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CAS No. : | 2935-35-5 | MDL No. : | MFCD00064403 |
Formula : | C8H9NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZGUNAGUHMKGQNY-ZETCQYMHSA-N |
M.W : | 151.16 | Pubchem ID : | 99291 |
Synonyms : |
H-Phg-OH
|
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: | H302-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 |
---|---|---|
94% | With hydrogen In water at 60℃; for 12 h; Autoclave | The selective hydrogenation of the optically active phenyl amino acid was carried out in a magnetically stirred stainless-steel autoclave (100 ml). Prior to the loading of the catalyst, the autoclavewas purged three times with hydrogen to expel the air. Typically, a freshly prepared suspension of nanoRu(at)hectorite (0.01592 mmol Ru, 10 ml H2O) and the appropriate amount of the substrate were carefully transferred into the autoclave under inert atmosphere, and then the autoclave was charged with H2 to the desired pressure. The autoclave was placed into the pre-heated heating mantle and the magnetic stirring was started for the indicated reaction time. After the reaction, the autoclave was cooled down and the pressure was released. The reactor was thoroughly rinsed with 2 N NaOH solution to wash out the entire product (in the case of acidic system, 2 N HCl was used). All the collected solutions were filtered (0.22 mm, PTFE) to remove the catalyst and then treated with diluted HCl (or NaOH) solution to adjust the pH to 5.5, which caused the partial precipitation of the product. The suspensionwas then reduced in vacuo to 10 ml in order to complete the precipitation. The precipitate was filtered off, washed with distilled water and dried in vacuo for 24 h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; at 0℃; for 5h;Reflux; | General procedure: L-amino acids (Glycine, Alanine, Valine, Phenylglycine, Carbamicacid, Serine) (1.0 equiv) were dissolved in ethanol solution, respectively.Thionyl chloride (3.0 equiv) was slowly dripped into the mixed solution at 0 C using ice salt bath. The mixture was heated to reflux for 3-6 h. Then, the reaction mixture was concentrated under reducedpressure to give the white solid (5a-d, 5-1, and 5-2). |
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 |
---|---|---|
100% | With thionyl chloride | |
76.4% | With hydrogenchloride for 15h; Reflux; | |
39% | With sulfuric acid at 50℃; | Intermediate 33a: Ethyl (25)-2-amino-2-phenyl-acetate [00424] Intermediate 33a: Ethyl (25)-2-amino-2-phenyl-acetate[00425] A stirred solution of (2S)-2-amino-2-phenyl-acetic acid (5.OOg, 33.O8mmol) in EtCH(l5OmL) and H2S04 (2.23mL, 39.6gmmol) was heated at 50 °C overnight. The solution wasconcentrated in vacuo and the residue was poured into EtOAc (5OmL) and NaHCO3 (5OmL). The product was extracted twice more with EtOAc (2 x 5OmL), organic fractions combined, dried over Na2SO4 and concentrated in vacuo to yield ethyl (2S)-2-amino-2-phenyl-acetate (2.34g, 13.O8mmol, 39% yield)1H NMR (CDCI3, 400MHz) O/ppm: 7.33-7.18 (5H, m), 4.52 (1H, 5), 4.17-4.00 (2H, m), 1.78, (2H, br5), 1.14 (3H, t, J= 7.0Hz). |
With hydrogenchloride | ||
With thionyl chloride Reflux; | ||
With sulfuric acid for 6h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With thionyl chloride for 10h; Ambient temperature; | |
97% | With thionyl chloride for 8h; Heating; | |
97% | With thionyl chloride In methanol at 20℃; Cooling with ice; |
97.6% | With thionyl chloride at 0℃; for 2h; | 2 Example 2 Amino-phenyl-acetic acid methyl ester hydrochloride salt (8). To a stirred solution of (S)-phenylglycine (50 g, 0.3 mol) in MeOH (500 mL) at 0° C. was added thionyl chloride (42.84 g, 0.36 mol) dropwise. After stirring for 2 h, the solvent was concentrated, and the precipitated solid was washed with diethyl ether to afford product 8 (65 g, 97.6%). 1H NMR (400 MHz, D2O) δ 3.70 (s, 3 H), 5.17 (s, 1 H), 7.35-7.41 (m, 5 H). |
97.7% | With thionyl chloride at 0 - 75℃; for 2h; | First step General procedure: The methyl-esterification reaction of L-phenylalanine.To a suspension of L-phenylalanine (1 g, 6.05 mmol, 1.0 equiv) inmethanol (25 mL) cooled to 0 C was added thionyl chloride(475 mL, 6.66 mmol, 1.5 equiv) slowly. After 10 min, the reactionmixture was heated to 75 C to reflux for 2 h. After completion(monitored by TLC), the solvent was removed in vacuo, and at thistime, a white solid was formed methyl L-phenylalaninate hydrochloride(1.23 g, quantitative yield). |
92% | With thionyl chloride for 0.333333h; Heating; | |
92% | With thionyl chloride at 0℃; | |
86% | With thionyl chloride at 0 - 75℃; for 6.5h; | |
85% | With hydrogenchloride for 30h; Ambient temperature; | |
78% | With thionyl chloride Heating; | |
With thionyl chloride 1) RT, 30 min, 2) 40 deg C, 2 h; Yield given; | ||
With thionyl chloride at 40℃; for 3h; | ||
With thionyl chloride 2 h, room temperature; reflux; | ||
1.3 g | With thionyl chloride for 48h; Ambient temperature; | |
With thionyl chloride for 20h; Ambient temperature; Yield given; | ||
With thionyl chloride | ||
With thionyl chloride | ||
With hydrogenchloride at 20℃; | ||
With thionyl chloride at 20℃; | ||
With thionyl chloride | ||
With thionyl chloride at 20℃; Cooling; | ||
With thionyl chloride | ||
With thionyl chloride | ||
With thionyl chloride In tetrahydrofuran at 0℃; for 4.75h; Reflux; | ||
With thionyl chloride Inert atmosphere; | ||
With thionyl chloride at 0 - 70℃; for 18h; | 126.e e) (S)-Methyl 2-amino-2-phenylacetate hydrochloride To a suspension of (S)-2-amino-2-phenylacetic acid (10 g, 66.15 mmol) in anhydrous MeOH (150 mL) was slowly added SOCI2 (7.22 mL, 99.22 mmol) at 0 °C. Then the mixture was stirred for 18 h at 60-70 °C. The solvent was removed in vacuo to give the title compound (13 g) as a white solid, which was used to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With acetic anhydride at 0 - 20℃; | |
78% | With acetic anhydride 1) 0 deg C, 10 min, 2) room temperature, 4 h; | |
75% | With acetic anhydride at 0 - 20℃; | 1.64.1 Step 1 To a solution on (2S)-amino(phenyl)ethanoic acid (1000.00 mg; 6.62 mmol; 1.00 eq.) in formic acid (50.00 mL; 50.00 V) at 0 °C was added acetic anhydride (18.76 mL; 198.46 mmol; 30.00 eq.) drop-wise. After complete addition, the solution was allowed to come to ambient temperature and stirred overnight. The mixture was diluted with water (36 mL) and the solvent was removed under reduced pressure. [402] The white residue was re-crystallized from boiling water, and the solid thus formed was collected by filtration and air dried to provide a white powder consistent with (2S)-2-formamido-2- phenylacetic acid (570 mg). A second crop collected as described above provided an additional 324 mg of pure material for a total yield of 894 mg (75 %).1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.89 (d, J = 7.6 Hz, 1H), 8.04 (dd, J = 1.6, 0.9 Hz, 1H), 7.45 - 7.19 (m, 5H), 5.35 (dd, J = 7.7, 0.9 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydroxide In 1,4-dioxane at 0 - 20℃; for 2h; | |
95% | With potassium carbonate In tetrahydrofuran; water at 20℃; for 18h; | 2 Example 2 Preparation of N- -phenylglycinePhenylglycine Example 2 Preparation of N- -phenylglycinePhenylglycine (5.1 g, 33.76 mmol) is suspended in a 1 : 1 mixture of water and THF (50 ml) at room temperature and potassium carbonate (K2CO3, 1 1.66 g, 84,4 mmol) and Boc anhydride (7.36 g, 84.4 mmol) are added. The suspension is stirred at room temperature for 18 hours, controlling by LC-MS. The solids are removed by filtration and THF is evaporated under reduced pressvire. The remaining aqueous phase is acidified with a 2N HC1 aqueous solution and extracted two times with dichloromethane (40 ml each time). The organic phases are combined and dried on sodium sulphate. The suspension is filtered and the solvent is evaporated under reduced pressure. Petroleum ether is added during the evaporation to facilitate the precipitation. A white solid is obtained, which is filtered and dried to give 8.02 g of the title product (31.91 mmol; yield 95%). MS (ESI+): 252.2 ( +H4"), 525.3 (2M+Na) 1HNMR (400 MHz, DMSO): 12.75 (s, 1H, -OH), 7.55 (d, 1Η, -NH-Boc, J=8.4 Hz) 7.41-7.33 (m, 5H, Ph), 5.11 (d, 1H, Ha, J - 8.4 Hz), 1.39 (s, 9H, 3x -CH3). |
94% | With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 21h; |
90% | With sodium hydroxide In 1,4-dioxane for 14h; | |
90% | With potassium carbonate In methanol; water at 10 - 20℃; | 2.1 (1) A mixture of (S)-2-amino-2-phenylacetic acid (100 g, 0.66 mol), potassium carbonate (109 g, 0.79 mol) was dissolved in water (1.0 L) and methanol (0.25 L), cooling to T <10 deg. C, di-tert-butyl dicarbonate (144 g, 0.66 mol) was added dropwise, room temperature reaction overnight, pH 4 to 5 with 1 N HCl, extraction with ethyl acetate (0.5 L * 3), saturated brine (0.5 L * 1) was washed, concentrated to give 150 g of a white solid, yield 90%. |
89% | With sodium hydroxide In 1,4-dioxane | |
88.7% | Stage #1: (S)-2-phenylglycine With sodium hydroxide In 1,4-dioxane; water at 2.5℃; for 0.166667h; Stage #2: di-<i>tert</i>-butyl dicarbonate In 1,4-dioxane; water at 20℃; for 6h; | 1-2 Example 1 In a 250ml four-neck flask, dissolve 4.53g (30mmol) of L-phenylglycine in 60ml of dioxane and 30ml of water, cool to 2.5±2.5, add 30ml of 1N NaOH solution, stir for 10 minutes and add 7.2g of BOC anhydride (33mmol), warm up to room temperature, and continue to stir for 6 hours. After the reaction is over, add 13% potassium hydrogen sulfate dilute solution to adjust the pH of the reaction solution to 2.0, add 50ml ethyl acetate, separate the layers, extract the aqueous phase with 30ml×2 ethyl acetate, combine the organic phases, wash with 50ml purified water, and anhydrous sulfuric acid Sodium is dry. Filter and evaporate the solvent under reduced pressure to dryness to obtain a colorless transparent viscous oil.Weigh, add 0.5% by weight of N-Boc-L-phenylglycine seed crystals (HPLC purity 99.3%) to this oil, let stand at room temperature for 24 hours, the oil is completely solidified and turned into a white solid, add 10 times the volume /Weight ether, beaten at room temperature for 2 hours, and filter. The product was obtained by drying under reduced pressure at 60°C for 15 hours. (Yield 88.7%, HPLC purity 99.1%). |
87% | With sodium hydroxide In 1,4-dioxane; water at 20℃; Cooling with ice; | |
86% | With triethylamine In methanol; water at 25℃; for 8h; | |
86% | With triethylamine In methanol; water at 20℃; for 8h; | |
86% | With triethylamine In methanol; water at 20℃; for 8h; | 1 Synthesis of: Compound (6) (S) -2 - ((t - t-butyl carbonyl) amino) -2-phenylacetic acid The L- phenylglycine (15.1g, 100mmol) placed in a reaction flask was added 200mL of methanol: water (3: 1), room temperatureStirring to dissolve, was added Et3N (15.1mL, 150mmol), the (Boc) 2O (32.7g, 150mmol) was added dropwise to the reaction mixture, followed by stirring at room temperature for 8 hours, the solvent is removed by rotary evaporation, dissolved in 100mL of citric acid, with acetic acid ethyl ester (3 × 50mL) and extracted with anhydrous sodium sulfate, crude did spin with hexane to give product 6 (21.8g, 86% yield). |
82% | With sodium hydroxide In <i>tert</i>-butyl alcohol at 20℃; for 1h; | 24.1 Step 1: (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid To a solution of (S)-2-amino-2-phenylacetic acid (3.0 g, 19.8 mmol) in 1 M sodium hydroxide solution (28 mL) was added a solution of di-tert-butyl dicarbonate (4.75 g, 21.78 mmol) in tert-butyl alcohol (16 mL). The resulting suspension was stirred at roomtemperature for 1 h. The volatile solvent was removed under reduced pressure and the pH of the remaining solution was adjusted with citric acid to 3. The solid was filtered and dried to give (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (4.1 g, 16.3 mmol, 82 % yield). LCMS (2.5 min formic acid): Rt = 1.48 min, [M+H]+= 273.9. |
60% | With triethylamine In methanol; water for 6h; | |
With sodium hydroxide In 1,4-dioxane for 18h; Ambient temperature; | ||
With sodium hydroxide In <i>tert</i>-butyl alcohol | ||
With sodium hydroxide In tetrahydrofuran; water at 20℃; | ||
With sodium hydroxide In 1,4-dioxane at 20℃; | ||
With sodium hydrogencarbonate In tetrahydrofuran at 23℃; for 12h; | ||
With sodium hydroxide In tetrahydrofuran at 20℃; for 18h; | ||
Stage #1: (S)-2-phenylglycine With potassium carbonate In water at 100℃; for 2h; Stage #2: di-<i>tert</i>-butyl dicarbonate In 1,4-dioxane at 20℃; for 24h; Further stages.; | ||
With tert-butylimino-tris(dimethylamino)phosphorane In acetonitrile at 20℃; for 16h; | ||
With triethylamine In tetrahydrofuran; water at 20℃; | ||
With triethylamine In N,N-dimethyl-formamide | General Procedure: Compounds 1-15 were synthesized by standard solution phase peptide synthesis by which sequential elongation and coupling of an amine to a carboxylic acid was performed in DMF with benzotriazol-1-yl-oxytris-(dimethylamino)phosphonium hexafluorophosphate (BOP) or N,N'-carbonyldiimidazole (CDI) as coupling reagent and Et3N as base. Although BOP was favored over CDI for coupling to the P'1 residue, CDI showed higher coupling reactivity with bulky amines. Peptide coupling to the P1 residue was accomplished using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBt) as additive, without a base, to avoid reported side-reactions. Attachment of a Boc protection group to an amino group was achieved with Boc2O and Et3N in DMF, while the removal of the Boc protection group was achieved with 4 N HCl in dioxane. The hydroxyl group in compounds 2 and 9 was acetyl protected with acetic anhydride in pyridine, and eventually removed by a 50% v/v mixture of 4 N NaOH(aq) and MeOH. The N-terminal cap was appended in DMF and Et3N as base by a reaction with methyl chloroformate for compounds 2 and 3, or with benzylbromide for compound 13. The nucleophilic substitution reactions in compounds 11, 12, 14 and 15 was performed with methyl iodide or ethyl iodide, respectively, to afford a mixture of mono- and disubstituted products. After preparative HPLC purification, all target compounds (1-15) were >95% pure by analytical HPLC. The identities of the compounds were confirmed by TOF MS and ESI-Q MS. | |
With sodium hydroxide In methanol | ||
Stage #1: (S)-2-phenylglycine With sodium hydroxide In 1,4-dioxane; water for 0.0833333h; Cooling with ice; Stage #2: di-<i>tert</i>-butyl dicarbonate With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 18h; | ||
With triethylamine In methanol; water | ||
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 4h; | General Procedure for the Synthesis of Compounds 6a-d General procedure: Amino acid derivative (5 mmol) was dissolved in a mixture of tetrahydrofuran (50 mL) and water (20 mL). A 1 N NaOH (6 mL) was added followed by the addition of 1.1 g di-tert-butyl dicarbonate (5mmol) dropwise at room temperature. After stirring for 4 h, the tetrahydrofuran was evaporated under vacuum from the reaction mixture. To the residue was added ethyl acetate (50 mL) and 5% citric acid (30 mL). The organic layer was separated, washed with water (20 mL × 3), dried with anhydrous MgSO4 and rotary evaporated to dryness. The crude residue was used the next reaction without purification. A mixture of the above N-Boc protected amino acids (2.2 mmol), compound 4 (0.98 g, 2 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.42 g,2.2 mmol), 1-hydroxybenzotriazole (0.30 g, 2.2 mmol), triethylamine (0.30 g, 3.0 mmol) and dichloromethane (50 mL) was stirred at room temperature for 36 h. The mixture was washed with saturated aqueous NaHCO3 and water then, evaporated under vacuum and the residue was treated with a mixture of trifluoroacetic acid (TFA, 10 mL) and dichloromethane (10 mL) at room temperature for 30 min. The reaction mixture was quenched with 25% aqueous NaHCO3 (30 mL) and washed with water, dried with anhydrous Na2SO4 overnight and rotary evaporated to dryness. The crude residue thus obtained was purified by silica gel column chromatography (petroleum ether-ethyl acetate 1:2 v/v) to afford the desired compounds. | |
With sodium hydroxide In tetrahydrofuran at 0 - 20℃; for 3h; | 1 Step 1: (S)-2-((terf-butoxycarbonyl)amino)-2-phenylacetic acid At 0°C, to a solution of (S)-2-amino-2-phenylacetic acid (3.0 g, 19.9 mmol) in THF (20 mL) were added 10% NaOH solution (20 mL, 50 mmol) and Boc20 (4.8 g, 22 mmol) and the contents were stirred at ambient temperature. After 3 hr, the reaction mixture was cooled to 0°C and was acidified carefully with 50% citric acid solution (10 mL) until the pH of the solution is 4. The organic contents were extracted with EtOAc (3x25 mL) and the combined organic extracts were washed with brine (1x20 mL), dried over Na2S04, concentrated to afford (S)-2- ((tert-butoxycarbonyl)amino)-2-phenylacetic acid. The residue thus obtained was taken directly for step 2 without further purification. MS ESI calc'd. for Ci3Hi8N04 [M+l]+ 252, found 252.2. | |
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 1h; | ||
With sodium hydroxide | ||
With sodium hydroxide In water; <i>tert</i>-butyl alcohol | ||
Stage #1: (S)-2-phenylglycine With sodium hydroxide In water; <i>tert</i>-butyl alcohol at 20℃; for 0.25h; Stage #2: di-<i>tert</i>-butyl dicarbonate In water; <i>tert</i>-butyl alcohol | ||
With sodium hydrogencarbonate; sodium hydroxide In 1,4-dioxane; water at 25℃; Cooling with ice; | ||
With triethylamine In methanol at 20℃; for 16h; | ||
With sodium hydroxide In water; <i>tert</i>-butyl alcohol at 20℃; for 1h; | Step 1: (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (115a). A solution of (S)-2-amino-2-phenylacetic acid 114a (1.0 g, 6.6 mmol) in NaOH (1 M aqueous solution, 1.4 mL) was treated with a solution of Boc2O (1.68 mL, 7.34 mmol) in tBuOH (1.4 mL). The resulting suspension was stirred at rt for 1 h. After completion, the solvent was removed under reduced pressure and the pH of the remaining solution was adjusted to 3 with 4 M aq. HCl solution. The resulting suspension was diluted with CHCl3 (2 mL), the layers were separated, and the aqueous solution was extracted with CHCl3 (2 × 1 mL). The combined organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product (1.56 g, 93%, white powder) was used in the next step without further purification. LCMS (ES+) m/z calculated for C13H17NO4 251.12, found 152 (M+H-Boc)+. | |
With sodium hydroxide In water; <i>tert</i>-butyl alcohol at 20℃; for 1h; | Step 1: (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (115a). A solution of (S)-2-amino-2-phenylacetic acid 114a (1.0 g, 6.6 mmol) in NaOH (1 M aqueous solution, 1.4 mL) was treated with a solution of Boc2O (1.68 mL, 7.34 mmol) in tBuOH (1.4 mL). The resulting suspension was stirred at rt for 1 h. After completion, the solvent was removed under reduced pressure and the pH of the remaining solution was adjusted to 3 with 4 M aq. HCl solution. The resulting suspension was diluted with CHCl3 (2 mL), the layers were separated, and the aqueous solution was extracted with CHCl3 (2 × 1 mL). The combined organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product (1.56 g, 93%, white powder) was used in the next step without further purification. LCMS (ES+) m/z calculated for C13H17NO4 251.12, found 152 (M+H-Boc)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With hydrogen; In water; at 60℃; under 30003.0 Torr; for 12h;pH 14;Autoclave; | The selective hydrogenation of the optically active phenyl amino acid was carried out in a magnetically stirred stainless-steel autoclave (100 ml). Prior to the loading of the catalyst, the autoclavewas purged three times with hydrogen to expel the air. Typically, a freshly prepared suspension of nanoRu(at)hectorite (0.01592 mmol Ru, 10 ml H2O) and the appropriate amount of the substrate were carefully transferred into the autoclave under inert atmosphere, and then the autoclave was charged with H2 to the desired pressure. The autoclave was placed into the pre-heated heating mantle and the magnetic stirring was started for the indicated reaction time. After the reaction, the autoclave was cooled down and the pressure was released. The reactor was thoroughly rinsed with 2 N NaOH solution to wash out the entire product (in the case of acidic system, 2 N HCl was used). All the collected solutions were filtered (0.22 mm, PTFE) to remove the catalyst and then treated with diluted HCl (or NaOH) solution to adjust the pH to 5.5, which caused the partial precipitation of the product. The suspensionwas then reduced in vacuo to 10 ml in order to complete the precipitation. The precipitate was filtered off, washed with distilled water and dried in vacuo for 24 h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With lithium aluminium tetrahydride In tetrahydrofuran Heating; | |
97% | With lithium aluminium tetrahydride In tetrahydrofuran Heating; | |
95% | With lithium aluminium tetrahydride In tetrahydrofuran Heating; |
89% | With lithium aluminium tetrahydride In tetrahydrofuran for 48h; Inert atmosphere; Reflux; | |
86% | With lithium borohydride; chloro-trimethyl-silane In tetrahydrofuran at 0 - 20℃; for 25h; | |
85% | With lithium borohydride; chloro-trimethyl-silane In tetrahydrofuran 1) 0 degC, 1 h, 2) r.t., 24 h; | |
85% | With potassium borohydride; sulfuric acid In tetrahydrofuran at 27 - 30℃; for 3h; | 1-5 Potassium borohydride (9.3 g) and compound 8 (10g) were put into the tetrahydrofuran (42g) system in 10 batches, and sulfuric acid (8.0g) was slowly added dropwise when the system temperature was 27; after the addition, the system was at 30°C Incubate for 3h, the reaction is over; cool the system to 10, add dropwise 25g sodium hydroxide aqueous solution with a mass concentration of 20% to the system, reflux the system at 100°C for 2h, stir for 30min, and then naturally cool to 70°C, stand for separation and collect; The organic phase was dried and concentrated under reduced pressure to obtain intermediate compound 9 with a yield of 85%. |
81% | With sodium tetrahydroborate; boron trifluoride diethyl etherate In tetrahydrofuran at 25℃; for 15h; | |
81% | With sodium tetrahydroborate; iodine In tetrahydrofuran at 0℃; for 18h; Reflux; | |
77% | With lithium borohydride; chloro-trimethyl-silane In tetrahydrofuran | |
76% | With lithium aluminium tetrahydride In tetrahydrofuran at 10℃; for 16.5h; Inert atmosphere; Reflux; | |
74% | With lithium aluminium tetrahydride In tetrahydrofuran Heating; | |
70% | With sodium tetrahydroborate; iodine In tetrahydrofuran Reflux; | |
65.3% | With sodium tetrahydroborate; iodine In tetrahydrofuran at 0℃; for 18h; Inert atmosphere; Sealed tube; Reflux; | (S)-2-Phenylglycinol (3) A 250-mL 3-neck round-bottomed ask was tted with a magnetic stir bar,a reux condenser, and an addition funnel. The ask was charged with 3.31 g (91 mmol) of sodium borohydrideand 100 mL of THF (predried over sodium). L-phenylglycine (5.74 g, 38 mmol) was added in one portion. Theremaining neck was sealed with a septum and an argon line attached, and the ask was cooled to 0 C in an icebath. A solution of 9.65 g (38 mmol) of iodine dissolved in 25 mL of THF was poured into the addition funneland added dropwise over 30 min, resulting in vigorous evolution of hydrogen. After addition, the reaction wascomplete and gas evolution had ceased, and the ask was heated to reux for 18 h and then cooled to ambienttemperature, and methanol was added cautiously until the mixture became clear. After stirring for 30 min, thesolvent was removed by rotary evaporation, leaving a white paste, which was dissolved by adding 150 mL of20% aqueous NaOH. The solution was stirred for 4 h and extracted with CH2 Cl2 (50 mL 3). The organicphase was dried with anhydrous Na2SO4 and concentrated in a vacuum. Then the white crude product wasrecrystallized in toluene to aord 3 as a colorless crystal. Yield: 65.3%; mp 72{73 C (lit. 26 = 69{71 C). |
54% | With lithium aluminium tetrahydride In tetrahydrofuran Inert atmosphere; | 1 Preparation of NHC precursor VI from l-phenylglycine 4.2.3.1 (S)-2-Amino-2-phenylethanol 39 This compound was prepared from l-phenylglycine (0.496 g, 3.28 mmol) and LiAlH4 (0.311 g, 8.19 mmol) in THF (10 mL) according to the literature. 12 The work-up was performed by adding NaSO4 (1 M, 11 mL), extraction with ether (3 * 9 mL) and the organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo to provide (S)-2-amino-2-phenylethanol (0.244 g, 54%) as an orange solid. The 1H NMR was in accordance with the literature. |
With lithium aluminium tetrahydride In tetrahydrofuran | ||
With lithium aluminium tetrahydride In tetrahydrofuran Heating; | ||
With sodium tetrahydroborate; iodine In tetrahydrofuran | ||
With lithium aluminium tetrahydride In tetrahydrofuran for 6h; Heating; | ||
With sodium tetrahydroborate; iodine In tetrahydrofuran for 18h; Heating; | ||
With lithium aluminium tetrahydride In tetrahydrofuran at 65℃; | ||
With lithium aluminium tetrahydride In tetrahydrofuran for 6h; Heating; | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 3 h / 40 °C 2: sodium borohydride / ethanol; H2O / 5.5 h / Heating | ||
Multi-step reaction with 2 steps 1: 99 percent / SOCl2 / 10 h / Ambient temperature 2: 83 percent / NaBH4 / aq. ethanol / 1) RT, 9h, b) 5.5h, reflux, c) RT, 8h | ||
With lithium borohydride; chloro-trimethyl-silane In tetrahydrofuran at 0℃; | ||
With lithium aluminium tetrahydride In tetrahydrofuran | ||
With sodium tetrahydroborate; iodine In tetrahydrofuran at 70℃; | ||
With sodium tetrahydroborate; iodine | ||
With sodium tetrahydroborate; iodine In tetrahydrofuran | ||
Multi-step reaction with 2 steps 1.1: thionyl chloride / Reflux 2.1: sodium tetrahydroborate / tetrahydrofuran / 0.25 h / 65 °C 2.2: 65 °C | ||
With sodium tetrahydroborate; iodine In tetrahydrofuran at 70℃; | ||
With sodium tetrahydroborate; sodium iodide In tetrahydrofuran | ||
With sodium tetrahydroborate; iodine In tetrahydrofuran Inert atmosphere; | ||
With lithium aluminium tetrahydride In tetrahydrofuran for 24h; Reflux; | ||
With sodium tetrahydroborate; iodine In tetrahydrofuran Inert atmosphere; Schlenk technique; | ||
Stage #1: (S)-2-phenylglycine With sodium tetrahydroborate; sulfuric acid In tetrahydrofuran; diethyl ether at 0 - 20℃; Inert atmosphere; Stage #2: With hydrogenchloride In tetrahydrofuran; diethyl ether; water at 20℃; for 2h; Inert atmosphere; Stage #3: With sodium hydroxide In tetrahydrofuran; diethyl ether; water at 20℃; for 3h; Inert atmosphere; | ||
With sodium tetrahydroborate; iodine In tetrahydrofuran | ||
With sodium tetrahydroborate; iodine | ||
With sodium tetrahydroborate; iodine In tetrahydrofuran | ||
With lithium aluminium tetrahydride In tetrahydrofuran for 18h; Reflux; Inert atmosphere; Glovebox; Schlenk technique; | ||
With lithium aluminium tetrahydride In tetrahydrofuran | 2.2 General procedure for the synthesis of chiral aziridines 1a, 1p and1q General procedure: The compounds were prepared in a similar manner as described before9. The chiralamino acid was reduced to the amino alcohol by treatment with LiAlH4 in THF. Thereaction was quenched with water. The solid was filtered off and the filtrate was driedover anhydrous sodium sulfate. The solvent was removed under reduced pressure togive the crude product. Subsequent treatment of the crude product with TsCl andK2CO3 in MeCN afforded pure chiral aziridines. | |
With sodium tetrahydroborate; iodine In tetrahydrofuran at 0℃; for 18h; Reflux; Inert atmosphere; | ||
Stage #1: (S)-2-phenylglycine 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 General procedure: 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. | |
1.298 g | With sodium tetrahydroborate; iodine In tetrahydrofuran at 0 - 80℃; for 12h; Inert atmosphere; Schlenk technique; | |
With sodium tetrahydroborate; iodine In tetrahydrofuran for 48h; Reflux; Inert atmosphere; | ||
Multi-step reaction with 2 steps 1: thionyl chloride / -15 - 60 °C / Inert atmosphere 2: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / 20 °C / Cooling with ice; Inert atmosphere | ||
With sodium tetrahydroborate; iodine In tetrahydrofuran at 65℃; for 18h; | ||
With lithium aluminium tetrahydride In tetrahydrofuran | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 0 - 60 °C 2: sodium tetrahydroborate; lithium chloride; ethanol / 0 - 15 °C | ||
With sodium tetrahydroborate; iodine In tetrahydrofuran at 0℃; for 18h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydroxide; In water; at 0 - 5℃; for 2.33333h; | To a solution of L-Phenyl glycine (2.5g, 16.7mmol), in aqueous NaOH (3N; lOmi), ethyl chioroformate (l.2m1, l0.5mmol) was added and the reaction mixture wasstirred for 20 mm. at 0-5C. The second portion of aqueous NaOH (3N; 7m1), ethyl chioroformate (l.2m1, 10.5mmol) was added and the reaction mixture was stirred for 2h at 0-5C. The mixture was filtered and washed with diethyl ether. The aqueous layer was acidified with 6N HC1 (pH4) to get the solid (S)-2-((ethoxycarbonyl)amino)-2- phenylacetic acid (3.4g, 92% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In methanol for 18h; Ambient temperature; | ||
Stage #1: (S)-2-phenylglycine With lithium hydroxide monohydrate In methanol at 20℃; for 0.333333h; Stage #2: benzaldehyde In methanol for 1h; | General synthetic procedure for 5 - 9a - f General procedure: The amino acid specified below was dissolved in methanol (100 mL). LiOH.H20 was added, and the solution stirred at room temperature for 20 minutes. The corresponding aldehyde was added dropwise, and stirred for 1 hour. Sodium borohydride was then added portionwise. After 30 minutes, the solvent was removed under reduced pressure and the resulting solid was dissolved in water (100 mL). Using 1M HCl, the pH was adjusted to 6.5 and then filtered. The crude white solid was carried on without further purification. | |
With sodium hydroxide In water at 20℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In various solvent(s) at 20℃; for 0.166667h; | |
91% | With sodium hydroxide In water at 0 - 20℃; for 0.75h; | |
85% | With sodium hydroxide |
80% | With sodium hydrogencarbonate; sodium carbonate In acetone at 15 - 20℃; for 3h; | 52.1 Step 1 : Preparation of (S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetic acid To a solution (5)-2-amino-2-phenylacetic acid (20 g, 0.1 2 mol) in water (500 mL) was added sodium carbonate (27.97 g, 0.264 mol) and sodium bicarbonate (1 1.1 g, 0.132 mol) at ambient temperature. The mixture was stirred to get a clear solution. Acetone (40 mL) was added and the resulting slightly turbid solution was cooled (in an ice water bath) to 15-20 °C. Cbz-Cl (28.15 g, 0.165 mol) was added slowly, with stirring, and the reaction mixture allowed to warm to ambient temperature. After stirring for an additional three hours, the mixture was extracted with methyl tertbutyl ether ( 100 mL). The pH of aqueous layer was adjusted to 2 using aqueous HC1. The resulting oil was extracted into ethyl acetate (100 mL x 2). The combined organic layer was washed with water and concentrated under vacuum to get (S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetic acid (30.2 g, 80% yield) as a white solid. |
67% | With sodium hydroxide In water at 20℃; for 5h; | 1; 1.A Step A.Z-(S)-Phenylglycine. To a solution of (S)-(+)-phenylglycine (2.0 g, 13.2 mmol) in 2 N NaOH aqueous solution (30 mL) was added benzyl chloroformate (2.3 mL, 16.2 mmol) at room temperature. The resulting solution was stirred at room temperature for 5 h, and acidified to pH = 1. The resulting white solid was collected by filtration, washed with water and driedin vacuo to yield the title compound (2.5 g, 8.8 mmol, 67%). 1H NMR (CDCl3): δ 8.05 (d, J = 8.4, 1H), 7.40-7.28 (m, 10H), 5.12 (d, J = 8.4, 1H), 5.03 (s, 2H). |
62% | Stage #1: (S)-2-phenylglycine; benzyl chloroformate With sodium hydroxide In water at 5 - 20℃; for 4h; Stage #2: With hydrogenchloride In water | |
47% | With sodium hydrogencarbonate at 20 - 35℃; for 18h; | 1.i Step (i): Synthesis of (S)-2-(benzyloxycarbonylamino)-2-phenylacetic acidExperimental procedure: To a solution of L-phenyl glycine (50 g, 0.33 mol), in aqueous NaHC03 solution (66 g, 0.8 mol, 330 mL) was added benzyl chloroformate (101 g, 0.6 mol), and the reaction mixture was allowed to stir for 2 h at about 20-35 °C. Then another portion of aqueous NaHC03 solution (33 g, 0.4 mol, 170 mL), benzyl chloroformate (101 g, 0.6 mol) was added to the reaction mixture and the mixture was allowed to stir at about 20-35 °C for 16 h. The reaction mixture was filtered and the filtrate was washed with diethyl ether (250 mL). The aqueous layer was acidified with 6N HCl to pH ~ 4.0 and the obtained solid (benzyloxymethyl-amino)-phenyl-acetic acid was filtered and dried (45 g, 47%).1H NMR (400 MHz, DMSO- ¾: δ 12.8 (bs, 1H), 8.03 (d, J= 8.06 Hz, 1H), 7.46-7.23 (m, 10 H), 5.13 (d, J = 4.7Hz, 1H), 5.05 (s, 2H); IR (KBr, cm"1): 3400, 3034, 1734, 1672, 1531, 1247; MS (ES) m/z 286.6 (M++l) |
With sodium hydroxide | ||
With sodium hydroxide In water at 0 - 20℃; for 0.5h; | ||
With sodium hydroxide at 0 - 20℃; for 0.5h; | B.B-3 [Example B-3]; A β-aminocarbonyl derivative was synthesized by an asymmetric Mannich reaction (see Chemical Formula 3). More specifically, distilled acetonitrile (2 mL) was added to a Schlenk reaction tube containing (R)-1,1'-binaphthyl-2,2'-disulfonic acid (5.2 mg, 0.0125 mmol) and 2,6-diphenylpyridine (5.8 mg, 0.025 mmol) in a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 15 minutes. Then, the solvent was evaporated under reduced pressure, and the reaction product was dried at 1 to 2 Torrs for 1 hour. Subsequently, distilled CH2Cl2 (1.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The resulting solution was cooled to 0°C, and benzaldehyde imine whose nitrogen is protected with Cbz (compound 8) (59.8 mg, 0.25 mmol in 0.5 mL of CH2Cl2) and then acetyl acetone (27.5 mg, 0.275 mmol in 0.5 mL of CH2Cl2) were dropped into the solution over a period of 1 hour. Then, the reaction mixture was further stirred at 0°C for 30 minutes. After confirming the completion of the reaction by TLC, saturated aqueous solution of sodium hydrogencarbonate (10 mL) was added, and the mixture was returned to room temperature. The organic phase was extracted from this solution with ethyl acetate (15 mL x 2). The extracted organic phase was rinsed with saturated aqueous solution of sodium chloride (10 mL), and was dried with anhydrous sodium sulfate. After being dried, the organic phase was filtered through cerite, and the solvent was evaporated under reduced pressure. The resulting concentrate was purified through a silica gel column chromatography (hexane/ethyl acetate = 3/1) to obtain a (β-aminocarbonyl derivative (compound 9) shown in Chemical Formula 3 with an yield of 74%. Furthermore, the enantiomeric excess of the product was determined to be 92% ee by a high performance liquid chromatography (hexane/ethanol = 9/1, 1.0 mL/min) charged with chiral column (AD-H). The spectrum data of compound 9 are shown below. 1H NMR (300 MHz, CDCl3) δ 2.10 (s, 3H), 2.19 (brs, 3H), 4.24 (d, J = 6.3 Hz, 1H), 5.07 (s, 2H), 5.55 (br, 1H), 6.11 (br, 1H), 7.23-7.36 (m, 10H). 13C NMR (75 MHz, CDCl3) δ 30.0, 30.4, 54.2, 67.0, 71.4, 126.3 (2C), 127.8 (2C), 127.9, 128.1, 128.4 (2C), 128.8 (2C), 136.0, 139.3, 155.7, 202.2, 204.4. IR (KBr) 3362, 1730, 1692, 1530, 1254, 1026, 757, 701 cm-1. [α]D23.7 = -3.2 (c 0.5, CHCl3). C20H21NNaO4 [M+Na]+ 362.1368, found 362.1374. HPLC (Daicel Chiralpack AD-H, Hexane:EtOH = 9:1, flow rate = 1 mL/min) tR = 47.3 min (minor, S), 52.3 min (major, R). [Show Image] [Show Image] Compound 8 was synthesized according to the process described in J. Am. Chem. Soc., vol. 124, pp. 12964-12965 (2002) and J. Org. Chem., vol. 59, pp. 1238-1240 (1994). Compound 9 was converted to a methyl ester form (compound 10) according to formula (1) in Chemical Formula 4. Meanwhile, (S)-methyl ester form and (R)-methyl ester were prepared from commercially available (S)-phenylglycine and (R)-phenylglycine according to formulae (2) and (3), respectively. The resulting products were used as reference compounds. Then, compound 10 and the (S)- and (R)-methyl ester forms (reference compounds) were analyzed by a chiral high performance liquid chromatography, and compound 10 was thus determined to be in (S)-methyl ester form (92% ee). Thus, the absolute configuration of compound 9 was determined to be R-form. Chemical Formula 4 is obtained from J. Am. Chem. Soc., vol. 126, p. 5356 (2004). [Show Image] [Show Image] | |
With sodium hydroxide In toluene at 20℃; for 4h; | ||
Stage #1: (S)-2-phenylglycine With sodium hydrogencarbonate; sodium carbonate In water at 20℃; Stage #2: benzyl chloroformate In water; acetone at 15 - 20℃; for 3h; | 25.1 Step 1 : Preparation of (S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetic acid. Step 1 : Preparation of (S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetic acid. [00159] To a solution (5)-2-amino-2-phenylacetic acid (20 g, 0.132 mol) in water (500 mL) was added Na2C03 (27.97 g, 0.264 mol) and NaHC03 (11.1 g, 0.132 mol) at ambient temperature. The mixture was stirred to give a clear solution. Acetone (40 mL) was added and the slightly turbid solution was cooled in an ice water bath to 15 -20 °C. Cbz-Cl (28.15 g, 0.165 mol) was added slowly, with stirring, and the reaction mixture allowed to warm to ambient temperature. After stirring for an additional three hours, the mixture was extracted with MTBE (100 mL). The pH of an aqueous layer was adjusted to 2 using aqueous HC1. The resulting oil was extracted into EtOAc (100 mL x 2). The combined organic layer was washed with H20 and then concentrated in vacuo to give (S)-2- (((benzyloxy)carbonyl)amino)-2-phenylacetic acid (30.2 g, 80% yield) as a white color solid. | |
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; | 4.1.1 General procedures for the preparation of capping groups CG 1-20 General procedure: A 500mL round bottom flask was equipped with a magnetic stir bar, charged with distilled H2O (100mL) and NaOH (100mmol, 4.0g) and cooled in an ice bath to 0°C. l-Phenylglycine/l-Methionine/d-Phenylglycine/d-Methionine (35mmol) was added, and stirred until the solution was homogeneous. The corresponding carbonyl chloride (45.5mmol) in 1,4-dioxane (40mL) was added dropwise using an addition funnel. The reaction mixture was left to stir overnight at room temperature. The solution was extraction of the solution with Et2O (3×50mL) was done, and the organic layers were discarded. The aqueous layer was cooled in an ice bath to 0°C, and concentrated HCl was added dropwise until the pH=2. The re-extraction of the aqueous solution was done with Et2O (3×100mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuum to give the product as clear viscous oil. No further purification was required. | |
With sodium hydroxide In 1,4-dioxane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With sodium hydroxide In tetrahydrofuran; water at 70 - 80℃; for 0.5h; | |
With sodium hydroxide In diethyl ether at 20℃; for 5h; | ||
With sodium hydroxide In diethyl ether at 0℃; for 4h; |
With sodium hydroxide In diethyl ether at 20℃; | ||
Stage #1: (S)-2-phenylglycine; p-toluenesulfonyl chloride With sodium hydroxide In water at 20 - 60℃; Stage #2: With hydrogenchloride In water at -5℃; | ||
In water; acetone at 20℃; for 24h; Alkaline conditions; | 3 4.1.1 General procedure for the synthesis of substituted sulfonamides using different aminoacids (14-21 and 22-35) General procedure: L-isomers of different amino acids were used for the synthesis and in 1H NMR spectra it was found that only one isomer was formed indicating that there is retention in configuration. The substituted aromatic or aliphatic sulfonylchlorides (1-13, 58, 59) (0.0143mol, 1 equivalent) were dissolved in the acetone (2ml). The mixture was added to water (2ml) containing glycine/phenylglycine/phenylalanine (0.0143mol, 1 equivalent) and sodiumbicarbonate (0.0429mol, 3 equivalent). The final reaction mixture was stirred at room temperature (rt) for 24h. The reaction was monitored by TLC using ethylacetate and methanol (8:2) as the mobile phase. The acetone was evaporated under reduced pressure and reaction mixture was neutralized with 1N HCl to get the product. The product was filtered and recrystallized with methanol to get the pure compound [34]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine In 1,4-dioxane; water at 0℃; for 0.75h; | 1 To a solution of L-phenylglycine (0.227g, 1.5mmol) in water (5 ml) and dioxane (5ml) was added triethylamine (0.42ml, 3.0mmol) followed by slow addition of 4- nitrobenzene sulphonyl chloride (0.5g, 2.3mmol) in dioxane (5ml) at O0C. After stirring for 45 minutes the reaction mixture was evaporated to dryness, re-dissolved in EtOAc and washed with saturated NaHCO3 solution (2x20ml) and water (10ml). The EtOAc layer was dried over Na2SO4, filtered and evaporated to dryness. LCMS purity 75%, (molecular ion not observed) yield 0.58g, (76%). This material was used without any purification. |
16% | With sodium hydroxide In tetrahydrofuran; water at 70 - 80℃; for 0.5h; | |
In water; acetone at 20℃; for 24h; Alkaline conditions; | 3 4.1.1 General procedure for the synthesis of substituted sulfonamides using different aminoacids (14-21 and 22-35) General procedure: L-isomers of different amino acids were used for the synthesis and in 1H NMR spectra it was found that only one isomer was formed indicating that there is retention in configuration. The substituted aromatic or aliphatic sulfonylchlorides (1-13, 58, 59) (0.0143mol, 1 equivalent) were dissolved in the acetone (2ml). The mixture was added to water (2ml) containing glycine/phenylglycine/phenylalanine (0.0143mol, 1 equivalent) and sodiumbicarbonate (0.0429mol, 3 equivalent). The final reaction mixture was stirred at room temperature (rt) for 24h. The reaction was monitored by TLC using ethylacetate and methanol (8:2) as the mobile phase. The acetone was evaporated under reduced pressure and reaction mixture was neutralized with 1N HCl to get the product. The product was filtered and recrystallized with methanol to get the pure compound [34]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: (S)-2-(diphenylmethyl)amino-2-phenylacetonitrile With hydrogenchloride; water; trifluoroacetic acid at 80℃; for 18h; Stage #2: With sodium hydroxide In water at 5℃; | |
66% | With hydrogenchloride; water; trifluoroacetic acid at 80℃; for 18h; | |
With hydrogenchloride at 60℃; for 6h; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrogenchloride In water at 20℃; | |
94% | With hydrogenchloride at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sodium hydroxide In water at 0 - 20℃; for 0.5h; | XX.a a. Preparation of intermediate 70 L-Phenylglycine 69 (1 .00 g, 6.61 mmol, 1 .0 eq.) was suspended in water (10 ml_). Solubilization occurs after sodium hydroxide (1 .06 g, 26.5 mmol, 4.0 eq.) addition. Reaction mixture was cooled down at 0°C, and propargylchloroformate 5 (1 .58 g, 13.2 mmol, 1 .3 ml_, 2.0 eq.) was added dropwise. Reaction mixture was allowed to warm up to room temperature for 30 minutes. Reaction mixture was acidified with (12N) hydrochloric acid solution, extracted with ethyl acetate (3 x 100 ml_), dried over magnesium sulfate and solvents were evaporated under vacuum. The residue was purified by flash chromatography [Biotage ; column AIT 40g; eluant: Cyclohexane / EtOAc; gradient: 100/0 -> 0/100 (12 CV)] affording compound 70 (977 mg, 63% yield) as a white solid. |
63% | With sodium hydroxide In water at 0 - 20℃; for 0.5h; | (S)-2-phenyl-2-(((prop-2-yn-1-yloxy)carbonyl)amino)acetic acid 18 L-Phenylglycine (1.00 g, 6.61 mmol, 1.0 eq.) 16 was suspended in water (10 mL). Solubilizationoccurs after sodium hydroxyde (1.06 g, 26.5 mmol, 4.0 eq.) addition. Reaction mixture was cooleddown at 0°C, and propargylchloroformate (1.58 g, 13.2 mmol, 1.3 mL, 2.0 eq.) was added dropwise.Reaction mixture was allowed to warm up to room temperature for 30 minutes. Reaction mixture wasacidified with (12N) hydrochloric acid solution, extracted with ethyl acetate (3 x 100 mL), dried overmagnesium sulfate and solvents were evaporated under vacuum. The residue was purified by flashchromatography [40 g of SiO2; eluant: Cyclohexane / EtOAc; gradient: 100/0 0/100 (12 CV)]affording compound 18 (977 mg, 4.16 mmole, 63% yield) isolated as a white solid. |
With sodium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With resin bound tetrathiomolybdate In methanol at 28℃; for 1.5h; ultrasonic bath; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: (S)-2-phenylglycine; methyl chloroformate With sodium hydroxide In tetrahydrofuran; water monomer at 0 - 20℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water monomer | 16.1 Step 1) the preparation of compound 16-1 To a solution of L-phenylglycine (10.0 g, 66.1 mmol) in THF (10 mL) was added a solution of NaOH (10.6 g, 265 mmol) in H2O (60 mL) followed by methyl chloroformate (10.2 mL, 133 mmol) dropwise at 0 °C. The mixture was stirred at rt overnight, adjusted to pH 3 with hydrochloric acid (1 M) and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound 16-1 as a white solid (12.6 g, 91%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6): δ 12.84 (brs, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.41-7.29 (m, 5H), 5.14 (d, J = 8.3 Hz, 1H), 3.55 (s, 3H). |
91% | With sodium hydroxide In tetrahydrofuran; water monomer at 0 - 20℃; | 16.1 the preparation of compound 16-1 To a solution of L-phenylglycine (10.0 g, 66.1 mmol) in THF (10 mL) was added a solution of NaOH (10.6 g,265 mmol) in H2O (60 mL) followed by methyl chloroformate (10.2 mL, 133 mmol) dropwise at 0 °C. The mixture wasstirred at rt overnight, adjusted to pH 3 with hydrochloric acid (1 M) and extracted with EtOAc. The organic layer wasdried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound 16-1 as a white solid (12.6 g, 91%).The compound was characterized by the following spectroscopic data:1H NMR (400 MHz, DMSO-d6): δ 12.84 (brs, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.41-7.29 (m, 5H), 5.14 (d, J = 8.3 Hz,1H), 3.55 (s, 3H). |
90% | With anhydrous sodium carbonate; sodium hydroxide In water monomer at 20℃; Cooling with ice; | 1 (S)-2-((methoxycarbonyl)amino)-2-phenylacetic acid 15: Na2C03 (1.83 g, 17.2 mmol) was added to a solution NaOH (33 mL of 1M/H20, 33 mmol) and L-phenylglycine (5.0 g, 33.29 mmol), then the resulting solution was cooled with ice bath, Methyl chloro formate (2.8 mL, 36.1 mmol) was added dropwise to the cooled solvent. After completion of addition, the reaction mixture was stirred at rt for 3.25 hr. The reaction mixture was washed with ether (30 mL x 3), and the aqueous phase was cooled with ice bath and acidified with concentrated HC1 to a pH region of 1-2, and extracted with CH2C12 (30 mL x 3), dried over sodium sulfate and concentrated under vacuum to afford white solid, 6.2 g, 90%. |
70% | Stage #1: (S)-2-phenylglycine With sodium hydroxide In water monomer at 0℃; for 0.0833333h; Stage #2: methyl chloroformate In 1,4-dioxane; water monomer at 25 - 30℃; for 24h; | 5.1.2 Procedure for the synthesis of amino acids carbamate (caps) which are shown in Scheme 1 General procedure: In a round-bottomed flask, the required amino acid (24mmol) was dissolved in an aqueous solution of NaOH (75mL, 1M) and left to cool in an ice bath at 0°C for 5min. Then, the respective chloroformate (33mmol) in 1,4-dioxane (30mL) was added portionwise to the above solution and stirred overnight at 25-30°C. Then, the reaction mixture was extracted twice using diethyl ether and the aqueous layer was acidified using HCl until the pH=2. The respective carbamates were isolated from the aqueous layer by extraction with diethyl ether (twice). The organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum to give the product. The product was used without further purification. |
70% | Stage #1: (S)-2-phenylglycine With sodium hydroxide In water monomer at 0℃; for 0.0833333h; Stage #2: methyl chloroformate In 1,4-dioxane; water monomer at 25 - 30℃; for 24h; | 5.1.2 Procedure for the synthesis of amino acids carbamate (caps) which are shown in Scheme 1 General procedure: In a round-bottomed flask, the required amino acid (24mmol) was dissolved in an aqueous solution of NaOH (75mL, 1M) and left to cool in an ice bath at 0°C for 5min. Then, the respective chloroformate (33mmol) in 1,4-dioxane (30mL) was added portionwise to the above solution and stirred overnight at 25-30°C. Then, the reaction mixture was extracted twice using diethyl ether and the aqueous layer was acidified using HCl until the pH=2. The respective carbamates were isolated from the aqueous layer by extraction with diethyl ether (twice). The organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum to give the product. The product was used without further purification. |
52% | With anhydrous sodium carbonate; sodium hydroxide In water monomer at 20℃; for 2h; Cooling with ice; | 4 Preparation of (S)-2-(methoxycarbonylamino)-2-phenylacetic acid Sodium carbonate (0.631 g, 5.95 mmol) Phenylglycine (D-phenyl glycine) (1.8 g, 11.9 mmol) Of sodium hydroxide aqueous solution (10 mL of 1 M / H 2 O, 10 mmol) The reaction mixture was cooled in an ice-water bath. Methylene chloroformate (1.01 mL, 13.1 mmol) was added portionwise, Remove the ice bath The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with ether (3 X 18 mL), the water layer was cooled in an ice bath, then conc.HCl was added Acidified to pH 1-2 and extracted with dichloromethane (3 X 18 mL). The organic layer was dried over anhydrous magnesium sulfate After filtration and concentration in vacuo, the resulting oil residue was treated with diethyl ether / hexane (5/4, 10 mL) to give a precipitate Water was produced. The resulting precipitate was filtered, washed with diethyl ether / hexane (1/3) and then dried under vacuum to give the desired (S) -2- (methoxycarbonylamino) -2-phenylacetic acid (1.3 g, 52% yield) as a white solid. |
With Sodium hydrogenocarbonate In chloroform; water monomer | ||
With potassium carbonate In acetone | ||
With anhydrous sodium carbonate; sodium hydroxide In water monomer at 20℃; for 3h; | ||
With sodium hydroxide; anhydrous sodium carbonate; sodium hydroxide In 1,4-dioxane; water monomer at 20℃; for 3h; | ||
With sodium hydroxide In 1,4-dioxane; water monomer at 0 - 20℃; | 4.1.1 General procedures for the preparation of capping groups CG 1-20 General procedure: A 500mL round bottom flask was equipped with a magnetic stir bar, charged with distilled H2O (100mL) and NaOH (100mmol, 4.0g) and cooled in an ice bath to 0°C. l-Phenylglycine/l-Methionine/d-Phenylglycine/d-Methionine (35mmol) was added, and stirred until the solution was homogeneous. The corresponding carbonyl chloride (45.5mmol) in 1,4-dioxane (40mL) was added dropwise using an addition funnel. The reaction mixture was left to stir overnight at room temperature. The solution was extraction of the solution with Et2O (3×50mL) was done, and the organic layers were discarded. The aqueous layer was cooled in an ice bath to 0°C, and concentrated HCl was added dropwise until the pH=2. The re-extraction of the aqueous solution was done with Et2O (3×100mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuum to give the product as clear viscous oil. No further purification was required. | |
With sodium hydroxide In 1,4-dioxane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: (S)-2-phenylglycine With sodium hydroxide at 25℃; for 0.5h; Stage #2: 2-Nitrobenzenesulfonyl chloride With sodium hydroxide In tetrahydrofuran at 0 - 25℃; for 20h; | |
84.6% | With sodium hydroxide In tetrahydrofuran at 0 - 20℃; for 20h; | 1.A 2-Nitro-benzenesulfonylamino)-1-(S)-phenyl-acetic acid Step A: 2-Nitro-benzenesulfonylamino)-1-(S)-phenyl-acetic acid To a stirred solution of 1 N sodium hydroxide (725 cm3, 725 mmol) was added (S)-(+)-2 phenylglycine (100.0 g, 662 mmol) that dissolved after 30 minutes at ambient temperature. Tetrahydrofuran (500 cm3) was added at ambient temperature and the solution cooled to 0° C. in an ice bath. Simultaneously both 6N sodium hydroxide (100 cm3, 600 mmol) and 2-Nitrobenzenesulfonyl chloride (154.9 g, 695 mmol) dissolved in tetrahydrofuran (225 cm3) were added dropwise with stirring at 0° C. over 1 hour. The solution was allowed to warm and stir at ambient temperature for 20 hours. Volatile fractions were removed in vacuo and the aqueous solution acidified with 6N hydrochloric acid to pH 1.0 to form a precipitate. The mixture was vacuum filtered to afford a yellow precipitate. The precipitate was washed with water (3*100 ml) and vacuum dried at 50° C. to a constant weight to afford the title compound as a yellow solid (188.2 g, 84.6%) with a negative ion ESI (M-H) -335.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: (S)-2-phenylglycine With N,N,N',N'-tetramethylguanidine In methanol for 0.0833333h; Stage #2: ethyl trifluoroacetate, In methanol at 20℃; for 30h; | |
With 1,1,3,3-tetramethylguanidine In methanol at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triflic azide; potassium carbonate; copper(II) sulfate In methanol; dichloromethane; water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With toluene-4-sulfonic acid In cyclohexane at 135℃; for 12h; Heating / reflux; | II To a slurry of (S)-phenylglycine (5g, 33.1 mmol) in cyclohexane (150ml) was added cyclopentanol (29.84ml, 331 mmol) and p-toluene sulfonic acid (6.92g, 36.4mmol). The reaction was fitted with a Dean-Stark receiver and heated to 135°C for complete dissolution. After 12h, the reaction was cooled to RT leading to the precipitation of a white solid. The solid was filtered and washed with EtOAc before drying under reduced pressure to give the required product as a white powder (11.01 g, 85%). 1H NMR (300MHz, d6-DMSO) δ: 8.82 (2H, br s), 8.73 (1 H, br s), 7.47 (7H, m), 7.11 (2H, d), 5.25 (1 H, br s), 5.18 (1 H, m), 2.29 (3H, s), 1.87-1.36 (8H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In cyclohexane at 135℃; for 12h; | F.1 Intermediate F; Scheme 3; Stage 1; - Cyclopentyl (2S)-amino(phenyl)acetate tosylate salt (Intermediate F)To a slurry of (S)-phenylglycine (5g, 33.1mmol) in cyclohexane (150ml) was added cyclopentanol (29.8ml, 0.33mol) and p-toluene sulfonic acid (6.92g, 36.4mmol). The reaction was fitted with a Dean-Stark receiver and heated to 1350C for complete dissolution. After 12 hours, the reaction was cooled to RT leading to the precipitation of a white solid. The solid was filtered and washed with EtOAc before drying under reduced pressure to give the title intermediate as a white powder (11.Og, 85%). 1H NMR (300 MHz, c/6-DMSO) δ: 8.82 (2H, br EPO s), 8.73 (1 H, br s), 7.47 (7H, m), 7.11 (2H, d), 5.25 (1 H1 br s), 5.18 (1 H, m), 2.29 (3H, s), 1.87-1.36 (8H1 m). |
85% | In cyclohexane at 135℃; for 12h; | II.1 Route Il; Stage 1 - Ester formation to yield (1S)-2-(cyclopentyloxy)-2-oxo-1-phenylethanaminium 4- methylbenzenesulfonate (Intermediate C); To a slurry of (S)-phenylglycine (5g, 33.1mmol) in cyclohexane (15OmL) was added cyclopentanol (29.84mL, 331mmol) and p-toluene sulfonic acid (6.92g, 36.4mmol). The reaction was fitted with a Dean-Stark receiver and heated to 135°C for complete dissolution. After 12h, the reaction was cooled to RT leading to the precipitation of a white solid. The solid was filtered and washed with EtOAc before drying under reduced pressure to give the required product as a white powder (11.01 g, 85%). 1H NMR (300MHz, d6- EPO 33DMSO) δpδ.82 (2H, br s), 8.73 (1 H, br s), 7.47 (7H, m), 7.11 (2H, d), 5.25 (1 H, br s), 5.18 (1 H, m), 2.29 (3H, s), 1.87-1.36 (8H, m). |
85% | In cyclohexane at 135℃; for 12h; | B9 Intermediate B9; Scheme 3Cyclopentanol (29.8 mL, 331 mmol) and p-toluene sulfonic acid (6.92 g, 36.4 mmol) were added to a slurry of (S)-phenylglycine (5.00 g, 33.1 mmol) in cyclohexane (15OmL). The reaction was fitted with a Dean-Stark receiver and heated to 135 0C for complete dissolution. After 12 hours, the reaction was allowed to cool to room temperature leading to the precipitation of a white solid. The solid was collected by filtration, washed with EtOAc and dried under reduced pressure to afford the title compound as a white solid (11.01 g, 85 % yield).1H NMR (300MHz, DMSO-Cf6) 8.82 (2H, br s), 8.73 (1 H, br s), 7.47 (7H1 m), 7.11 (2H, d), 5.25 (1 H, br s), 5.18 (1H, m), 2.29 (3H, s), 1.87-1.36 (8H, m). |
85% | In cyclohexane at 135℃; for 12h; | 3c.II.1 Stage 1 - (1S)-2-(cyclopentyloxy)-2-oxo-1-phenylethanaminium A- methylbenzenesulfonate (Intermediate 3c)To a slurry of (S)-phenylglycine (5 g, 33.1 mmol) in cyclohexane (150 ml) was added cyclopentanol (29.84 ml, 331 mmol) and p-toluene sulfonic acid (6.92 g, 36.4 mmol). The reaction was fitted with a Dean-Stark receiver and heated to 1350C for complete dissolution. After 12 hr, the reaction was cooled to RT leading to the precipitation of a white solid. The solid was filtered and washed with EtOAc before drying under reduced pressure to give the required product as a white powder (11.01 g, 85%). 1H NMR (300MHz, d6-DMSO) δ; 8.82 (2H, br s), 8.73 (1 H, br s), 7.47 (7H, m), 7.11 (2H, d), 5.25 (1 H, br s), 5.18 (1 H, m), 2.29 (3H, s), 1.87-1.36 (8H, m). |
85% | In cyclohexane at 135℃; for 12h; | 11.1 To a slurry of (S)-phenylglycine (5 g, 33.1 mmol) in cyclohexane (150 ml) was added cyclopentanol (29.84 ml, 331 mmol) and p-toluene sulfonic acid (6.92 g, 36.4 mmol). The reaction was fitted with a Dean-Stark receiver and heated to 135 0C for complete dissolution. After 12 hrs, the reaction was cooled to RT leading to the precipitation of a white solid. The solid was filtered and washed with EtOAc before drying under reduced pressure to give the required product as a white powder (11.01 g, 85 % yield).1H NMR (300MHz, DMSO-d6) δ; 8.82 (2H, br s), 8.73 (1 H1 br s), 7.47 (7H, m), 7.11 (2H, d), 5.25 (1H, br s), 5.18 (1H, m), 2.29 (3H, s), 1.87-1.36 (8H, m). |
85% | In cyclohexane at 135℃; for 12h; | II.1 Route Il (exemplified for Intermediate 10); Stage 1 - Ester formation to yield (1S)-2-(cyclopentyloxy)-2-oxo-1-phenylethanaminium 4-methylbenzenesulfonate (Intermediate 10); To a slurry of (S)-phenylglycine (5g, 33.1 mmol) in cyclohexane (150ml) was added cyclopentanol (29.84ml, 331 mmol) and p-toluene sulfonic acid (6.92g, 36.4mmol). The reaction was fitted with a Dean-Stark receiver and heated to 135°C for complete dissolution. After 12h, the reaction was cooled to RT leading to the precipitation of a white solid. The solid was filtered and washed with EtOAc before drying under reduced pressure to give the required product as a white powder (11.01 g, 85%). 1H NMR (300MHz, GVDMSO) δ; 8.82 (2H, br s), 8.73 (1H, br s), 7.47 (7H, m), 7.11 (2H, d), 5.25 (1 H, br s), 5.18 (1 H, m), 2.29 (3H, s), 1.87-1.36 (8H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In cyclohexane at 135℃; for 12h; | Method II.1 Method Il (exemplified for Intermediate LD; Stage 1 - Ester formation to yield cyclopentyl (2S)-amino(phenyl)acetate tosylate salt(Intermediate L1); To a slurry of (S)-phenylglycine (5g, 33.1mmol) in cyclohexane (15OmL) was added cyclopentanol (29.84mL, 331 mmol) and p-toluene sulfonic acid (6.92g, 36.4mmol). The reaction was fitted with a Dean-Stark receiver and heated to 1350C for complete dissolution. After 12h, the reaction was cooled to RT leading to the precipitation of a white solid. The solid was filtered and washed with EtOAc before drying under reduced pressure to give the required product as a white powder (11.01g, 85%). 1H NMR (300MHz, Cf6-DMSO) δ: 8.82 (2H1 br s), 8.73 (1 H, br s),7.47 (7H1 m), 7.11 (2H, d), 5.25 (1 H, br s), 5.18 (1 H, m), 2.29 (3H, s), 1.87-1.36 (8H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1.1: AcCl / Heating 2.1: Et3N / CH2Cl2 / 20 °C 3.1: tetrahydrofuran / -78 °C 4.1: NaH / tetrahydrofuran / 20 °C 5.1: O3; NaOH / CH2Cl2 / -78 °C 6.1: HCl / methanol / 20 °C 7.1: 75 percent / Zn(BH4)2 / tetrahydrofuran / -78 °C 8.1: NaHCO3 / methanol / 0 °C 9.1: SOCl2 / CH2Cl2 / Heating 10.1: HCl / H2O; methanol / Heating 10.2: NaHCO3 / H2O; methanol / 50 °C | ||
Multi-step reaction with 7 steps 1: 100 percent / SOCl2 / diethyl ether / -10 °C 2: 58 percent / Li2CO3 / tetrahydrofuran / 16 h / Heating 3: 73 percent / HCl 4: NaBH4 5: 62 percent / pyridine 6: 70 percent / K2CO3 / methanol; H2O 7: KF / H2O | ||
Multi-step reaction with 7 steps 1: 100 percent / SOCl2 / diethyl ether / -10 °C 2: 58 percent / Li2CO3 / tetrahydrofuran / 16 h / Heating 3: 73 percent / HCl 4: 72 percent / Baker's yeast 5: 62 percent / pyridine 6: 70 percent / K2CO3 / methanol; H2O 7: KF / H2O |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Stage #1: (S)-2-phenylglycine With thionyl chloride In methanol at 0 - 20℃; Stage #2: (S)-2-phenylglycine In methanol at 20℃; Stage #3: With ammonia In water; toluene at 20℃; | 64 Example 64N-[(1S)-2-amino-1-phenylethyl]-3-(benzoylamino)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide Preparation of compound 64d: (S)-benzyl 2-amino-2-phenylethylcarbamateSOCl2 (785 g, 6.6 mol) was added dropwise to CH3OH (1.5 L) at 0, then the reaction mixture was warmed to room temperature and stirred for 2 h. After addition of L-amino-phenyl-acetic acid (250 g, 1.66 mol) portionwise, the mixture was stirred at room temperature overnight. The mixture was evaporated to dryness to give compound a white powder. This white solid was then dissolved in 1.5 liter of toluene. NH3,H2O (875 mL, 28%) was then added dropwise. The resulting mixture was stirred at room temperature for 30 h. The mixture was evaporated to a small volume, and the precipitate was filtered and washed with anhydrous ether to provide compound 64a (120 g, 46%) as a white solid. Compound 64a (120 g, 0.81 mol) and trimethyl amine (78 g, 0.77 mol) in anhydrous CH2Cl2 (1.5 L) was added dropwise a solution of triphenylmethyl chloride (214 g, 0.77 mol) in anhydrous CH2Cl2 (200 mL). The mixture was stirred at room temperature overnight, and TLC (CH2Cl2/MeOH 10:1) indicated that the reaction was complete. The mixture was quenched with water and extracted with CH2Cl2 (500 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated to give a pale yellow solid which was washed with ether to afford compound 64b as a white solid (300 g, 95%). Compound 64b (300 g, 0.76 mol) in anhydrous ethyl ether (1.5 L) was added LiAlH4 (300 g, 7.89 mol) at 0 in portions, then the reaction mixture was warmed to room temperature and stirred for 60 h. TLC (pentane/ethyl acetate 1:1) showed the reaction was complete. To the reaction mixture was added H2O slowly (100 mL) at -10, and the resulting mixture was then filtered and evaporated to give a pale yellow oil. This yellow pale oil and triethylamine (63.32 g, 0.58 mol) in CH2Cl2 (1.5 L) was added dropwise CbzCl (98 g, 0.58 mol) at 0. The reaction mixture was stirred at room temperature overnight. The mixture was washed with water and brine. The organic layer was evaporated to dryness and the residue was purified by column chromatography to give compound 64c (150 g, 56%). Compound 64c (150 g, 0.29 mol) in CH3OH (200 L) was added dropwise HCl/CH3OH (200 mL, 7 mol/L) at 0, and the mixture was stirred overnight. TLC (CH2Cl2/CH3OH 20:1) showed the reaction was complete. The reaction mixture was evaporated until solid precipitated. The solid was filtered and washed with ethyl ether to afford compound 64d (58.6 g, 74%) as a HCl salt. H1 NMR in dmso-d6 δ ppm: 8.8-8.6 (m, 3H, b), 7.55-7.15 (m, 10H), 4.97 (s, 2H), 4.45-4.25 (m, 1H), 3.60-3.40 (m, 2H). |
Multi-step reaction with 2 steps 1: 92 percent / thionyl chloride / 0.33 h / Heating 2: 68 percent / 28percent aq. NH3 / 96 h / Ambient temperature | ||
Multi-step reaction with 2 steps 2: methanol; NH3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With sodium hydrogencarbonate In ethanol; water at 72 - 75℃; for 70 - 80h; | 22 (S)-7-[Carboxy(phenyl)methyl]amino}-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid [(S)-V-13a] Example 22 (S)-7-[Carboxy(phenyl)methyl]amino}-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid [(S)-V-13a] A stirred mixture of (S)-phenylglycine [1.36 g, 9 mmol], VII (1.0 g, 3 mmol) and sodium hydrogen carbonate (1.5 g, 18 mmol) in 50 % aqueous ethanol (140 ml) was heated at 72-75 °C for 70-80 h under reflux conditions. Work-up of the reaction mixture as described for V-1a above, gave the title compound as fluorescent yellow solid that was recrystallized from chloroform / ethanol (2:1, v/v). Yield 0.70 g (53 %), mp 205 - 207 °C; MS(FAB): m/z (% rel. int.): 442[100, (M+H)+ / calcd. for C21H16FN3O7 441(M)]; 1H NMR (300 MHz, DMSO-d6): δ 0.96(m, 4H, H2-2'/ H2-3'), 3.68(m, 1H, H-1'), 5.67(dt, J= 6 Hz, 3 Hz, 1H, α-CH-Ph), 7.31(m, 5H, H-2'/ H-6', H-3'/ H-5', H-4'), 7.95(d, 3JH-F = 13.2 Hz, 1H, H-5), 8.04(br d, J= 6 Hz, 1H, N-H), 8.75(s, 1H, H-2), 13.36(br s, 1H, CH-CO2H), 14.48(br s, 1H, C(3)-CO2H); 13C NMR (75 MHz, DMSO-d6): δ 10.1(C-2'/ C-3'), 40.8(C-1'), 61.4(α-CH-Ph), 109.8(C-3), 115.1(d, 2JC-F = 21.9 Hz, C-5), 117.8(d, 3JC-F = 6.8 Hz, C-4a), 127.2(C-2'/ C-6'), 129.0(C-4'), 129.1(d, 3JC-F = 5.5 Hz, C-8), 129.5(C-3'/ C-5'), 135.6(C-8a), 137.0(d, 2JC-F = 15.9 Hz, C-7), 138.1(C-1'), 150.0(d, 1JC-F = 249 Hz, C-6), 152.2(C-2), 165.3(C(3)-CO2H), 172.2(CH-CO2H), 175.5(d, 4JC-F = 2.3 Hz, C-4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | Stage #1: 2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one; (S)-2-phenylglycine With 4-methyl-morpholine Heating / reflux; Stage #2: With potassium hydrogensulfate In water | 6 10 ml of N-methylmorpholine was added to 583 mg (3.9 mmol) of L-phenylglycine and 500 mg (1.9 mmol) of 2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and heated under reflux overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium hydrogensulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 92 mg (22%) of the title compound.1H-NMR (CDCl3, δ): 1.25-1.58 (3H, m), 1.60-1.81 (3H, m), 1.85-2.05 (2H, m), 2.17-2.39 (2H, m), 3.86 (3H, s), 4.45 (1H, d, J=6 Hz), 6.01 (1H, s), 6.82-7.00 (3H, m), 7.19-7.38 (4H, m), 7.57-7.83 (3H, m) |
22% | Stage #1: 2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one; (S)-2-phenylglycine With 4-methyl-morpholine Heating / reflux; Stage #2: With potassium hydrogensulfate In water | 237 REFERENCE EXAMPLE 237N-[[[1-[(4-Methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycine 10 ml of N-methylmorpholine was added to 583 mg (3.9 mmol) of L-phenylglycine and 500 mg (1.9 mmol) of 2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and heated under reflux overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium hydrogensulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 92 mg (22%) of the title compound.1H-NMR (CDCl3, δ): 1.25-1.58 (3H, m), 1.60-1.81 (3H, m), 1.85-2.05 (2H, m), 2.17-2.39 (2H, m), 3.86 (3H, s), 4.45 (1H, d, J=6 Hz), 6.01 (1H, s), 6.82-7.00 (3H, m), 7.19-7.38 (4H, m), 7.57-7.83 (3H, m) |
22% | Stage #1: 2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one; (S)-2-phenylglycine With 4-methyl-morpholine Heating / reflux; Stage #2: With potassium hydrogensulfate In water | 193 N-[[[1-[(4-Methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycine Reference Example 193 N-[[[1-[(4-Methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycine 10 ml of N-methylmorpholine was added to 583 mg (3.9 mmol) of L-phenylglycine and 500 mg (1.9 mmol) of 2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and heated under reflux overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium hydrogensulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 92 mg (22%) of the title compound. 1H-NMR (CDCl3, δ): 1.25-1.58 (3H, m), 1.60-1.81 (3H, m), 1.85-2.05 (2H, m), 2.17-2.39 (2H, m), 3.86 (3H, s), 4.45 (1H, d, J=6Hz), 6.01 (1H, s), 6.82-7.00 (3H, m), 7.19-7.38 (4H, m), 7.57-7.83 (3H, m) |
22% | With 4-methyl-morpholine Heating / reflux; | 220 Reference example 220 ; N-[[[1-[(4-Methoxyphenyl)carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycine [Show Image] 10 ml of N-methylmorpholine was added to 583 mg (3.9 mmol) of L-phenylglycine and 500 mg (1.9 mmol) of 2-(4-methoxyphenyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and refluxed under heating overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained orgnanic layer was dried with anhydrous sodium hydrogensulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 92 mg (22%) of the title compound. 1H-NMR (CDCl3, δ) : 1.25-1.58 (3H, m), 1.60-1.81 (3H, m), 1.85-2.05 (2H, m), 2.17-2.39 (2H, m), 3.86 (3H, s), 4.45 (1H, d, J=6Hz), 6.01 (1H, s), 6.82-7.00 (3H, m), 7.19-7.38 (4H, m), 7.57-7.83 (3H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | Stage #1: 2-(1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one; (S)-2-phenylglycine With 4-methyl-morpholine Heating / reflux; Stage #2: With potassium hydrogensulfate In water | 4 10 ml of N-methylmorpholine was added to 583 mg (3.9 mmol) of L-phenylglycine and 500 mg (1.9 mmol) of 2-(1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and heated under reflux overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 120 mg (17%) of the title compound.1H-NMR (CDCl3, δ): 1.18-2.08 (9H, m), 2.18-2.30 (1H, m), 5.63 (1H, d, J=7 Hz), 6.16-6.23 (1H, m), 6.25 (1H, s), 6.61-6.83 (2H, m), 7.17-7.35 (3H, m), 7.41 (2H, d, J=8 Hz), 7.83 (1H, d, J=7 Hz), 10.92 (1H, s) |
17% | Stage #1: 2-(1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one; (S)-2-phenylglycine With 4-methyl-morpholine Heating / reflux; Stage #2: With potassium hydrogensulfate In water | 235 REFERENCE EXAMPLE 235N-[[[1-[(1H-Pyrrol-2-yl)carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycine 10 ml of N-methylmorpholine was added to 583 mg (3.9 mmol) of L-phenylglycine and 500 mg (1.9 mmol) of 2-(1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and heated under reflux overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 120 mg (17%) of the title compound.1H-NMR (CDCl3, δ): 1.18-2.08 (9H, m), 2.18-2.30 (1H, m), 5.63 (1H, d, J=7 Hz), 6.16-6.23 (1H, m), 6.25 (1H, s), 6.61-6.83 (2H, m), 7.17-7.35 (3H, m), 7.41 (2H, d, J=8 Hz), 7.83 (1H, d, J=7 Hz), 10.92 (1H, s |
17% | Stage #1: 2-(1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one; (S)-2-phenylglycine With 4-methyl-morpholine Heating / reflux; Stage #2: With potassium hydrogensulfate In water | 191 N-[[[1-[(1H-Pyrrol-2-yl)carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycine Reference Example 191 N-[[[1-[(1H-Pyrrol-2-yl)carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycine 10 ml of N-methylmorpholine was added to 583 mg (3.9 mmol) of L-phenylglycine and 500 mg (1.9 mmol) of 2-(1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and heated under reflux overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 120 mg (17%) of the title compound. 1H-NMR (CDCl3, δ): 1.18-2.08 (9H, m), 2.18-2.30 (1H, m), 5.63 (1H, d, J=7Hz), 6.16-6.23 (1H, m), 6.25 (1H, s), 6.61-6.83 (2H, m), 7.17-7.35 (3H, m), 7.41 (2H, d, J=8Hz), 7.83 (1H, d, J=7Hz), 10.92 (1H, s) |
17% | With 4-methyl-morpholine Heating / reflux; | 218 Reference example 218; N-[[[1-[(1H-Pyrrol-2-yl)carbonyl]amino]cyclohexyl]carbonyl]-L-phenylglycine [Show Image] 10 ml of N-methylmorpholine was added to 583 mg (3.9 mmol) of L-phenylglycine and 500 mg (1.9 mmol) of 2-(1H-pyrrol-2-yl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and refluxed under heating overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 120 mg (17%) of the title compound. 1H-NMR (CDCl3, δ): 1.18-2.08 (9H, m), 2.18-2.30 (1H, m), 5.63 (1H, d, J=7Hz), 6.16-6.23 (1H, m), 6.25 (1H, s), 6.61-6.83 (2H, m), 7.17-7.35 (3H, m), 7.41 (2H, d, J=8Hz), 7.83 (1H, d, J=7Hz), 10.92 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Stage #1: 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one; (S)-2-phenylglycine With 4-methyl-morpholine Heating / reflux; Stage #2: With potassium hydrogensulfate In water | 2 10 ml of N-methylmorpholine was added to 530 mg (3.5 mmol) of L-phenylglycine and 500 mg (1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and heated under reflux overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 259 mg (34%) of the title compound.1H-NMR (CDCl3, δ): 1.25-1.80 (6H, m), 1.83-2.03 (2H, m), 2.12-2.40 (2H, m), 4.47 (1H, d, J=5 Hz), 6.11 (1H, s), 7.18-7.55 (8H, m), 7.79 (1H, s), 7.80-7.91 (2H, m) |
34% | Stage #1: 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one; (S)-2-phenylglycine With 4-methyl-morpholine Heating / reflux; Stage #2: With potassium hydrogensulfate In water | 233 REFERENCE EXAMPLE 233N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycine 10 ml of N-methylmorpholine was added to 530 mg (3.5 mmol) of L-phenylglycine and 500 mg (1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and heated under reflux overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 259 mg (34%) of the title compound.1H-NMR (CDCl3, δ): 1.25-1.80 (6H, m), 1.83-2.03 (2H, m), 2.12-2.40 (2H, m), 4.47 (1H, d, J=5 Hz), 6.11 (1H, s), 7.18-7.55 (8H, m), 7.79 (1H, s), 7.80-7.91 (2H, m) |
34% | With 4-methyl-morpholine Heating / reflux; | 216 Reference example 216; N-[[1-[(2-Benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-phenylglycine [Show Image] 10 ml of N-methylmorpholine was added to 530 mg (3.5 mmol) of L-phenylglycine and 500 mg (1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and refluxed under heating overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 259 mg (34%) of the title compound. 1H-NMR (CDCl3, δ): 1.25-1.80 (6H, m), 1.83-2.03 (2H, m), 2.12-2.40 (2H, m), 4.47 (1H, d, J=5Hz), 6.11 (1H, s), 7.18-7.55 (8H, m), 7.79 (1H, s), 7.80-7.91 (2H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Stage #1: (S)-2-phenylglycine With N-ethyl-N,N-diisopropylamine; 2-bromo-3,4-dimethyl-thiazolium bromide In dichloromethane at 0℃; for 0.5h; Stage #2: L-alanine methyl ester hydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 2h; | 1,5 g (5,26 mmol) Z-(S)-Phenylglycin werden bei - 5C in 10 ml abs. Dichlormethan gelost und mit 1,36 g (10,52 mmol) Ethyldiisopropylamin versetzt, gefolgt von 1,44g (5,26 mmol) 2-Brom-3,4-dimethylthiazoliumbromid. Man ruhrt bei 0C 30 min nach und versetzt mit einer Mischung aus 0,73 g (5,26 mmol) L-Alaninmethylesterhydrochlorid und 0,68 g (5,26 mmol) Ethyldiisopropylamin in 10 ml Dichlormethan. Man ruhrt fur 2 h bei 0C nach und versetzt zur Aufarbeitung mit 20 ml Dichlormethan und wascht die organische Phase nacheinander mit gesattigter Ammoniumchloridlosung und gesattigter Natriumchloridlosung. Die organische Phase wird uber MgSO4 getrocknet und das Losungs-mittel am Rotationsverdampfer abdestilliert. Der Ruckstand wird an Kieselgel mit Essigsaureethylester/Hexan 3:7 filtriert. Ausbeute: 0,6 g (31 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lipase AS 'Amano'; at 35℃; for 24h;pH 6.5;Enzymatic reaction; | General procedure: Kinetic resolution of <strong>[14257-84-2](RS)-<strong>[14257-84-2]2-acetamido-2-phenylacetic acid</strong></strong> (Table 2, entry 1). A 25 ml round-bottomed flask was charged with <strong>[14257-84-2](RS)-<strong>[14257-84-2]2-acetamido-2-phenylacetic acid</strong></strong> at a concentration of 50 mM and 5 mL of phosphorus buffer solution at pH 6.5. Next, 4.2 mg of free enzyme powder of lipase AS ?Amano? was added to the mixture. When this was completed, the resulting mixture was stirred at 35 C for 24 h. Yields and ee values of the products were determined by HPLC analysis. When the reaction was completed, the solution was filtered through a pad of cotton. The solution was changed to pH 7.0, extracted with ethyl acetate three times, and the combined organic solution was dried over anhydrous magnesium sulfate and then evacuated to remove the organic solvent. The resulting residues were purified by column chromatography on silica gel with petroleum ether/ethyl acetate (1:10-1:5) to afford the pure amino acids. |
Yield | Reaction Conditions | Operation in experiment |
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With dicyclohexyl-carbodiimide;dmap; In dichloromethane; at 0 - 35℃; for 5.16667h; | Example 12: Preparation of (S)-((S)-5-carbamoyl-10,ll-dihydro-5H-dibenzo [b,fj azepin-10-yI) 2-amino-2-phenylacetate compound of formula-9a.; 10-hydroxy-10,l l-dihydro-5H-dibenz[b,fJazepine-5-carboxamide compound of formula-4 (1 g) was added to a solution of (S)-2-amino-2-phenyl acetic acid compound of formula-8a (0.62 g) in dichloro methane (10 ml), followed by dimethylamino pyridine (0.12 g) and then cooled to 0-5C. Dicyclohexylcarbodiimide (1.269 g) was added to the reaction mixture and stirred for 10 minutes, Further the reaction mixture temperature was raised to 25-35C and stirred for 5 hours at 25-35C. After completion of the reaction, the reaction mixture was cooled to 0-5C. Filtered the reaction mixture to remove the undissolved product and washed with dichloro methane. The obtained filtrate was washed with 10% sodium bicarbonate solution, followed by water. Distilled off dichloromethane completely under reduced pressure and then added cyclohexane, further the reaction mixture was stirred for 1 hour at 25-35C. Filtered the solid and washed with cyclohexane. To the obtained solid further added water and stirred for 1 hour at 25-35C. Filtered the solid, washed with water and then dried to get the title compound. The obtained compound was further recrystallized twice from isopropyl alcohol to get the pure title compound. Yield: 6 grams; Purity by HPLC: 98%. |
Yield | Reaction Conditions | Operation in experiment |
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38% | Stage #1: (S)-2-phenylglycine; pivaloyl chloride With sodium hydroxide In water at 20℃; Stage #2: With hydrogenchloride In water | 3 4.3 (2R)- and (2S)-[(2,2-Dimethylpropanoyl)amino](phenyl)acetic acid General procedure: To a solution of (R)- or (S)-phenylglycine (1.512 g, 10 mmol) in 4% aqueous NaOH (30 mL) was added pivaloyl chloride (1.568 g, 13 mmol), and the resulting mixture was stirred at rt overnight. The solution was acidified to pH 1 using concentrated aqueous HCl solution, and the precipitate was filtered off. The crude product was recrystallized from water to give the pure acids [799 mg, 34% for the (R)-enantiomer and 901 mg, 38% for the (S)-enantiomer] as white crystals. (R)-enantiomer, mp: 134-137 °C; (c 1.0, MeOH). (S)-enantiomer, mp: 135-138 °C; (c 1.0, MeOH); IR (KBr) νmax 3422, 3300-2400, 1733, 1633, 1587, 1516, 1456, 1416, 1365, 1315, 1298, 1253, 1200, 1183, 1162, 1072, 1030, 979, 900, 862, 724, 701, 665, 636, 582, 533, 491 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 1.14 (s, 9H), 5.38 (d, J = 10 Hz, 1H), 7.30 (t, J = 7 Hz, 1H), 7.35 (t, J = 7 Hz, 2H), 7.40 (d, J = 7 Hz, 2H), 7.88 (d, J = 7 Hz, 1H, NH) 12.82 (br s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ 27.17, 38.00, 56.20, 127.67, 127.70, 137.58, 172.02, 177.12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With pyridine; acetic acid; at 20℃;Reflux; | General procedure: 2.942 g (10.00 mmol) of 3, 3, 4, 4- biphenyltetracarboxylic dianhydride 1, 20.00 mmol of L-amino acids 2a-f, 80 mL of mixture of acetic acid/pyridine (3:2) and a stirring bar were placed into a 250-mL round-bottomed flask. The mixture was stirred at room temperature overnight and refluxed for 4-10 h. The solvent was removed under reduced pressure, and the residue was dissolved in 100 mL of cold acidic water. A white to cream precipitate was formed, filtered off, and dried to give compounds [N, N-(4, 4-diphtaloyl)-bis-L-amino diacid]s 3a-f. |
Yield | Reaction Conditions | Operation in experiment |
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90% | With sodium azide In ethanol at 80℃; | 3.3. General procedure for the synthesis of tetrazoles General procedure: Amino acid (10 mmole), sodium azide (0.65 g, 10 mmole) and Cu nano catalyst (20 mg) were added to a solution of TEOF (4.4 g,5 ml, 30 mmole) in ethanol (5 ml). The solution was stirred and the mixture heated at 80 °C for 1-7 h depends on the substrate and completion of the reaction which monitored with TLC. Then,H2O (20 ml) was added, the Cu catalyst filtered, the filtrate concentrated and the solvent removed in vacuo. The obtained tetrazoles recrystallized in ethanol and characterized by comparing its physical and spectroscopic data with those reported in the literature(Scheme 1). |
65% | With sodium azide; acetic acid at 80℃; for 1h; | General Experimental Procedure for the Synthesis of 1-substituted-1H-1,2,3,4-tetrazoles from L-α-amino Acids General procedure: L--amino acid (0.01 mole) and sodium azide (0.65 g,0.01 mole) were added to a solution of TEOF (4.4 g, 5 mL,0.03 mole) and glacial acetic acid (20 mL) while stirring andthe mixture was heated at 80 °C for 1-7 h depending substrates(Table 1). The reaction mixture was then cooled andevaporated in a vacuum. For entries 1-3, the residue wasdissolved in acetone (50 mL), filtered and the filtrate wasevaporated in a vacuum. Distilled water was added (20 mL)and the pH of the solution adjusted to 9-10 with NaOH solution(5 M). The solution was refluxed with activated carbon(1.5 g) for 30 min, filtered, cooled and the pH adjusted to 2with HCl solution (2 M). Due to the low pKa of 1Htetrazoles(ca. 3-5) and their high crystalline nature [24],products were precipitated, separated and dried in vacuum at60 °C.For entries 4 and 5, after removal of HOAc, the residuewas dissolved in acetone (50 mL), and filtered, the filtrateconcentrated to 5 mL, CH2Cl2 (15 mL) added and allowedfor slow precipitation. The precipitate was filtered off to givethe white crystalline products.For entries 6-8 (Table 1), after removal of HOAc, theresidue was dissolved in distilled water, the pH adjusted to 9adding a solution of NaOH (5 M) and refluxed with activatedcarbon (1.5 g) for 30 min. After cooling, the solution wasfiltered, the pH of filtrate adjusted to 7 adding a solution ofHCl (1 M) and then evaporated in a vacuum. The crudeproduct was dissolved in dry ethanol (20 mL), cooled in afridge for 1h and filtered; the filtrate was concentrated to 10mL and acetone (70 mL) added to filtrate and allowed toslowly precipitate in a fridge. The precipitate was filtered offto give tetrazoles (55-80 %). All products were characterizedby NMR, FT-IR, elemental analysis (CHN), and meltingpoints. |
Yield | Reaction Conditions | Operation in experiment |
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With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h; | (f) 5-Hydroxy-6-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-thiazol-2-yl]-nicotinonitrile General procedure: To a solution of [2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetic acid (25 mg, 0.096 mmol), pyrrolidine (8.83 μl, 0.106 mmol), TBTU (33.8 mg, 0.106 mmol) and DMF (2 ml), triethylamine of 40 μl was added at room temperature. After 12 hours at this temperature, the reaction mixture was diluted with ethyl acetate and was washed with water three times. The organic layer was dried with magnesium sulfate and was concentrated under reduced pressure. The residue was purified via Prep-HPLC (Acetonitrile/0.1% formic acid solution) and the target compound of 21.5 mg was obtained. (72% yield)1H NMR (300MHz, DMSO-d6): δ 12.189 (s, 1H), 8.580 (d, J=1.8 Hz, 1H), 8.048 (d, J=1.5 Hz, 1H), 7.777 (s, 1H), 3.932 (s, 2H), 3.523 (t, 2H), 3.296 (t, 2H), 1.870 (m, 2H), 1.779 (m, 2H). MS: m/z 315 [M+1] | |
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h; | (f) 5-Hydroxy-6-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-thiazol-2-yl]-nicotino nitrile General procedure: To a solution of [2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetic acid (25 mg, 0.096 mmol), pyrrolidine (8.83 μl, 0.106 mmol), TBTU (33.8 mg, 0.106 mmol) and DMF (2ml), triethylamine of 40 μl was added at room temperature. After 12 hours at this temperature, the reaction mixture was diluted with ethyl acetate and was washed with water three times. The organic layer was dried with magnesium sulfate and was concentrated under reduced pressure. The residue was purified via Prep-HPLC (Acetonitrile/0.1% formic acid solution) and the target compound of 21.5 mg was obtained. (72% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 18 h / Reflux; Inert atmosphere; Glovebox; Schlenk technique 2: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere; Glovebox; Schlenk technique 3: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere; Glovebox; Schlenk technique 4: tetrahydrofuran / 16 h / -40 - 20 °C / Inert atmosphere; Glovebox; Schlenk technique 5: trifluoroacetic acid / dichloromethane / 15 h / 0 - 20 °C / Inert atmosphere; Glovebox; Schlenk technique | ||
Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate; iodine / tetrahydrofuran / 18 h / 65 °C 2.1: potassium carbonate / 3 h / 135 °C 3.1: toluene / 0.5 h / 20 °C / Schlenk technique; Inert atmosphere 3.2: 24 h / Schlenk technique; Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.2% | With sodium hydrogencarbonate In methanol for 0.5h; | 2.4.1 General procedure for synthesis of [(η5-Cp R)Ir(aa)Cl] complexes General procedure: A round bottom flask was charged with appropriate amounts of the respective [Cp R IrCl2]2, amino acid, sodium hydrogen carbonate, and methanol with magnetic stirring. The initially orange solution changed to yellow over the course of approximately 30min. The solvent was then removed under reduced pressure. The product was extracted away from unreacted amino acid and sodium hydrogen carbonate with dichloromethane (3×10mL) and filtered. The complexes were recrystallized from dichloromethane and ether or hexanes and collected on a frit as yellow crystalline powders. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In water; N,N-dimethyl-formamide at 20℃; for 1.5h; | Typical experimental procedure for the preparation of amino acid thiohydantoin General procedure: To a solution of amino acid (02 mmol) with TEA in (8:2) DMF and water (10 mL), phenylisothiocyanate (02 mmol) was added. The reaction mixture was stirred at room temperature. The progress of reaction was monitored by TLC (30% EtOAc: Hexane or 5-10% MeOH: CHCl3). The solid product was obtained after acidification with 1N HCl. Filter the solid and recrystallize with aq. EtOH to afford pure products. |
Yield | Reaction Conditions | Operation in experiment |
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84% | With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; Cooling with ice; | 1 The synthesis of (6 -2-(((methylperoxy)methyl)amino)-2-phenylacetic acid L-a-phenylglycine (4 g, 26.46 mmol) was dissolved in THF (80 mL) followed by the addition of sodium bicarbonate (6.68 g, 79.54 mmol) in water (80 mL) then added methylchloroformate (2.25 mL, 29.18 mmol) under ice-bath cooling. The reaction mixture was stirred at room temperature overnight. The mixture was acidified to pH 2-3 with 6N HC1, then concentrated in vacuo to remove THF. The aqueous layer was extracted with ethyl acetate (20 mL x 2), the organic layer was dried over sodium sulfate, filtered, concentrated to afford the pale-yellow solid, triturated several times with a mixture solvent of ethyl acetate and hexane (V/V 20/60) to get white solid, 4.73 g, 84%. (0193) (1) (5)-2-(((methylperoxy)methyl)amino)-2-phenylacetic acid using sodium hydroxide method gave a trace amount of racemization when synthesized the final compound. The sodium bicarbonate method may give a complete single isomer. |
Yield | Reaction Conditions | Operation in experiment |
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76% | With sodium hydroxide In ethanol; water at 60 - 70℃; | General Method for Synthesizing Colchicine C-10-Amino-Acid Derivatives 2-14 General procedure: A solution of colchicine (1, 4.00 g, 10 mmol) in EtOH (10 mL) was treated with a solution of the appropriate amino acid (20 mmol) and NaOH (0.80 g ,20 mmol) in distilled H2O (10 mL), stirred vigorously, and heated (60-70°C) for 5-7 h (end of reaction determined by TLC). After the reaction was finished, the EtOH was removed in vacuo in a rotary evaporator. The residue was extracted with EtOAc (3 ϰ 10 mL). The aqueous phase was acidified to pH 5. The resulting precipitate of 2-14 was filtered off and crystallized from aqueous EtOH. The organic phase was dried over anhydrous Na2SO4. The EtOAc was removed in vacuo in a rotary evaporator. The residue was triturated with Et2O to isolate 15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sulfuric acid; potassium carbonate In toluene at 70 - 75℃; for 1.5h; | 6-7 Preparation of compound 10: Add potassium carbonate (8.22g) and compound 9 (10g) to the solvent toluene (80g), raise the temperature to 70°C and stir; slowly add 8.6g diethyl carbonate dropwise under the control of the system at 75°C, and keep it warm after dripping. Stir and react for 1.5h. After the heat preservation is completed, atmospheric distillation is carried out. When the internal temperature is 95°C, an azeotrope of toluene and water will flow out. After the distillation, the temperature of the system will be lowered to below 40°C; after replacing the system with nitrogen, under nitrogen protection Add potassium carbonate (2g) in batches, stir and raise the temperature after the addition is complete; keep the temperature at 100°C and reflux for 30 minutes and then cool to below 40°C; add acetic acid (1.5g) and water (33g) dropwise; after the addition, cool the system to 10°C After stirring for 1 hour, (S)-4-phenyl-2-oxazolidinone compound 10 was obtained by filtration with a yield of 83%. |
77% | With potassium carbonate at 130 - 140℃; | 4.2.1 Synthesis of (R,S) 4-phenyloxazolidin-2-one 13 General procedure: A dry 250ml three-necked round bottom flask equipped with a thermometer and a 10cm vigreux column with a distillation head, was charged with 4.3g of the (R,S)-phenylglycinol (31.4mmol) obtained and added of 9.3g of diethyl carbonate (79.0mmol) and 0.43g of K2CO3 (3.10mmol). The mixture was heated carefully to 130-140°C and the ethanol was distils as it formed. The oily residue was cooled and added by 50ml of CH2Cl2 to facilitate the filtration of the remaining potassium carbonate. The organic phase was then washed with a satured solution of NaHCO3, separated and dried over anhydrous Na2SO4, filtrate and evaporated in vacuo. The residue was crystallized from AcOEt/Etp (1:3) to afford 4.3g (26.4mmol, 85%) of 13 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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53% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In methanol at 20℃; | A general procedure for synthesizing 2-amino-4-oxo-3,4-dihydropteridine-7-carboxamides (1a-o) General procedure: To a suspension of 7-methoxycarbonylpterin (7-MCP) in MeOH (0.5-1.0 mM) was added DBU (2 eq. vs. 7-MCP and 1 eq. vs. acidic functional groups) to give a clear solution. Amino acid was added to the mixture, which was then stirred at room temperature for 4-53 h. After confirming the consumption of the starting 7-MCP and the formation of the product by ESI mass spectrometry, the reaction mixture was diluted with MeOH and then acidified with 6 M HCl. The resulting precipitate was collected and then dissolved in diluted aqueous NaOH,which was passed through an LH-20 (100 g) column eluted with 0.1 M NaCl. The second yellow fraction was collected and acidified with 6 M HCl until pH ~2 to give a yellow precipitate, which was collected and dried in vacuo to give the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 3-Phenylpropionic acid With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.5h; Green chemistry; Stage #2: (S)-2-phenylglycine With water In tetrahydrofuran at 0℃; for 0.5h; Green chemistry; | General procedure: To a colorless solution of 75 mg (0.50 mmol) of 1 in 10 mL of THF were added at 0 °C 67 μL (0.70 mmol, 1.4 equiv) of ethyl chloroformateand 209 μL (1.5 mmol, 3.0 equiv) of triethylamine. After stirring at 0 °C for 30 min, a solution of 124 mg (0.75 mmol,1.5 equiv) of 2a in 10 mL of H2O was added at 0 °C to the colorless suspension. The mixture was stirred at 0 °C for 30 min and concentratedin vacuo. To the residue was added a 1.0 M aqueous HCl solution to adjust to pH 2. The resulting suspension was extractedwith 50 mL of EtOAc, washed with 10 mL of brine, and dried over MgSO4. The crude product was chromatographed on silica gel witha 2:1 mixture of hexane and EtOAc containing 1% AcOH to afford 145 mg (97% yield) of N-(3-phenylpropanoyl)-L-Phe-OH 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With iodine; oxygen; sodium hydrogencarbonate In N,N-dimethyl-formamide at 60℃; for 1h; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: (S)-2-phenylglycine With sodium tetrahydroborate; iodine In tetrahydrofuran for 19h; Inert atmosphere; Cooling with ice; Reflux; Stage #2: di-<i>tert</i>-butyl dicarbonate With triethylamine In tetrahydrofuran; methanol at 20℃; for 3h; Inert atmosphere; Cooling with ice; | |
91% | Stage #1: (S)-2-phenylglycine With thionyl chloride In methanol at 0℃; for 3.5h; Reflux; Stage #2: di-<i>tert</i>-butyl dicarbonate With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 10h; Stage #3: With sodium tetrahydroborate; ethanol; lithium chloride In tetrahydrofuran at 0 - 20℃; for 4.5h; | 1-3 Example 1 Preparation of Compound 4 Dissolve 10.0g of Compound I in 200mL of methanol solvent, slowly add 23.79g of thionyl chloride in an ice-water bath at 0°C. After dripping for 30min, the temperature will be raised to reflux for 3h. After the reaction, it will be concentrated under reduced pressure; the concentrate is added with 400mL of tetrahydrofuran- Water (1:1, V/V) mixed solvent, add 16.80g of sodium bicarbonate solid, add 14.40g of Boc anhydride, react at room temperature for 10h, after the reaction, concentrate under reduced pressure, add 300mL purified water, add 250mL*3 ethyl acetate The ester was extracted three times, the organic phases were combined, washed with 200 mL saturated brine, and allowed to stand for liquid separation. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the concentrated solution was added with 600 mL of tetrahydrofuran-ethanol (1:1, V/ V) Mixed solvents, add 7.57g sodium borohydride and 8.48g lithium chloride at 0 °C, stir for 30min after addition, warm to room temperature and react for 4h, concentrate under reduced pressure, add 400mL purified water and 400mL ethyl acetate, and slowly add dropwise Concentrated hydrochloric acid, the water phase was added with ethyl acetate 300mL*2 and extracted twice, the organic phases were combined, washed with saturated brine 300mL, separated, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to obtain 14.25g of white solid compound 4. The rate is 91.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In water; acetone at 20℃; for 24h; Alkaline conditions; | 3 4.1.1 General procedure for the synthesis of substituted sulfonamides using different aminoacids (14-21 and 22-35) General procedure: L-isomers of different amino acids were used for the synthesis and in 1H NMR spectra it was found that only one isomer was formed indicating that there is retention in configuration. The substituted aromatic or aliphatic sulfonylchlorides (1-13, 58, 59) (0.0143mol, 1 equivalent) were dissolved in the acetone (2ml). The mixture was added to water (2ml) containing glycine/phenylglycine/phenylalanine (0.0143mol, 1 equivalent) and sodiumbicarbonate (0.0429mol, 3 equivalent). The final reaction mixture was stirred at room temperature (rt) for 24h. The reaction was monitored by TLC using ethylacetate and methanol (8:2) as the mobile phase. The acetone was evaporated under reduced pressure and reaction mixture was neutralized with 1N HCl to get the product. The product was filtered and recrystallized with methanol to get the pure compound [34]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.3% | With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In methanol; at 28℃; under 760.051 Torr; for 18h; | Weigh 5.00 g of 4-ethynylbenzoic acid at normal temperature and normal pressure.According to 4-ethynylbenzoic acid,L-phenylglycinol and 4-(4,6-dimethoxytriazine)-4-methylmorpholine hydrochloride have a molar ratio of 1:1:1.1, and weigh L-phenylglycinol and 4 -(4,6-dimethoxytriazine)-4-methylmorpholine hydrochloride,Dissolving 4-ethynylbenzoic acid, L-phenylglycine, and 4-(4,6-dimethoxytriazine)-4-methylmorpholine hydrochlorideAmidation reaction in 175 mL of methanol,The reaction temperature is 28 C,The reaction time was 18 h.After the reaction is over,Filter the reaction solution,Rotary evaporation,Purified by column chromatography.The eluent used in the column chromatography was n-hexane/acetone (5/4, V/V).The product is a white flake solid,The product is namedPAA-Phg-OH, yield 6.93 g, yield 76.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[125114-77-4]7-bromo-1-indanone</strong> (6.33g, 30mmol) in 120mL anhydrous toluene was added S-phenylglycine (4.52g, 33mmol) and p-toluenesulfonic acid (0.52g, 3mmol), the resulting mixture was stirred at refluxed for 48 hours.After removal of the solvent, the residue was dissolved in 60mLanhydrous dichloromethane was added TMSCN (6.48g, 60mmol) dropwise at 0 and stirred at 0 for 3 hours. Evaporated the solvent and the corresponding crude 4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: (S)-2-phenylglycine With n-butyllithium In tetrahydrofuran at -20℃; for 0.5h; Inert atmosphere; Stage #2: With tert-butyldimethylsilyl chloride In tetrahydrofuran at 20℃; for 8h; Stage #3: chloro-diphenylphosphine Further stages; | 1 Example 1 Under N2 protection, the chiral phenylglycine was dissolved in THF and lowered to -20 °C.Add n-butyl lithium dropwise for 30 minutes, and add a solution of t-butyldimethylchlorosilane in THF.Raise to room temperature and stir for 8 h.The THF was removed by rotary evaporation, and the obtained solution was dissolved in Et 2 O, cooled to -20 ° C, and n-butyl lithium was added dropwise to room temperature.Stir at room temperature for 2 h; again to -20 ° C, add dropwiseDiphenylphosphine chloride was raised to room temperature and stirred for 6 h;The reaction was quenched with a saturated ammonium chloride solution.Extracted with EtOAc and dried MgSO4Filter, concentrate and dissolve the solution in MeOH.Add concentrated hydrochloric acid and stir for 3 hours.Concentrated to remove methanol,Add water to dissolve,Extracted with EtOAc,Drying with MgSO4,Filtered, concentrated,Column chromatography to give orthophosphorous substituted chiral phenylglycine I,Recrystallization from CH2Cl2 with n-hexane,Got a white solid,The yield was 78%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: (S)-2-phenylglycine With sodium hydroxide In ethanol at 20℃; for 2h; Stage #2: dimethyl N-(1,3-benzothiazol-2-yl) dithio imidocarbonate In ethanol at 20℃; for 96h; | 3.2. General Method for Isothiourea Carboxylates 5a-f General procedure: Amino acid (3.94 mmol), NaOH (3.94 mmol), and 15 mL of ethanol were added into a 100 mLround flask and the mixture was stirred for 2 h at room temperature. Then, compound 2 (1.0 g,3.94 mmol) was added and the mixture was stirred for additional 96 h at room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium hydroxide In water at 20℃; for 0.25h; | 5 Example 5.N-(3-nitro-4-alkoxy)benzoylamino acid Add L-phenylglycine (0.16 g, 1.1 mmol) to a 100 mL reaction flask.20 mL of water, NaOH (0.2 g, 5 mmol), 3-nitro-4-ethoxybenzoyl chloride (0.2 g, 0.9 mmol) was slowly added dropwise at low temperature, and reacted at room temperature for 15 min to adjust pH-2.The solvent was evaporated under reduced pressure, and then filtered, and then filtered, m.A yellow solid was obtained in a yield of 77%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: [2-methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetic acid With 1-hydroxy-pyrrolidine-2,5-dione; diisopropyl-carbodiimide In 1,4-dioxane at 20℃; for 2h; Stage #2: (S)-2-phenylglycine With sodium hydrogencarbonate In 1,4-dioxane; water | General Method for Synthesizing N-([2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)aminoAcids 6-19. General procedure: A solution of 5 (1.03 g, 3 mmol) and SuOH (0.38 g, 3.3 mmol) in anhydrous dioxane (20 mL) was stirredvigorously, treated with DIC (0.52 mL, 3.3 mol), and stirred for 2 h (course of reaction monitored by TLC). The resultingactivated ester was treated with a solution of the appropriate amino acid (3.3 mmol) and NaHCO3 (0.28 g, 3.3 mmol) in H2O(20 mL), and stirred vigorously for 2-4 h (course of reaction monitored by TLC). When the reaction was finished,the precipitate of diisopropylurea was filtered off. The filtrate was treated with H2O (200 mL) and acidified to pH 5-6.The resulting precipitate was filtered off and crystallized from aqueous i-PrOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; | 4.1.1 General procedures for the preparation of capping groups CG 1-20 General procedure: A 500mL round bottom flask was equipped with a magnetic stir bar, charged with distilled H2O (100mL) and NaOH (100mmol, 4.0g) and cooled in an ice bath to 0°C. l-Phenylglycine/l-Methionine/d-Phenylglycine/d-Methionine (35mmol) was added, and stirred until the solution was homogeneous. The corresponding carbonyl chloride (45.5mmol) in 1,4-dioxane (40mL) was added dropwise using an addition funnel. The reaction mixture was left to stir overnight at room temperature. The solution was extraction of the solution with Et2O (3×50mL) was done, and the organic layers were discarded. The aqueous layer was cooled in an ice bath to 0°C, and concentrated HCl was added dropwise until the pH=2. The re-extraction of the aqueous solution was done with Et2O (3×100mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuum to give the product as clear viscous oil. No further purification was required. | |
With sodium hydroxide In 1,4-dioxane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; | 4.1.1 General procedures for the preparation of capping groups CG 1-20 General procedure: A 500mL round bottom flask was equipped with a magnetic stir bar, charged with distilled H2O (100mL) and NaOH (100mmol, 4.0g) and cooled in an ice bath to 0°C. l-Phenylglycine/l-Methionine/d-Phenylglycine/d-Methionine (35mmol) was added, and stirred until the solution was homogeneous. The corresponding carbonyl chloride (45.5mmol) in 1,4-dioxane (40mL) was added dropwise using an addition funnel. The reaction mixture was left to stir overnight at room temperature. The solution was extraction of the solution with Et2O (3×50mL) was done, and the organic layers were discarded. The aqueous layer was cooled in an ice bath to 0°C, and concentrated HCl was added dropwise until the pH=2. The re-extraction of the aqueous solution was done with Et2O (3×100mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuum to give the product as clear viscous oil. No further purification was required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In ethanol at 70℃; for 8h; | Synthesis of spirocycloadducts 9a-e (General method). General procedure: Enedione 1a-e (1.0 mmol) was added to a stirredsuspension of acenaphthenequinone 5 (200 mg, 1.1 mmol)and L-phenylglycine 7 (166 mg, 1.1 mmol) in EtOH(4 ml). The mixture was stirred at 70° for 8 h, and thencooled down to room temperature. The formed precipitatewas filtered; water (10 ml) was added to the filtrate and theprecipitate was collected by filtration, washed with hexane(3×2 ml), then with H2O (2×5 ml), dried at 80°, and, ifnecessary, reprecipitated from a CH2Cl2-hexane, 1:4 mixture. |
Tags: 2935-35-5 synthesis path| 2935-35-5 SDS| 2935-35-5 COA| 2935-35-5 purity| 2935-35-5 application| 2935-35-5 NMR| 2935-35-5 COA| 2935-35-5 structure
[ 25705-52-6 ]
(R)-2-Amino-2-phenylacetic acid hydrochloride
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[ 1393112-57-6 ]
(R)-2-Amino-2-(naphthalen-2-yl)acetic acid hydrochloride
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[ 90271-39-9 ]
2-Amino-2-(3-aminophenyl)acetic acid
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(R)-2-Amino-2-(4-aminophenyl)acetic acid dihydrochloride
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