indicated by TLC analysis, then added 2-aminobutanoic acid2b(1.0mmol) and stirred at 110°C for 15min. Then added 50mL water and 30mL saturated brine solution to the mixture and extracted with EtOAc three times (3×50mL). The extract was washed with 10% Na2S2O3solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/EtOAc=4:1) to afford the product3bas a yellow solid. 4.3.2 2-Ethyl-5-(1H-indol-3-yl)oxazole (3b pimprinethine) 4.3.16 5-(4-Methoxyphenyl)-2-phenyloxazole (5b uguenenazole) Yield 88%; white solid; mp=78-79 °C. IR (KBr): 3057, 2969, 2840, 1656, 1607, 1498, 1252, 1173, 1021 cm-1. 1H NMR (600 MHz, CDCl3) δ (ppm) 8.09 (d, J=7.2 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.50-7.41 (m, 3H), 7.32 (s, 1H), 6.96 (d, J=8.4 Hz, 2H), 3.84 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 160.48, 159.76, 151.26, 130.08, 128.74, 127.47, 126.09, 125.69, 121.83, 120.79, 114.34, 55.31. HRMS (APCI): m/z [M+H]+ calcd for C16H14NO2: 252.1019; found: 252.1021. |
85% | With iodine; 4-aminobenzene sulfonic acid In dimethyl sulfoxide at 100℃; for 5h; | Typical Procedure for the Preparation of 2,5-Diphenyloxazole General procedure: A test tube was charged with 1a (0.32 mmol), 2a (0.38 mmol), I2 (2.0 equiv.) and PABS (0.5equiv.). Then 2 mL DMSO was added to the reaction system. The reaction was stirred at 100 oCfor 5 h. After cooling to room temperature, the solvent diluted with 10 mL ethyl acetate andwashed with 5 mL brine and dried over anhydrous Na2SO4. After the solvent was evaporated invacuo, the residues were purified by column chromatography, eluting with petroleum ether/EtOAc to afford pure 3aa. |
58% | With oxone; iodine In dimethyl sulfoxide at 95℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 20℃; for 2h; | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With iodine; 4-aminobenzene sulfonic acid In dimethyl sulfoxide at 100℃; for 5h; | Typical Procedure for the Preparation of 2,5-Diphenyloxazole General procedure: A test tube was charged with 1a (0.32 mmol), 2a (0.38 mmol), I2 (2.0 equiv.) and PABS (0.5equiv.). Then 2 mL DMSO was added to the reaction system. The reaction was stirred at 100 oCfor 5 h. After cooling to room temperature, the solvent diluted with 10 mL ethyl acetate andwashed with 5 mL brine and dried over anhydrous Na2SO4. After the solvent was evaporated invacuo, the residues were purified by column chromatography, eluting with petroleum ether/EtOAc to afford pure 3aa. |
87% | Stage #1: 1-(3,4-dimethoxyphenyl)ethanone With iodine; dimethyl sulfoxide at 110℃; for 0.75h; Stage #2: phenylglycin at 110℃; for 0.333333h; | 17 General procedure: A mixture of 1-(1H-indol-3-yl)ethanone1(0.5mmol), I2(1.0mmol) in DMSO (3.0mL) was stirred at 110°C for 45min till almost full conversion of the substrates was indicated by TLC analysis, then added 2-aminobutanoic acid2b(1.0mmol) and stirred at 110°C for 15min. Then added 50mL water and 30mL saturated brine solution to the mixture and extracted with EtOAc three times (3×50mL). The extract was washed with 10% Na2S2O3solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/EtOAc=4:1) to afford the product3bas a yellow solid. 4.3.2 2-Ethyl-5-(1H-indol-3-yl)oxazole (3b pimprinethine) 4.3.17 5-(3,4-Dimethoxyphenyl)-2-phenyloxazole (5c balsoxine) Yield 87%; white solid; mp=95-97 °C. IR (KBr): 3079, 3000, 2955, 2929, 2831, 2055, 1827, 1638, 1545, 1508, 1455, 1350, 1281, 1285, 1228, 1138, 1007, 1027 cm-1. 1H NMR (600 MHz, CDCl3) δ (ppm) 8.10 (d, J=7.2 Hz, 2H), 7.47 (m, 3H), 7.34 (d, J=2.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.19 (s, 1H), 6.93 (d, J=8.4 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 160.55, 151.22, 149.37, 149.25, 130.12, 128.73, 127.41, 126.11, 122.14, 120.96, 117.19, 111.39, 107.33, 55.95. MS (EI): m/z (%) 14 =282.25 (19), 281.24 (100), 266.20 (26), 238.25 (11), 107.17 (9). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With dipotassium peroxodisulfate; water; copper diacetate; palladium diacetate; In dimethyl sulfoxide; at 120℃; for 24h;Inert atmosphere; | General procedure: A mixture of 1 (0.5 mmol), 2 (0.6 mmol), DMSO (5% H2O aq, 5mL), Pd(OAc)2 (5 mol%), Cu(OAc)2 (10 mol%), and K2S2O8 (2equiv) was stirred at 120 C under Ar atmosphere for 24 h. Thereaction mixture was washed with H2O, and the aqueous phasewas extracted with EtOAc (3×). The combined organic layer waswashed with brine, dried over Na2SO4, and evaporated underreduced pressure. The crude product was purified by silica gelcolumn chromatography to give the corresponding products(3a-d,7b 3f-k,7b 3n-s7b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With dipotassium peroxodisulfate; water; copper diacetate; palladium diacetate; In dimethyl sulfoxide; at 120℃; for 24h;Inert atmosphere; | General procedure: A mixture of 1 (0.5 mmol), 2 (0.6 mmol), DMSO (5% H2O aq, 5mL), Pd(OAc)2 (5 mol%), Cu(OAc)2 (10 mol%), and K2S2O8 (2equiv) was stirred at 120 C under Ar atmosphere for 24 h. Thereaction mixture was washed with H2O, and the aqueous phasewas extracted with EtOAc (3×). The combined organic layer waswashed with brine, dried over Na2SO4, and evaporated underreduced pressure. The crude product was purified by silica gelcolumn chromatography to give the corresponding products(3a-d,7b 3f-k,7b 3n-s7b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With dipotassium peroxodisulfate; water; copper diacetate; palladium diacetate; In dimethyl sulfoxide; at 120℃; for 24h;Inert atmosphere; | General procedure: A mixture of 1 (0.5 mmol), 2 (0.6 mmol), DMSO (5% H2O aq, 5mL), Pd(OAc)2 (5 mol%), Cu(OAc)2 (10 mol%), and K2S2O8 (2equiv) was stirred at 120 C under Ar atmosphere for 24 h. Thereaction mixture was washed with H2O, and the aqueous phasewas extracted with EtOAc (3×). The combined organic layer waswashed with brine, dried over Na2SO4, and evaporated underreduced pressure. The crude product was purified by silica gelcolumn chromatography to give the corresponding products(3a-d,7b 3f-k,7b 3n-s7b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With dipotassium peroxodisulfate; water; copper diacetate; palladium diacetate In dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere; | Synthesis of 3a-v General procedure: A mixture of 1 (0.5 mmol), 2 (0.6 mmol), DMSO (5% H2O aq, 5mL), Pd(OAc)2 (5 mol%), Cu(OAc)2 (10 mol%), and K2S2O8 (2equiv) was stirred at 120 °C under Ar atmosphere for 24 h. Thereaction mixture was washed with H2O, and the aqueous phasewas extracted with EtOAc (3×). The combined organic layer waswashed with brine, dried over Na2SO4, and evaporated underreduced pressure. The crude product was purified by silica gelcolumn chromatography to give the corresponding products(3a-d,7b 3f-k,7b 3n-s7b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With iodine; 4-aminobenzene sulfonic acid; In dimethyl sulfoxide; at 100℃; for 5h; | A test tube was charged with 1a (0.32 mmol), 2a (0.38 mmol), I2(2.0 equiv), and PABS (0.5 equiv). Then DMSO (2 mL) was addedto the reaction system. The reaction was stirred at 100 C for 5h. After cooling to r.t., the solvent diluted with EtOAc (10 mL)and washed with brine (5 mL) and dried over anhydrousNa2SO4. After the solvent was evaporated in vacuo, the residueswere purified by column chromatography, eluting with PE-EtOAc to afford pure 3aa as a yellow solid (64 mg, 90%); mp 58-60 C. 1H NMR (400 MHz, CDCl3): delta = 8.11-8.08 (m, 2 H), 7.70-7.68 (m, 2 H), 7.48-7.39 (m, 6 H), 7.30 (t, J = 7.2 Hz, 1 H).13C NMR (100 MHz, CDCl3): delta = 161.02, 151.14, 130.20, 128.81,128.70, 128.31, 127.91, 127.37, 126.18, 124.08, 123.37. ESIHRMS:m/z calcd for C15H12NO [M + H]+: 222.0914; found:222.0916 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With pyridine; iodine at 110℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With di-tert-butyl peroxide; iodine; copper(II) bis(trifluoromethanesulfonate) In toluene at 120℃; for 10h; Sealed tube; | |
92% | With di-tert-butyl peroxide; iodine In toluene at 120℃; for 12h; Sealed tube; | 22 4.3. General procedure for the heterogeneous copper(II)-catalyzedsynthesis of 1,3-disubstituted imidazo[1,5-a]pyridines General procedure: To a 10mL reaction tube were added L-Proline-MCM-41-Cu(OTf)2 (71mg, 0.045mmol), 2-benzoylpyridine 1 (0.3mmol), amino acid 2(0.9mmol), molecular iodine (0.045mmol), DTBP (0.75mmol), and toluene (2mL). The reaction tube was sealed and placed in an oil bath at room temperature. The reaction mixture was stirred at 120 °C for 12 h. After being cooled to room temperature, the reaction mixture was diluted with 15 mL of EtOAc, and filtered. The L-Proline-MCM-41-Cu(OTf)2 complex was washed with EtOAc (25mL) and ethanol (2 5mL), and reused in the next run. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (petroleum ether: EtOAc 15:1-20:1) to provide the desired product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium carbonate In toluene at 120℃; for 12h; Schlenk technique; Sealed tube; | 10 Embodiment 10 In a clean dry 10 ml Schlenk reaction tube, sequentially adding a 5-fluoro-2-nitro-phenol 39 mg, benzene glycine 113 mg, potassium carbonate 75 mg, in order to 1 ml of toluene as a solvent, the reaction tube seal, in the 120 °C reaction under 12 hours. After the reaction, the reaction mixture directly by rotating the evaporimeter turns on lathe does, then the volume ratio of 30:1 of petroleum ether and ethyl acetate as the eluant, by separating by silica gel column, to obtain 48 mg white solid, yield 91%. |
Multi-step reaction with 2 steps 1: potassium carbonate / toluene; water / 20 h / 150 °C / Schlenk technique; Inert atmosphere 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / toluene; water / 8 h / 150 °C / Schlenk technique |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; In toluene; at 140℃; for 24h;Schlenk technique; Sealed tube; | In a clean dry 10 ml Schlenk reaction tube, sequentially adding a 2-nitro-N-methylaniline 38 mg, benzene glycine 113 mg, potassium carbonate 80 mg, in order to 1 ml of toluene as a solvent, the reaction tube seal, in 140 °C reaction under 24 hours. After the reaction, the reaction mixture directly by rotating the evaporimeter turns on lathe does, then the volume ratio of 8:1 of petroleum ether and ethyl acetate as the eluant, by separating by silica gel column, to obtain 39 mg light yellow solid, yield 79percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With palladium; In water; at 130℃; for 20h;Inert atmosphere; Schlenk technique; | In a clean dry 10 ml Schlenk reaction tube, the mass fraction of sequentially adding 10% Pd/C4 . 5 mg, 5-methyl-2-nitro-acetophenone 45 mg, benzene glycine 113 mg, 1 ml of water as a solvent, is condensed on the return is, under the protection of nitrogen 130 o C reaction 20 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 is 40:1) dissolving, through a short silica gel column of column separation, to obtain 54 mg white solid, yield 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With 2,6-Di-tert-butyl-1,4-benzoquinone; oxygen; triethylamine In water; acetonitrile at 70℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With tert.-butylhydroperoxide; diphenyl-phosphinic acid; tetra-(n-butyl)ammonium iodide In dimethyl sulfoxide at 90℃; for 8h; Sealed tube; | Imidazole-Fuse Azaarenes 3; General Procedure General procedure: A sealed tube equipped with a magnetic stirring bar was chargedwith substituted (2-azaaryl)methane 1 (0.3 mmol), α-amino acid 2(0.45 mmol), Ph 2 PO 2 H (0.15 mmol), TBHP (0.6 mmol), and TBAI (0.06mmol) in DMSO (2 mL). The mixture was stirred under air at 90 °C for8 h. Then the mixture was cooled to r.t. and filtered through a shortsilica gel column (EtOAc). The filtrate was diluted with brine (60 mL)and extracted with EtOAc (2 × 30 mL). The combined organic layerswere dried (MgSO 4 ) and the solvent was removed in vacuo to afford aresidue. The residue was purified by column chromatography (silicagel, petroleum ether/EtOAc) to provide the product. |
47% | With ammonium iodide In dimethyl sulfoxide at 100℃; Electrochemical reaction; | |
37% | With tert.-butylhydroperoxide; iodine In N,N-dimethyl-formamide at 80℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With di-tert-butyl peroxide; iodine; In toluene; at 120℃; for 12h;Sealed tube; | General procedure: To a 10mL reaction tube were added L-Proline-MCM-41-Cu(OTf)2 (71mg, 0.045mmol), 2-benzoylpyridine 1 (0.3mmol), amino acid 2(0.9mmol), molecular iodine (0.045mmol), DTBP (0.75mmol), and toluene (2mL). The reaction tube was sealed and placed in an oil bath at room temperature. The reaction mixture was stirred at 120 C for 12 h. After being cooled to room temperature, the reaction mixture was diluted with 15 mL of EtOAc, and filtered. The L-Proline-MCM-41-Cu(OTf)2 complex was washed with EtOAc (25mL) and ethanol (2 5mL), and reused in the next run. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (petroleum ether: EtOAc 15:1-20:1) to provide the desired product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With copper(II) nitrate trihydrate; iodine; In dimethyl sulfoxide; at 60℃; for 5h;Sealed tube; | General procedure: The mixture of phenylacetylene 1a (1.0 mmol), 2-amino-4-methylpentanoic 2c (1.0 mmol) was mixedwith Cu(NO3)2?3H2O (0.5 mmol), and I2(1.0 mmol). The mixture was heated at 60 C in 4 mL of DMSO in asealed vessel for 5 h till almost completed conversion of the substrates monitored by TLC analysis. Then 50mL water was added to the mixture, which was extracted with EtOAc three times (3 × 50 mL). The extractwas washed with Na2S2O3 solution, dried over anhydrous Na2SO4 then the solvent was removed underreduced pressure. The crude product was purified by column chromatography on silica gel (eluent:petroleum ether/EtOAc = 50/1) to afford the product 3ac |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With copper(II) nitrate trihydrate; iodine; In dimethyl sulfoxide; at 60℃; for 5h;Sealed tube; | General procedure: The mixture of phenylacetylene 1a (1.0 mmol), 2-amino-4-methylpentanoic 2c (1.0 mmol) was mixedwith Cu(NO3)2?3H2O (0.5 mmol), and I2(1.0 mmol). The mixture was heated at 60 C in 4 mL of DMSO in asealed vessel for 5 h till almost completed conversion of the substrates monitored by TLC analysis. Then 50mL water was added to the mixture, which was extracted with EtOAc three times (3 × 50 mL). The extractwas washed with Na2S2O3 solution, dried over anhydrous Na2SO4 then the solvent was removed underreduced pressure. The crude product was purified by column chromatography on silica gel (eluent:petroleum ether/EtOAc = 50/1) to afford the product 3ac |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; at 170℃; under 18751.9 Torr; | The 2-amino-phenylacetonitrile aqueous solution (cyanamide) obtained above and potassium carbonate having a mass percentage of 50% by weight207 g of aqueous solution (cyanohydrin: potassium ion = 1.0: 1.5) was simultaneously pumped into the microchannel reactor via a metering pump, 2-amino-phenylethylThe flow rate of the aqueous solution of nitrile ammonia in the microchannel was 7.0 g/min, and the flow rate of the aqueous solution of potassium carbonate in the microchannel was 5.18 g/min.The temperature for controlling the reaction is 170 C, the pressure is 2.5 MPa, and the residence time is 30 min (that is, the time during which the reaction liquid flows through the microchannel).The liquid flowing out is a clear yellowish transparent liquid, and the liquid is subjected to deamination to obtain an aqueous solution of potassium phenylglycine containing potassium carbonate.415.4543g, wherein the mass percentage of phenylglycine is 36.39wt%, and the mass percentage of potassium ion is 14.08wt%,The yield of phenylglycine is 99.9% or more. The obtained hydrolyzate was diluted with water to a potassium ion content of 8.5 wt%, phenylglycolamideThe acid content was 21.97 wt%, and after dilution, 688.11 g of hydrolyzate was obtained.The hydrolyzate obtained above is introduced into carbon dioxide gas, and the pressure of the carbon dioxide gas is 0.2 MPa.And the temperature is 20 C, the stirring speed is 120r / min, the carbon dioxide is neutralized and the end point pH is 8.0, the solid is filtered off, and washed with water.Drying to obtain 115.6860g of phenylglycine product, the main content is 98wt%, the product is in the form of powder, after recrystallization operation,To the crystalline DL-phenylglycine product, the purity is above 99.5 wt%, and the recrystallization mother liquor is recycled. The filtrate is containing benzeneThe aqueous potassium hydrogencarbonate solution of glycine has a mass of 632.5018 g, wherein the mass percentage of potassium ions is 9.25 wt%.The mass percentage of phenylglycine is 5.97 wt%, and the filtrate is decarburized by heating and concentrated to a mass percentage of potassium ion.After 30.0 wt%, 195.0214 g of an aqueous solution of potassium carbonate containing potassium phenylglycine was obtained, wherein the mass percentage of phenylglycineAt 19.36 wt%, the aqueous solution was recycled to the next batch of hydantoin hydrolysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In water; at 178℃; under 18751.9 Torr; for 0.0666667h; | The aqueous <strong>[89-24-7]5-phenylhydantoin</strong> solution (hydantoin) obtained above and the aqueous solution of potassium carbonate having a mass percentage of 50% by weight were 276 g.(Heiin: potassium ion = 1.0:2.0) was simultaneously pumped into the microchannel reactor through a metering pump. The flow rate in the hyane microchannel was 58.9 g/min, and the flow rate of the potassium carbonate aqueous solution in the microchannel was 27.6 g/min. ,The temperature of the control reaction is 178 C, the pressure is 2.5 MPa, and the residence time is 4 min (ie, the time during which the reaction liquid flows through the microchannel).The liquid flowing out is a clear yellowish transparent liquid, and the liquid is subjected to deamination and carbon dioxide to obtain 458.8235 g of an aqueous potassium phenylglycine solution.The mass percentage of phenylglycine is 32.94 wt%, the mass percentage of potassium ion is 17.0 wt%, and the yield of phenylglycine is 99.9% or more.The obtained hydrolyzate was diluted with water to a potassium ion content of 8.5 wt%, and a phenylglycine content of 16.47 wt%, and after dilution, 917.647 g of a hydrolyzate was obtained. The hydrolyzate obtained above is introduced into carbon dioxide gas, the pressure of the carbon dioxide gas is 0.2 MPa, the neutralization temperature is 20 C, and the stirring speed is 120 r/min.The carbon dioxide neutralization end point pH was 8.0, the solid was filtered off with suction, washed with water, and dried to obtain 115.6860 g of phenylglycine product, the main content being 98 wt%.The product is in the form of powder and undergoes recrystallization operation to obtain a crystalline DL-phenylglycine product having a purity of 99.5 wt% or more, and the recrystallization mother liquor is recycled.The filtrate is an aqueous solution of potassium hydrogencarbonate containing phenylglycine. The mass of the filtrate is 901.78 g, wherein the mass percentage of potassium ion is 8.65 wt%, and the mass percentage of phenylglycine is 4.2 wt%.The filtrate was decarburized by heating and concentrated until the mass percentage of potassium ions was about 28.5 wt%, and then recycled to the next batch of hydantohydrolysis. The mass of the mother liquor obtained after decarburization and concentration was 273.698 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In ethanol; water; at 60 - 70℃; | General procedure: To well stirred ethanolic solutions (20 mL) of aldimine ligands (HL1-3), equimolar amounts of metal chlorides and phenyl glycine were gradually added, maintaining the reaction mixture temperature at 60-70 C. The resulting precipitated products were filtered, washed, and dried in vacuum over silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In ethanol; water; at 60 - 70℃; | General procedure: To well stirred ethanolic solutions (20 mL) of aldimine ligands (HL1-3), equimolar amounts of metal chlorides and phenyl glycine were gradually added, maintaining the reaction mixture temperature at 60-70 C. The resulting precipitated products were filtered, washed, and dried in vacuum over silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In ethanol; water; at 60 - 70℃; | General procedure: To well stirred ethanolic solutions (20 mL) of aldimine ligands (HL1-3), equimolar amounts of metal chlorides and phenyl glycine were gradually added, maintaining the reaction mixture temperature at 60-70 C. The resulting precipitated products were filtered, washed, and dried in vacuum over silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In ethanol; water; at 60 - 70℃; | General procedure: To well stirred ethanolic solutions (20 mL) of aldimine ligands (HL1-3), equimolar amounts of metal chlorides and phenyl glycine were gradually added, maintaining the reaction mixture temperature at 60-70 C. The resulting precipitated products were filtered, washed, and dried in vacuum over silica gel. |
Tags: 2835-06-5 synthesis path| 2835-06-5 SDS| 2835-06-5 COA| 2835-06-5 purity| 2835-06-5 application| 2835-06-5 NMR| 2835-06-5 COA| 2835-06-5 structure
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