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CAS No. : | 516-06-3 | MDL No. : | MFCD00004267 |
Formula : | C5H11NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 117.15 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.8 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 30.63 |
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) : | -8.62 cm/s |
Log Po/w (iLOGP) : | 1.03 |
Log Po/w (XLOGP3) : | -2.26 |
Log Po/w (WLOGP) : | 0.05 |
Log Po/w (MLOGP) : | -2.2 |
Log Po/w (SILICOS-IT) : | -0.54 |
Consensus Log Po/w : | -0.78 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.99 |
Solubility : | 1140.0 mg/ml ; 9.76 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 1.46 |
Solubility : | 3410.0 mg/ml ; 29.1 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | 0.29 |
Solubility : | 227.0 mg/ml ; 1.94 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.19 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P301+P312-P302+P352-P304+P340-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 |
---|---|---|
95% | With sodium hydroxide In water | Step A: N-Benzoylvaline Dissolve 0.1 mol (11.7 g) of valine in 50 ml of water, add 0.25 mol of sodium hydroxide in aqueous solution, heat to 30° C. and then add dropwise 0.15 mol (17.5 ml) of benzoyl chloride. Wash the aqueous solution with ether, acidify and suction off the N-benzoylvaline crystals. Melting point: 125° C. Yield: 95percent |
83% | Stage #1: With sodium hydroxide In water at 20℃; for 0.5 h; Stage #2: With sodium hydroxide In water at 0 - 20℃; for 3 h; |
A solution of 2-amino-3-methylbutanoic acid (500 mg, 4.27 mmol) in 2N NaOH (2.35 ml, 4.69 mmol) was stirred at RT for 30 minutes, then the reaction mixture was cooled at 0°C and benzoyl chloride (471 μ, 4.05 mmol) and 2N NaOH (2.35 ml, 4.69 mmol) were simultaneously added dropwise from two different syringes. The reaction was stirred at RT for 3h. Water was added, the aqueous phase was washed with Et2O, then acidified with 1M HCl and back-extracted with Et2O, dried over Na2SO4 and evaporated. The residue was triturated with z-Pr2O to obtain 2-benzamido-3-methylbutanoic acid (780 mg, 83percent yield). |
83% | at 0 - 20℃; for 3.5 h; | A solution of 2-amino-3-methylbutanoic acid (500 mg, 4.27 mmol) in 2N NaOH (2.35 ml, 4.69 mmol) was stirred at RT for 30 minutes, then the reaction mixture was cooled at 0° C., and benzoyl chloride (471 μl, 4.05 mmol) and 2N NaOH (2.35 ml, 4.69 mmol) were simultaneously added dropwise from two different syringes. The reaction was stirred at RT for 3 hours. Water was added, the aqueous phase was washed with Et2O, then acidified with 1M HCl and back-extracted with Et2O, dried over Na2SO4 and evaporated. The residue was triturated with i-Pr2O to obtain 2-benzamido-3-methylbutanoic acid (780 mg, 83percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium hydroxide In tetrahydrofuran; water | EXAMPLE 2 A dry, 12-liter glass reaction vessel equipped as described in Example 1 was charged with 900 grams (7.7 moles) of valine and 2.5 liters of tetrahydrofuran. Using the procedure described in Example 1, boron trifluoride diethyl etherate (1.05 liters, 8.5 moles) was added followed by 0.85 liter (8.5 moles) of borane-dimethyl sulfide at reflux. The addition took 8 hours and heating was continued for an additional 3 hours following the addition. The reaction mixture was then hydrolyzed with 0.75 liter of tetrahydrofuran/water followed by 24.6 moles of sodium hydroxide as an aqueous solution. The product was isolated as described in Example 1 giving 494 grams (62percent yield) of 2-amino-3-methyl-1-butanol, bp 78°-79°C at 8 mm, n20D 1.4543, purity by glc analysis: 97percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With thionyl chloride at 65℃; for 8h; | |
With thionyl chloride at 40℃; for 2h; | ||
With hydrogenchloride |
With thionyl chloride | ||
With acetyl chloride at 70℃; for 1h; | ||
With thionyl chloride at 0 - 20℃; | ||
With thionyl chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With aluminum oxide at 40℃; for 0.5h; Neat (no solvent); Cooling with ice; | |
86% | In N,N-dimethyl-formamide for 0.333333h; Heating; | |
67% | With acetic anhydride at 20℃; for 24h; | Valine derivative Valine (5.11 g, 43.60 mmol) was dissolved in formic acid (25 mL), was added acetic anhydride (2.9 eq, 13mL), it was stirred for 24 hours at room temperature the reaction. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, recrystallized by adding methanol, the corresponding formamide (3a) was obtained (4.27 g, 29.21 mmoL, 67%). Compound 3a (1.02 g, 7.03 mmol), and by DMF (20 mL) in benzyl bromide (1.5 eq, 1.25 mL) and potassium carbonate (3.0 eq, 2.92 g) and, then stirred at room temperature for 20 hours the reaction It was. After the reaction, the reaction mixture was quenched by adding water, extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and subjected to concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to give the corresponding benzyl ester (3b) was obtained (1.54 g, 6.56 mmol, 93%). Compound 3b (228.4 mg, 0.97 mmol) was added to the in DCM (1 mL), to the mixture obtained PhOPOCl2 (1.2 eq, 175 μL) andPyridine (5.0 eq, 0.39 mL) was added and stirring was carried out for 2 hours to react. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer, hydrochloric acid, sodium bicarbonate, washed sequentially with water, and saturated brine, and dried over magnesium sulfate, filtered, subjected to concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 9: 1) to give the isonitrile (3) (104.4 mg, 0.48 mmol, 50%). Yellow oil. |
With acetic anhydride at 55 - 60℃; | ||
With acetic anhydride for 3h; Ambient temperature; | ||
With acetic anhydride at 0 - 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydroxide; In water; | Step A: N-Benzoylvaline Dissolve 0.1 mol (11.7 g) of valine in 50 ml of water, add 0.25 mol of sodium hydroxide in aqueous solution, heat to 30 C. and then add dropwise 0.15 mol (17.5 ml) of benzoyl chloride. Wash the aqueous solution with ether, acidify and suction off the N-benzoylvaline crystals. Melting point: 125 C. Yield: 95% |
83% | A solution of 2-amino-3-methylbutanoic acid (500 mg, 4.27 mmol) in 2N NaOH (2.35 ml, 4.69 mmol) was stirred at RT for 30 minutes, then the reaction mixture was cooled at 0C and benzoyl chloride (471 mu, 4.05 mmol) and 2N NaOH (2.35 ml, 4.69 mmol) were simultaneously added dropwise from two different syringes. The reaction was stirred at RT for 3h. Water was added, the aqueous phase was washed with Et2O, then acidified with 1M HCl and back-extracted with Et2O, dried over Na2SO4 and evaporated. The residue was triturated with z-Pr2O to obtain 2-benzamido-3-methylbutanoic acid (780 mg, 83% yield). | |
83% | With sodium hydroxide; at 0 - 20℃; for 3.5h; | A solution of 2-amino-3-methylbutanoic acid (500 mg, 4.27 mmol) in 2N NaOH (2.35 ml, 4.69 mmol) was stirred at RT for 30 minutes, then the reaction mixture was cooled at 0 C., and benzoyl chloride (471 mul, 4.05 mmol) and 2N NaOH (2.35 ml, 4.69 mmol) were simultaneously added dropwise from two different syringes. The reaction was stirred at RT for 3 hours. Water was added, the aqueous phase was washed with Et2O, then acidified with 1M HCl and back-extracted with Et2O, dried over Na2SO4 and evaporated. The residue was triturated with i-Pr2O to obtain 2-benzamido-3-methylbutanoic acid (780 mg, 83% yield). |
With sulfuric acid; In tetrahydrofuran; | A. N-Benzoylvaline A solution of valine (20 g, 0.17 mole) in tetrahydrofuran (20 ml) and 2N NaOH (111 ml) was cooled down to 10 (ice-water bath) under nitrogen and treated dropwise with benzoyl chloride (23.8 ml, 0.21 mole). The reaction mixture was warmed up to room temperature, stirred for 3.0 hours then cooled back down to 0 (ice-salt bath) and treated with concentrated sulfuric acid (8.0 ml). The mixture was extracted with ethyl acetate (3*200 ml). The combined organic extracts were washed with water (100 ml), brine (50 ml), dried (anhydrous MgSO4), filtered and evaporated to dryness to give title compound as a solid (41.97 g, 100% crude yield). A small amount (260 mg) of the product was recrystallized from ethyl acetate and petroleum ether to give title compound as an analytical sample (205 mg, m.p. 132-3). TLC: Rf 0.10 (silica gel; acetone:hexane - 1:1). Anal Calcd: C, 65.14; H, 6.83; N, 6.33, Found: C, 64.81; N, 6.79; N, 6.29. MS (M+H)+ =222. | |
General procedure: A solution of 0.5g (6.66 mmol) of amino acidin 0.4 mL of 10% aqueous NaOH was stirred for 30 min,after which 0.68 mL of benzoyl chloride was addeddropwise in fi ve portions, and stirring was continued foran additional 30 min. The progress of the reaction wasmonitored by TLC. After the reaction had been complete,ice was added, and the pH of the mixture was adjustedto 2-3 by carefully adding dilute HCl. The crystals thatformed were fi ltered off, washed with cold water, dried,boiled in CCl4 for 5 min to remove excess benzoic acid,washed with water, and recrystallized from methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydroxide In diethyl ether; water at 20℃; for 20h; | General Procedure for the Synthesis of α-Amino Acid Sulfonamides. General procedure: Following a reported procedure,8 a 50mL drytwo-necked round-bottom flask equipped with a magneticstirrer was charged with valine (0.234 g, 2.0mmol), Et2O (10mL) and aqueous solution of NaOH (5 mL, 1.5 M). To the solutionwas added tosyl chloride (0.572 g, 3.0mmol) in one portion.The mixture was stirred at room temperature overnight(ca. 20 h), then extracted with Et2O. The aqueous layer wasacidified with 1N HCl solution to pH 23,then extracted withethyl acetate. The combined organic layers were dried overNa2SO4 and evaporated under reduced pressure. The crudematerial was then recrystallized from dichloromethane/hexaneto obtain pure sulfonamide 2a quantitatively. |
73.25% | With sodium hydroxide at 65 - 70℃; for 4h; | 2.3.1. General procedure for the synthesis ofbenzenesulfonyl valine acid chlorde (e) and ptoluenesulfonyl valine chloride (f ) General procedure: A mixture of valine (11.7 g, .1 mol) and benzenesulfonylchloride ((a); 17.6 g; .1 mol), and NaOH solution (1 N,200 ml) was stirred together at 65-70°C for four hours(John, 2000; Robert & Robert, 1992). A clear solutionwas obtained. The reaction mixture was cooled to 5 °Cand treated with concentrated HCl to make it slightlyacidic (pH 6.5). Benzenesulfonyl valine separated out aswhite crystals. It was recrystallized from hot water togive pure benzenesulfonyl valine ((b); 16.02 g; 69.95%;m.p. 118-120°). Similarly p-toluenesulfonyl valine wasprepared ((d); 17.8 g; 73.25%; m.p. 128-138°). Furtherbenzenesulfonyl valine ((b); 1 g; .004 mol) was dissolvedin dry benzene and an excess of freshly distilledthionyl chloride (5.0 g) was slowly added to it andstirred at room temperature for 20 mins. The reactionmixture was gently refluxed for 3 h. The solvent andexcess of thionyl chloride were then distilled off underreduced pressure to give acid chloride of benzenesulfonylvaline (e). Similar procedure was followed for thepreparation of p-toluenesulfonyl valine chloride (f ).These (e-f ) were used for next reaction without furtherpurification. |
With sodium hydroxide |
With sodium hydroxide In diethyl ether; water at 20℃; for 3h; | ||
With sodium hydroxide In diethyl ether at 20℃; for 3h; | ||
With sodium hydroxide | ||
With sodium carbonate In water at -5 - 20℃; for 5h; | ||
With sodium hydroxide In diethyl ether at 20℃; for 20h; Inert atmosphere; | ||
With sodium carbonate In water; toluene at 20℃; for 24h; | ||
With hydrogenchloride | ||
With sodium hydroxide In water at 40℃; for 20h; | 3.1 Synthesis of substrates 1a-1r General procedure: The starting amino acids (5.0 mmol) and para-toluenesulfonylchloride (6.0 mmol) weredissolved in 15 mL of 1.5 N NaOH. The reaction was heated to 40 overnight. Aftercooling, conc. HCl was added to the viscous white solution until it becomeshomogeneous. Ethyl acetate was added into the reaction mixture and the organic layerwas separated and the aqueous layer was extracted twice with ethyl acetate. The crudeproduct was recrystallized from ether and ethanol mixture to give pure compound aswhite solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | In sodium hydroxide; diethyl ether | B.35.A Step A. Step A. Preparation of N-(Phenylacetyl)valine To a stirred solution of 5.15 g (44 mmol) of valine (Bachem) in 50 mL (100 mmol) of 2N NaOH cooled to 0° C. was added dropwise 5.3 mL (40 mmol) of phenylacetyl chloride (Aldrich). A colorless oil precipitated. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, washed with 50 mL diethyl ether, acidified to pH 2-3 with aqueous HCl. The white precipitate formed was filtered off, washed thoroughly with water, followed by diethyl ether to give 7.1 g (30 mmol, 69% yield) of the title compound. NMR data was as follows: 1H-nmr (DMSO-d6): δ=12.63 (s, 1H), 8.25 (d, J=8.6 Hz, 1H), 7.27 (m, 5H), 4.15 (m, 1H), 3.56 (d, J=13.8 Hz, 1H), 3.47 (d, J=13.8 Hz, 1H), 2.05 (m, 1H), 0.87 (d, J=6.8, Hz, 3H), 0.84 (d, J=6.8 Hz, 3) 13C-nmr (DMSO-d6): δ=173.2, 170.4, 136.6, 129.0, 128.2, 126.3, 57.1, 41.9, 30.0, 19.2, 18.0 C13H17NO3 (MW=235.29; Mass Spectroscopy (MH+=236)) |
69% | With sodium hydroxide In water at 0 - 20℃; for 18h; | B35.A Step A. Preparation of N-(phenylacetyl) valine To a stirred solution of 5.15 g (44 mmol) of valine (Bachem) in 50 mL (100 mmol) of 2N NaOH cooled to 0°C was added dropwise 5.3 mL (40 mmol) of phenylacetyl chloride (Aldrich). A colorless oil precipitated. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, washed with 50 mL diethyl ether, acidified to pH 2-3 with aqueous HCl. The white precipitate formed was filtered off, washed thoroughly with water, followed by diethyl ether to give 7.1 g (30 mmol, 69% yield) of the title compound. NMR data was as follows 1H-nmr (DMSO-d6): δ = 12.63 (s, 1H), 8.25 (d, J = 8.6 Hz, 1H), 7.27 (m, 5H), 4.15 (m, 1H), 3.56 (d, J = 13.8 Hz, 1H), 3.47 (d, J = 13.8 Hz, 1H), 2.05 (m, 1H), 0.87 (d, J = 6.8, Hz, 3H), 0.84 (d, J = 6.8 Hz, 3) 13C-nmr (DMSO-d6): δ = 173.2, 170.4, 136.6, 129.0, 128.2, 126.3, 57.1, 41.9, 30.0, 19.2, 18.0 C13H17NO3 (MW=235.29; Mass Spectroscopy (MH+ = 236)) |
69% | With sodium hydroxide In water at 0 - 20℃; for 18h; | 35.A Step A. Preparation of N-(phenylacetyl) valine Step A. Preparation of N-(phenylacetyl) valine To a stirred solution of 5.15 g (44 mmol) of valine (Bachem) in 50 mL (100 mmol) of 2N NaOH cooled to 0°C was added dropwise 5.3 mL (40 mmol) of phenylacetyl chloride (Aldrich). A colorless oil precipitated. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, washed with 50 mL diethyl ether, acidified to pH 2-3 with aqueous HCl. The white precipitate formed was filtered off, washed thoroughly with water, followed by diethyl ether to give 7.1 g (30 mmol, 69% yield) of the title compound. NMR data was as follows: 1H-nmr (DMSO-d6): δ = 12.63 (s, 1H), 8.25 (d, J = 8.6 Hz, 1H), 7.27 (m, 5H), 4.15 (m, 1H), 3.56 (d, J = 13.8 Hz, 1H), 3.47 (d, J = 13.8 Hz, 1H), 2.05 (m, 1H), 0.87 (d, J = 6.8, Hz, 3H), 0.84 (d, J = 6.8 Hz, 3) 13C-nmr (DMSO-d6): δ = 173.2, 170.4, 136.6, 129.0, 128.2, 126.3, 57.1, 41.9, 30.0, 19.2, 18.0 C13H17NO3 (MW=235.29; Mass Spectroscopy (MH+ = 236)) |
With sodium hydroxide | ||
With pyridine | ||
With sodium hydroxide | ||
With sodium hydroxide In water at 20℃; for 2h; | 2.3.1. N-Phenylacetylation of α-amino acids General procedure: To a solution of amino acid (20 mmol) in 2 M NaOH (20 mL), phenylacetyl chloride (2.9 mL, 3.4 g, 22 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then acidified by the addition of 2M HCl. The crude product was filtered off, washed with distilled water and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With methyloxirane In tetrahydrofuran at 20℃; Inert atmosphere; | |
With sodium hydroxide | ||
With sodium carbonate Heating; |
With methyloxirane In tetrahydrofuran at 25℃; for 0.25h; | ||
With methyloxirane In tetrahydrofuran at 20℃; | ||
With methyloxirane In tetrahydrofuran at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With perchloric acid; at 20℃; for 36h; | Step 1: tert-butyl 2-amino-3-methylbutanoateTo a stirred solution of DL- valine (25 g, 0.213 mol) in tert-butyl acetate (250 mL) at 0C, was added HCI04 (64.2 g, 0.320 mol) portionwise. The reaction mixture was stirred for 36 h at RT. It was diluted with water and extracted in ethyl acetate (500 mL). The organic layer was washed with a 10% sodium bicarbonate solution (2x150 mL), dried over Na2S04 and concentrated, affording of the title compound as brown liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.31 (brs, 2H), 3.62(d, J = 4.4 Hz, 1 H), 1 .98 (d, J = 1.7 Hz, 1 H), 1.44(s, 9H), 0.95 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; sodium tetrahydroborate; sulfuric acid; In tetrahydrofuran; methanol; diethyl ether; | 1. 2-Amino-3-methyl-butan-1-ol To a stirred suspension of NaBH4 (1.136 g; 29.9 moles) in THF (12 L) is added DL-valine (1.4 Kg; 11.95 moles). The flask is immersed in an ice-water bath, and a solution of concentrated H2SO4 (1,325 g; 14.94 moles; 1.25 eq.) in diethyl ether (total volume of 2.4 L) is added dropwise at such a rate as to maintain the reaction mixture below 20 C. (addition time ~10 hours). Stirring of the reaction mixture is continued at room temperature overnight, and methanol (1.5 L) is added carefully to destroy excess BH3. The mixture is stirred for 3 hours at room temperature and then concentrated. 5 L NaOH (8 L; 5 M sol.) is added and the mixture is distilled. The solvent that distills below 100 C. is removed. The mixture is then heated at reflux for 3 hours. The turbid aqueous mixture is cooled and extracted with CH2Cl2 (2*5 L) and dried over MgSO4. Evaporation of the solvent gives crude product which is purified via vacuum distillation (90-95 C./10-15 mmHg) yielding 724 g (59%) of pure 2-Amino-3-methyl-butan-1-ol (a). | |
With sodium tetrahydroborate; iodine; In tetrahydrofuran; at 0 - 65℃; for 16h; | To a mixture of 2-amino-3-methylbutanoic acid (15 g, 128 mmol), and NaBH4 (19.5 g, 512 mmol) in THF (200 mL) was added ?2 (32 g, 128 mmol, dissolved in 100 mL of THF)dropwise at 0 C. The reaction mixture was stirred at 65 C for 16 h, quenched with MeOH (100 mL) and concentrated in vacuo. The white residue was dissolved in 225 mL of 20% aqueous KOH and stirred for 3 h at RT, extracted with EA (100 mL x 3), and the organic phases dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford 2-amino-3-methylbutan-1-ol (7 g, 50 %) as an oil. LC-MS m/z: 118.1 [M+H]1 Purity (214 nm): 90%; tR= 0.34 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydroxide; sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; | |
90% | With sodium carbonate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; water 1.) 0 deg C, 30 min; 2.) up to RT, 1 h; | |
With triethylamine In 1,4-dioxane; water |
With triethylamine In 1,4-dioxane; water | ||
With sodium hydroxide In dichloromethane; water at 20℃; for 16h; | ||
With sodium hydroxide In 1,4-dioxane; water at 20℃; for 6h; | ||
With sodium hydroxide In 1,4-dioxane; water at 20℃; for 1h; Cooling with ice; | 1 4.1 Synthesis of Boc-N-protected amino acids (8-10) General procedure: Amino group of amino acids (4-6) was protected with Boc group by following procedure: The solution of amino acid (4-6) in 75mL of dioxane, 40mL of H2O and 408mL solution of IM NaOH was stirred and cooled in an ice bath. (BOC)2O (9g, 41.14mmol) was added to solution and stirred for 1h at room temperature. The solution was concentrated under vacuum to about 30-40mL. Cooled in an ice water bath, covered with layer of ethyl acetate (25mL) and acidified with dilute solution of KHSO4 to pH 2-3. The aqueous layer was extracted with ethyl acetate and washed with distilled H2O, brine and dried over MgSO4. The solvent was removed under reduced pressure and residue was chromatographed on a silica gel column using methanol 2% solution in chloroform as an eluent to afford pure product in 82% yield. 4.1.1 2-(tert-butoxycarbonyl)-3-methylbutanoic acid (8) (0029) White powder, 1H NMR (300MHz, CDCl3): δ 0.98 (d, 6H, J=6.9Hz, CH3), 1.48 (s, 9H, 3× CH3), 2.41 (m, 1H, CH), 5.09 (d, 1H, CH), 7.95 (brs, 1H, NHBoc), 11.28 (br s, 1H, OH). | |
With sodium hydroxide In 1,4-dioxane; water for 1h; | N-Boc-protected amino acids 2a-2f (general procedure). General procedure: Amino acid (4.3 g, 37.4 mmol) wasdissolved in dioxane (75 mL) and after 30 min 1 MNaOH (38 mL) and H2O (38 mL) were added followedby (Boc)2O (9 g, 41.4 mmol). The reaction mixture wasstirred for 1 h and concentrated under reduced pressureto about 30-40 mL, after which ice and a little of ethylacetate. A dilute KHSO4 solution was then added verycarefully to the reaction mixture to adjust its pH to 2-3.The solution was then washed with brine and the productwas extracted with ethyl acetate and dried over MgSO4.The solvent was evaporated under reduced pressure. | |
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 16h; | 30.a Step-a: Step-a: Synthesis of (tert-butoxycarbonyl)-DL-valine To a stirred solution of DL-valine (2.0 g, 17.07 mmol) in THF (25 mL) and water (20 mL) at RT was added sodium hydroxide (0.82 g, 20.5 mmol) and di-tert-butyl dicarbonate (4.09 g, 18.77 mmol) and the reaction mixture was stirred for 16 h. The mixture was cooled to 0° C., acidified with 1 N HCl and extracted with EtOAc (2*50 mL). The combined organic layers were washed with brine solution (30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. Crude product (1.8 g) was used in the next step without any further purification, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With pyridinium polyhydrogen fluoride; potassium bromide; sodium nitrite for 48h; Ambient temperature; | |
With sulfuric acid; potassium bromide; sodium nitrite at 0℃; | ||
With hydrogen bromide; potassium bromide; sodium nitrite at -13℃; |
With hydrogen bromide; sodium nitrite In water; toluene at 0 - 20℃; for 4h; | ||
Stage #1: D,L-valine With hydrogen bromide In water at 0℃; for 0.166667h; Stage #2: With sodium nitrite In water at 0 - 20℃; for 3.5h; | 4.1.2.1. 2-Bromo-4-(methylthio)butanoic acid (35c). General procedure: To a solution ofDL-methionine (3.0 g, 20.1 mmol) in H2O (50 mL) was added 30% HBr (20 mL). The reaction mixture was stirred at 0 C for 10 min. A solution of sodium nitrite (1.7 g, 24 mmol) in H2O (50 mL) was added. The reaction mixture was stirred at 0 C for 30 min and thenwarmed to rt for 3 h. The reaction mixture was extracted withEtOAc (100 mL 3). The organic layer was washed with brine and dried over Na2SO4. The solid was filtered off, and the filtrate was concentrated under reduced pressure to give 3.6 g of intermediate 35c (83% yield). | |
Stage #1: D,L-valine With hydrogen bromide In water at 0℃; for 0.166667h; Stage #2: With sodium nitrite In water at 0 - 20℃; for 3.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In 1,4-dioxane; water Ambient temperature; | ||
With sodium hydroxide | ||
With sodium carbonate In water; toluene at 20℃; for 24h; |
With sodium hydroxide In diethyl ether; water at 20℃; for 20h; | General Procedure for the Synthesis of α-Amino Acid Sulfonamides. General procedure: Following a reported procedure,8 a 50mL drytwo-necked round-bottom flask equipped with a magneticstirrer was charged with valine (0.234 g, 2.0mmol), Et2O (10mL) and aqueous solution of NaOH (5 mL, 1.5 M). To the solutionwas added tosyl chloride (0.572 g, 3.0mmol) in one portion.The mixture was stirred at room temperature overnight(ca. 20 h), then extracted with Et2O. The aqueous layer wasacidified with 1N HCl solution to pH 23,then extracted withethyl acetate. The combined organic layers were dried overNa2SO4 and evaporated under reduced pressure. The crudematerial was then recrystallized from dichloromethane/hexaneto obtain pure sulfonamide 2a quantitatively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide | ||
With triethylamine In tetrahydrofuran; water at 20℃; for 15h; | 10 Example 10; 2-[(4-Fluoro-benzenesulfonyl)-methyl-amino]-3-methyl-butyric acid methyl ester To a solution of 6.00g (0.051 mol) of D, L-valine in 380 mL of THF/water (1:1) was added 10.9 mL (0.077 mol) of triethylamine followed by 9.94g (0.051 mol) of 4-fluorobenzenesulfonyl chloride and the resulting mixture was stirred for 15h at room temperature. The THF was then removed in vacuo and the resulting solution was extracted with ethyl acetate. The combined organics were washed with 10% HCl solution and water, dried over MgSO4, filtered and concentrated in vacuo to provide 4.8g of the sulfonamide as a white solid. | |
With sodium hydroxide In diethyl ether; water at 20℃; for 20h; | General Procedure for the Synthesis of α-Amino Acid Sulfonamides. General procedure: Following a reported procedure,8 a 50mL drytwo-necked round-bottom flask equipped with a magneticstirrer was charged with valine (0.234 g, 2.0mmol), Et2O (10mL) and aqueous solution of NaOH (5 mL, 1.5 M). To the solutionwas added tosyl chloride (0.572 g, 3.0mmol) in one portion.The mixture was stirred at room temperature overnight(ca. 20 h), then extracted with Et2O. The aqueous layer wasacidified with 1N HCl solution to pH 23,then extracted withethyl acetate. The combined organic layers were dried overNa2SO4 and evaporated under reduced pressure. The crudematerial was then recrystallized from dichloromethane/hexaneto obtain pure sulfonamide 2a quantitatively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: SOCl2 2: 2.462 g / Et3N / CH2Cl2 3: H2O; Acylase I on Eupergit C / 27 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: D,L-valine; 2-Bromopropionyl chloride With triethylamine In dichloromethane at 0 - 5℃; Stage #2: With hydrogenchloride In dichloromethane; water | 10a Example 10; a) N-(2-bromopropionyl)valine Zu 40 g (341,4 mmol) Valin und 103,7 g (1024 mmol) Triethylamin in 600 ml Methylenchlorid tropft man bei 0C 70,2 g (409,7 mmol) a-Brom-Propionsurechlorid zu. Dabei hlt man die Temperatur zwischen 0C - 5C. Man gibt 1000 ml 5 %ige aqu. Salzsure zu und trennt die organische Phase ab. Die organische Phase wird noch einmal mit 500 ml 5 %iger aqu. Salzsure extrahiert, ber Magnesiumsulfat getrocknet und im Vakuum zur Trockne eingedampft. Der Rckstand wird aus Aceton/ Di-isopropylether umkristallisiert. Ausbeute: 59,39 g (69 % d. Th.). Elementaranalyse (berechnet auf wasserfreie Substanz): ber. C 38,11 H 5,60 N 5,56 Br 31,69 ; gef. C 38,01 H 5,75 N 5,41 Br 31,48 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium hydroxide; In tetrahydrofuran; water; | EXAMPLE 2 A dry, 12-liter glass reaction vessel equipped as described in Example 1 was charged with 900 grams (7.7 moles) of valine and 2.5 liters of tetrahydrofuran. Using the procedure described in Example 1, boron trifluoride diethyl etherate (1.05 liters, 8.5 moles) was added followed by 0.85 liter (8.5 moles) of borane-dimethyl sulfide at reflux. The addition took 8 hours and heating was continued for an additional 3 hours following the addition. The reaction mixture was then hydrolyzed with 0.75 liter of tetrahydrofuran/water followed by 24.6 moles of sodium hydroxide as an aqueous solution. The product was isolated as described in Example 1 giving 494 grams (62% yield) of 2-amino-3-methyl-1-butanol, bp 78-79C at 8 mm, n20D 1.4543, purity by glc analysis: 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In not given | ||
With NaOH In not given |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With sodium hydroxide In diethyl ether; water at 20℃; for 20h; | General Procedure for the Synthesis of α-Amino Acid Sulfonamides. General procedure: Following a reported procedure,8 a 50mL drytwo-necked round-bottom flask equipped with a magneticstirrer was charged with valine (0.234 g, 2.0mmol), Et2O (10mL) and aqueous solution of NaOH (5 mL, 1.5 M). To the solutionwas added tosyl chloride (0.572 g, 3.0mmol) in one portion.The mixture was stirred at room temperature overnight(ca. 20 h), then extracted with Et2O. The aqueous layer wasacidified with 1N HCl solution to pH 23,then extracted withethyl acetate. The combined organic layers were dried overNa2SO4 and evaporated under reduced pressure. The crudematerial was then recrystallized from dichloromethane/hexaneto obtain pure sulfonamide 2a quantitatively. |
With sodium hydroxide In water; acetone for 18h; | 7 To a solution of 5.5 g (46.9 mmol) of DL-valine and 10.2 g (46.9 mmol) of 2- mesitylenesulfonyl chloride in 60 mL water and 200 mL acetone was added 1.87 g (46.9 mmol) of sodium hydroxide in 10 mL water. After 18 hours, the mixture was concentrated in vacuo to near dryness. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. The residue was crystallized from hexanes-ethyl acetate to afford 3-methyl-2-(2,4,6- trimethylbenzenesulfonylamino)butyric acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With triethylamine; In toluene; for 3.5h;Reflux; | [00113] Compound 22: 1 .8 ml of triethylamine was added slowly to a mixture of 15.1 g valine and25g <strong>[5466-84-2]4-nitro-phthalic anhydride</strong> in 200 ml anhydrous toluene. The mixture was heated to reflux and stirred for three and half hours, during which time 1.8 ml of water was removed by toluene to a Dean-Stark water collector apparatus. After the reaction system cooled to room temperature, all volatile components were removed by vacuum evaporation. 32g crude compound (22) was obtained.[00114] 5.73g crude compound 22 were dissolved in minimum amount of dichloromethane and absorbed by 6g of silica gel. The mixture was subjected to a 100g of silica gel with 1.7L 2:1 hexane/ethylacetate, as eluent. 4.93g purified compound 22 was obtained from 5.73g crude (73% yield from compound 21 ).[00115] 1 H NMR (DMSO-d6) delta 0.923-0.940 (3H, d), 1.171-1.188 (3H, d), 2.714-2.802 (1 H, m), 4.667-4.688 (1 H, d), 8.073-8.082 (1 H, d), 8.621-8.689 (2H, m).[00116] Mass spectrum: calculated for C^H^NzOs: 292.24. MS: m/z 293.87 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With oxone; iodine In dimethyl sulfoxide at 95℃; for 2h; | |
70% | With iodine; 4-aminobenzene sulfonic acid In dimethyl sulfoxide at 100℃; for 5h; | Typical Procedure for the Preparation of 2,5-Diphenyloxazole General procedure: A test tube was charged with 1a (0.32 mmol), 2a (0.38 mmol), I2(2.0 equiv), and PABS (0.5 equiv). Then DMSO (2 mL) was addedto the reaction system. The reaction was stirred at 100 °C for 5h. After cooling to r.t., the solvent diluted with EtOAc (10 mL)and washed with brine (5 mL) and dried over anhydrousNa2SO4. After the solvent was evaporated in vacuo, the residueswere purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: D,L-valine; Benzoyl isothiocyanate With 1-n-butyl-3-methylimidazolim bromide at 50℃; for 1h; Stage #2: ethyl Bromopyruvate at 50℃; for 3h; | 2-[4-(Ethoxycarbonyl)-2-(benzoylimino)thiazol-3(2H)-yl]-3-methylbutanoic acid (4g) General procedure: General procedure for the preparation of compounds 4: A mixture of α-amino acid 1 (1mmol) and aroylisothiocyanate 2 (1mmol) was stirred in 1mL of [bmim]Br for 1h at 50°C, and then α-bromo-carbonyl compound 3 (1mmol) was added. After stirring for 3h, 5mL of water was added and the mixture was extracted with Et2O (3×10mL). The solvent from the mixture was evaporated under reduced pressure to leave a residue that was purified by column chromatography (SiO2; hexane/EtOAc=4/1) to afford pure 4. The ionic liquid can be reused after extraction from the aqueous phase. Cream powder, yield: 0.34 g (92%); mp 183-184 °C; IR (KBr, cm-1): νmax 3500-2900 (CO2H), 1750, 1720, 1670, 1601, 1235, 1100. 1H NMR (300 MHz, CDCl3): δ 0.69 (d, 3J = 6.5 Hz, CH3), 1.33 (d, 3J = 6.5 Hz, CH3), 1.42 (t, 3J = 7.0 Hz, CH3), 3.22 (m, CH), 4.40 (q, 3J = 7.0 Hz, CH2), 6.06 (d, 3J = 9.3 Hz, CH), 7.48 (t, 3J = 7.2 Hz, 2 CH), 7.53 (t, 3J = 7.2 Hz, CH), 7.72 (s, CH), 8.19 (d, 3J = 7.2 Hz, 2 CH), 11.09 (s, COOH). 13C NMR (75 MHz, CDCl3):δ 14.5 (Me), 19.3 (Me), 21.7 (Me), 28.1 (CH), 62.8 (OCH2), 66.8 (CH), 121.6 (CH), 128.7 (2 CH), 129.0 (CH), 129.7 (2 CH), 132.7 (C), 135.8 (C), 158.9 (C=N), 164.8 (C=O), 172.4 (C=O), 174.3 (C=O). MS: m/z (%) 376 (M+, 4), 303 (29), 276 (59), 105 (100), 77 (38), 45 (67). Anal. Calcd. for C18H20N2O5S (376.43): C, 57.43; H, 5.36; N, 7.44. Found: C, 57.7; H, 5.2; N, 7.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium hydrogencarbonate In ethanol at 90℃; for 3h; | 2.3. Preparation of the solid complexes General procedure: The 1 : 1 : 1 [Cu:ATS:AA] complexes were prepared from hot ethanolic solutions (90 °C) by the addition of 25 mL of CuCl2*2H2O (1 mM, 0.170 g) dropwise to 25 mL of ATS (1 mM, 0.295 g) and AA (amino acid) (1 mM, 0.075 g Gly, 0.089 g Ala, 0.117 g Val). An equivalent amount of NaHCO3 was added to neutralize the released protons. The obtained mixture was refluxed with stirring for 3 h and then kept in the refrigerator overnight. Thus,the formed complexes were filtered, collected, and then washed several times with ethanol and then diethyl ether. The solid complexes were dried in a vacuum desiccator. The yield ranged from 70 to 74%. The dried complexes were subjected to elemental and spectroscopic analyses. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: D,L-valine With triethylamine In water; acetonitrile at 20℃; for 0.0833333h; Stage #2: (E)-[(diazene-1,2-diyl)bis(pyridine-6,2-diyl)]bis[(1H-benzo[d][1,2,3]triazol-1-yl)methanone] In water; acetonitrile at 70℃; for 0.0833333h; Microwave irradiation; | 2,2'-AzPy-Diacylamino Acids 7aa-cc and 7cb + 7cb'; General Procedure General procedure: Et3N (0.16 g, 1.58 mmol) was added to a suspension of amino acid 6a-c (1.58 mmol) in H2O (1.5 mL) in a 10 mL heavy-walled Pyrex tube containing a long stir bar. MeCN (3.5 mL) was added to the amino acid solution and stirred for 5 min at r.t. 2,2'-AzPy-diacylbenzotriazole 3 (0.15 g, 0.32 mmol) was added to this white suspension. The mixture was exposed to microwave irradiation (20 W, 70 °C) for the specified reaction time (15 min for 3a, 10 min for 3b, and 5 min for 3a) with vigorous stirring and simultaneous air cooling. The reactions were carried out until the disappearance of all colored solid starting materials 3 in the reaction vessel. After completion of the reaction, the mixture was cooled to r.t. and poured onto crushed ice-water mixture (~10 g). The mixture was acidified with aq 2 N HCl to pH 3-4. The precipitate formed was filtered and washed with aq 1 N HCl (3 × 5 mL), H2O, and Et2O, respectively (if a precipitate did not form upon acidification, the solution was saturated by adding solid NaCl and cooled for 2-3 h). Compound 7aa and 7ba were quite water soluble, so the compound in aqueous part (at pH 3-4) was recovered by extracting with EtOAc (3 × 10 mL). The combined organic phases were washed with brine (3 mL), dried (MgSO4), and evaporated under reduced pressure. The solid obtained was washed with Et2O and dried under vacuum to yield 2,2'-AzPy-diacylamino acids (Table 3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: carbon disulfide; D,L-valine With sodium hydroxide In water at 100℃; for 0.0833333h; Microwave irradiation; Stage #2: sodium monochloroacetic acid In water at 40 - 100℃; for 0.0833333h; Microwave irradiation; | General procedure for the microwave-assisted synthesisof N-substituted rhodanines (2a-g) General procedure: Mixture of amine or amino acid (1 mol), sodium hydroxide (22 %) and carbon disulfide (1 mol) in 3 ml water was reacted in a microwave reactor (CEM Discover, Benchmate,USA) for 5 min at 100 °C at 80 W. After automatedcooling to 40 °C, sodium chloroacetate (1 mol) was addedand the mixture was reacted again at 100 °C for 5 min.After cooling (40 °C), conc. HCl (3 ml) was added and thereaction was completed at 110 C for 20-30 min. Thecrude product was extracted with ethyl acetate and purified(Nitsche and Klein, 2012). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With caesium carbonate In ethylene glycol; dimethyl sulfoxide at 120℃; | Typical procedure for the condensation synthesis of quinazolinones General procedure: 2-Iodobenzamide 1a (1.0 equiv.), 2-aminoisovaleric acid 2a (3.0 equiv.), Cs2CO3 (3.0 equiv.) and GO/Fe3O4-CuI (Cu+ 0.03 equiv.) were added to DMSO/ethylene glycol (60:1, v/v) in a round bottom flask. The reaction was monitored by TLC. The product was purified by column chromatography with petroleum ether/ethyl acetate (3:1, v/v) to give pure white solid 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With caesium carbonate In ethylene glycol; dimethyl sulfoxide at 120℃; | Typical procedure for the condensation synthesis of quinazolinones General procedure: 2-Iodobenzamide 1a (1.0 equiv.), 2-aminoisovaleric acid 2a (3.0 equiv.), Cs2CO3 (3.0 equiv.) and GO/Fe3O4-CuI (Cu+ 0.03 equiv.) were added to DMSO/ethylene glycol (60:1, v/v) in a round bottom flask. The reaction was monitored by TLC. The product was purified by column chromatography with petroleum ether/ethyl acetate (3:1, v/v) to give pure white solid 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With caesium carbonate In ethylene glycol; dimethyl sulfoxide at 120℃; | Typical procedure for the condensation synthesis of quinazolinones General procedure: 2-Iodobenzamide 1a (1.0 equiv.), 2-aminoisovaleric acid 2a (3.0 equiv.), Cs2CO3 (3.0 equiv.) and GO/Fe3O4-CuI (Cu+ 0.03 equiv.) were added to DMSO/ethylene glycol (60:1, v/v) in a round bottom flask. The reaction was monitored by TLC. The product was purified by column chromatography with petroleum ether/ethyl acetate (3:1, v/v) to give pure white solid 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With caesium carbonate In ethylene glycol; dimethyl sulfoxide at 120℃; | Typical procedure for the condensation synthesis of quinazolinones General procedure: 2-Iodobenzamide 1a (1.0 equiv.), 2-aminoisovaleric acid 2a (3.0 equiv.), Cs2CO3 (3.0 equiv.) and GO/Fe3O4-CuI (Cu+ 0.03 equiv.) were added to DMSO/ethylene glycol (60:1, v/v) in a round bottom flask. The reaction was monitored by TLC. The product was purified by column chromatography with petroleum ether/ethyl acetate (3:1, v/v) to give pure white solid 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: D,L-valine; benzenesulfonyl chloride With sodium hydrogencarbonate In water Stage #2: With hydrogenchloride In water for 1h; | Synthesis of 3-methyl-2-(phenylsulfonamido)butanoic acid (1) and its metal complexes. Sulfonamide was prepared by using equimolar ratio of 2-amino-3-methylbutanoic acid and benzenesulfonyl chloride in 40 mL of water. The pH of the reaction mixture was maintained at 8-9 by addition of 1.0 M sodium bicarbonate solution. The 1.0 M HCl solution was added in 1 h which resulted in formation of white precipitate. |
69.95% | With sodium hydroxide at 65 - 70℃; for 4h; | 2.3.1. General procedure for the synthesis ofbenzenesulfonyl valine acid chlorde (e) and ptoluenesulfonyl valine chloride (f ) General procedure: A mixture of valine (11.7 g, .1 mol) and benzenesulfonylchloride ((a); 17.6 g; .1 mol), and NaOH solution (1 N,200 ml) was stirred together at 65-70°C for four hours(John, 2000; Robert & Robert, 1992). A clear solutionwas obtained. The reaction mixture was cooled to 5 °Cand treated with concentrated HCl to make it slightlyacidic (pH 6.5). Benzenesulfonyl valine separated out aswhite crystals. It was recrystallized from hot water togive pure benzenesulfonyl valine ((b); 16.02 g; 69.95%;m.p. 118-120°). Similarly p-toluenesulfonyl valine wasprepared ((d); 17.8 g; 73.25%; m.p. 128-138°). Furtherbenzenesulfonyl valine ((b); 1 g; .004 mol) was dissolvedin dry benzene and an excess of freshly distilledthionyl chloride (5.0 g) was slowly added to it andstirred at room temperature for 20 mins. The reactionmixture was gently refluxed for 3 h. The solvent andexcess of thionyl chloride were then distilled off underreduced pressure to give acid chloride of benzenesulfonylvaline (e). Similar procedure was followed for thepreparation of p-toluenesulfonyl valine chloride (f ).These (e-f ) were used for next reaction without furtherpurification. |
With sodium carbonate In water at -5 - 20℃; for 5h; |
With sodium hydroxide | ||
With potassium carbonate In water at 0 - 20℃; for 4h; Green chemistry; | ||
With sodium hydroxide In diethyl ether; water at 20℃; for 20h; | General Procedure for the Synthesis of α-Amino Acid Sulfonamides. General procedure: Following a reported procedure,8 a 50mL drytwo-necked round-bottom flask equipped with a magneticstirrer was charged with valine (0.234 g, 2.0mmol), Et2O (10mL) and aqueous solution of NaOH (5 mL, 1.5 M). To the solutionwas added tosyl chloride (0.572 g, 3.0mmol) in one portion.The mixture was stirred at room temperature overnight(ca. 20 h), then extracted with Et2O. The aqueous layer wasacidified with 1N HCl solution to pH 23,then extracted withethyl acetate. The combined organic layers were dried overNa2SO4 and evaporated under reduced pressure. The crudematerial was then recrystallized from dichloromethane/hexaneto obtain pure sulfonamide 2a quantitatively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.3% | Stage #1: D,L-valine With potassium carbonate In acetone at 40℃; for 0.5h; Stage #2: benzyl chloride With tetrabutylammomium bromide In acetone for 12h; Inert atmosphere; | 1.1 (1) valine from the nucleophilic reaction to obtain valine benzyl ester n particular,In the present embodiment,Valine benzyl ester synthesis using valine,The experimental procedure is as follows: In a 100 mL single-necked flask,2.00 g valine (17.1 mmol) was added,2.83 g of K2CO3 (1.2 eq.40 mL of acetone was added,40 ° C for 30 min,Tetrabutylammonium bromide was added,Nitrogen protection,A mixture of 2.05 g of benzyl chloride (0.95 eq. 16.2 mmol) in acetone (10 mL)Reaction 12h.After completion of the reaction,Coping,The filtrate was dried at 38 ° C,Dichloromethane dissolved,Saturated aqueous sodium chloride solution,The organic layer was dried over anhydrous sodium sulfate,Coping,The filtrate was dried at low temperature,Column chromatography [V (petroleum ether): V (ethyl acetate) = 4: 1] afforded 3.11 g of a colorless oily liquid,Yield 87.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; water; for 2h;Reflux; | General procedure: The metal chlorides of Fe(III), Co(II), Ni(II), Cu(II),Mn(II), Cr(III) andZn(II) solutions (1 mmol) in bidistilled water (25 mL) were added to25 mL ethanol solution of H2Ten (0.337 g, 1mmol) followed by additionof 25 mL of 1 mmol Val (0.117 g in bidistilled water) in the molar ratio1:1:1 (metal salt: H2Ten: Val) in total volume 75 mL mixture. Theresulting mixture was stirred under reflux for 2 h whereupon the complexes precipitated. They were removed by filtration, washed withhot ethanol followed by diethylether and dried in vacuum desiccatorsover anhydrous calcium chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; for 2h;Reflux; | General procedure: The metal chlorides of Fe(III), Co(II), Ni(II), Cu(II),Mn(II), Cr(III) andZn(II) solutions (1 mmol) in bidistilled water (25 mL) were added to25 mL ethanol solution of H2Ten (0.337 g, 1mmol) followed by additionof 25 mL of 1 mmol Val (0.117 g in bidistilled water) in the molar ratio1:1:1 (metal salt: H2Ten: Val) in total volume 75 mL mixture. Theresulting mixture was stirred under reflux for 2 h whereupon the complexes precipitated. They were removed by filtration, washed withhot ethanol followed by diethylether and dried in vacuum desiccatorsover anhydrous calcium chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; water; for 2h;Reflux; | General procedure: The metal chlorides of Fe(III), Co(II), Ni(II), Cu(II),Mn(II), Cr(III) andZn(II) solutions (1 mmol) in bidistilled water (25 mL) were added to25 mL ethanol solution of H2Ten (0.337 g, 1mmol) followed by additionof 25 mL of 1 mmol Val (0.117 g in bidistilled water) in the molar ratio1:1:1 (metal salt: H2Ten: Val) in total volume 75 mL mixture. Theresulting mixture was stirred under reflux for 2 h whereupon the complexes precipitated. They were removed by filtration, washed withhot ethanol followed by diethylether and dried in vacuum desiccatorsover anhydrous calcium chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; water; for 2h;Reflux; | General procedure: The metal chlorides of Fe(III), Co(II), Ni(II), Cu(II),Mn(II), Cr(III) andZn(II) solutions (1 mmol) in bidistilled water (25 mL) were added to25 mL ethanol solution of H2Ten (0.337 g, 1mmol) followed by additionof 25 mL of 1 mmol Val (0.117 g in bidistilled water) in the molar ratio1:1:1 (metal salt: H2Ten: Val) in total volume 75 mL mixture. Theresulting mixture was stirred under reflux for 2 h whereupon the complexes precipitated. They were removed by filtration, washed withhot ethanol followed by diethylether and dried in vacuum desiccatorsover anhydrous calcium chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; water; for 2h;Reflux; | General procedure: The metal chlorides of Fe(III), Co(II), Ni(II), Cu(II),Mn(II), Cr(III) andZn(II) solutions (1 mmol) in bidistilled water (25 mL) were added to25 mL ethanol solution of H2Ten (0.337 g, 1mmol) followed by additionof 25 mL of 1 mmol Val (0.117 g in bidistilled water) in the molar ratio1:1:1 (metal salt: H2Ten: Val) in total volume 75 mL mixture. Theresulting mixture was stirred under reflux for 2 h whereupon the complexes precipitated. They were removed by filtration, washed withhot ethanol followed by diethylether and dried in vacuum desiccatorsover anhydrous calcium chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; water; for 2h;Reflux; | General procedure: The metal chlorides of Fe(III), Co(II), Ni(II), Cu(II),Mn(II), Cr(III) andZn(II) solutions (1 mmol) in bidistilled water (25 mL) were added to25 mL ethanol solution of H2Ten (0.337 g, 1mmol) followed by additionof 25 mL of 1 mmol Val (0.117 g in bidistilled water) in the molar ratio1:1:1 (metal salt: H2Ten: Val) in total volume 75 mL mixture. Theresulting mixture was stirred under reflux for 2 h whereupon the complexes precipitated. They were removed by filtration, washed withhot ethanol followed by diethylether and dried in vacuum desiccatorsover anhydrous calcium chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; water; for 2h;Reflux; | General procedure: The metal chlorides of Fe(III), Co(II), Ni(II), Cu(II),Mn(II), Cr(III) andZn(II) solutions (1 mmol) in bidistilled water (25 mL) were added to25 mL ethanol solution of H2Ten (0.337 g, 1mmol) followed by additionof 25 mL of 1 mmol Val (0.117 g in bidistilled water) in the molar ratio1:1:1 (metal salt: H2Ten: Val) in total volume 75 mL mixture. Theresulting mixture was stirred under reflux for 2 h whereupon the complexes precipitated. They were removed by filtration, washed withhot ethanol followed by diethylether and dried in vacuum desiccatorsover anhydrous calcium chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: Thiocyanate; D,L-valine With benzoyl chloride In water for 0.5h; Green chemistry; Stage #2: ethyl Bromopyruvate With zinc(II) oxide In water at 20℃; Green chemistry; | 4.2.4. General Route for the Formation of 5a-5i General procedure: The mixture of amino acids in 5 mL water was added tothe mixture of acid chlorides (2 mmol) and ammoniumthiocyanate (2.5 mmol). This mixture was mixed for 30 min.After this, the mixture of alkyl bromides (2 mmol) andnanorods of ZnO (10% mol) in water was added to priormixture. The reaction is completed and confirmed with TLCmonitoring after 5 h. The product is considered to be as thesolid form separating by filtering. After the separation ofproduct, it was purified by washing with Et2O |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: Thiocyanate; D,L-valine With benzoyl chloride In water for 0.5h; Green chemistry; Stage #2: 2-Bromo-4'-methoxyacetophenone With zinc(II) oxide In water at 20℃; Green chemistry; | 4.2.4. General Route for the Formation of 5a-5i General procedure: The mixture of amino acids in 5 mL water was added tothe mixture of acid chlorides (2 mmol) and ammoniumthiocyanate (2.5 mmol). This mixture was mixed for 30 min.After this, the mixture of alkyl bromides (2 mmol) andnanorods of ZnO (10% mol) in water was added to priormixture. The reaction is completed and confirmed with TLCmonitoring after 5 h. The product is considered to be as thesolid form separating by filtering. After the separation ofproduct, it was purified by washing with Et2O |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With ammonium hydroxide; hydrogen; at 219.84℃; under 7500.75 Torr; for 2h;Autoclave; | General procedure: The catalytic transformation of lactic acid andother biomass-derived acids was performed in an autoclave. For example, forthe conversion of lactic acid, the Ru/CNT catalyst and lactic acid were added to the reactor that had been precharged with aqueous ammonia. After theintroduction of H2 at a pressure of 1 MPa, the reactor was placed in a metaljacket wafer on an electronic hotplate (typically 493 K). After a fixed time,the reaction was quickly terminated by cooling the reactor to room temperaturein cold water. The catalytic transformation of glucose to lacticacid was performed in a round-bottom flask with Schlenk line. Degassedwater was added to the reactor that had been precharged with glucose andBa(OH)2 under N2 atmosphere. The flask was put in an oil bath on an electronicstirrer. After a fixed time, the liquid product was neutralized withsulfuric acid and filtered to remove Ba2+. The filtrate was added equal mole ofNaOH to prevent organic acids lose during freeze-dry. After freeze-drying, theproducts were acidified with HCl and used as the substrates in the aminationstep. The liquid products were analyzed by HPLC (Shimazu LC-20A) equippedwith both RI and UV detectors. Glucose and hydroxyl acids were quantifiedon an Agilent Hi-Plex H column (7.7 × 300 mm, 8 mum) using a dilute H2SO4aqueous solution as the mobile phase, whereas amino acids were analyzed ona Poroshell 120 EC-C8 column (4.6 × 100 mm) by using a precolumn derivatizationmethod, where ortho-phthalaldehyde was used as the derivatization reagent.The dehydrogenation of isopropanol (IPA) over Ru and Pd catalysts was performed in a fixed bed flow reactor equipped with an online gaschromatography (GC, Agilent 7890A). A flame ionization detector (FID) andan Agilent Cyclodex-B column (30 m × 250 mum × 0.25 mum) were used todetect and analyze IPA and gas products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.47% | With triethylamine In water; acetonitrile at 20℃; for 24h; | 10 General method for synthesis of (2-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) acetamido) acids) (6 a-m), (7) General procedure: A solution of N-acylbenzotriazole derivative (5, 0.005 mol) and the appropriate amino acid (0.005 mol) in acetonitrile/water mixture (3:1) containing triethylamine (0.0075 mol) was stirred at room temperature for 24h, then acetonitrile was evaporated under reduced pressure and the residual water solution was then acidified with 1N HCl to pH∼5 and the resultant precipitate was then filtered, dried and crystalized from methanol to give the titled compounds (6 a-m and 7) in 32.18-78.47% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With tert.-butylhydroperoxide; diphenyl-phosphinic acid; tetra-(n-butyl)ammonium iodide In dimethyl sulfoxide at 90℃; for 8h; Sealed tube; | Imidazole-Fuse Azaarenes 3; General Procedure General procedure: A sealed tube equipped with a magnetic stirring bar was chargedwith substituted (2-azaaryl)methane 1 (0.3 mmol), α-amino acid 2(0.45 mmol), Ph 2 PO 2 H (0.15 mmol), TBHP (0.6 mmol), and TBAI (0.06mmol) in DMSO (2 mL). The mixture was stirred under air at 90 °C for8 h. Then the mixture was cooled to r.t. and filtered through a shortsilica gel column (EtOAc). The filtrate was diluted with brine (60 mL)and extracted with EtOAc (2 × 30 mL). The combined organic layerswere dried (MgSO 4 ) and the solvent was removed in vacuo to afford aresidue. The residue was purified by column chromatography (silicagel, petroleum ether/EtOAc) to provide the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With tert.-butylhydroperoxide; diphenyl-phosphinic acid; tetra-(n-butyl)ammonium iodide In dimethyl sulfoxide at 90℃; for 8h; Sealed tube; | Imidazole-Fuse Azaarenes 3; General Procedure General procedure: A sealed tube equipped with a magnetic stirring bar was chargedwith substituted (2-azaaryl)methane 1 (0.3 mmol), α-amino acid 2(0.45 mmol), Ph 2 PO 2 H (0.15 mmol), TBHP (0.6 mmol), and TBAI (0.06mmol) in DMSO (2 mL). The mixture was stirred under air at 90 °C for8 h. Then the mixture was cooled to r.t. and filtered through a shortsilica gel column (EtOAc). The filtrate was diluted with brine (60 mL)and extracted with EtOAc (2 × 30 mL). The combined organic layerswere dried (MgSO 4 ) and the solvent was removed in vacuo to afford aresidue. The residue was purified by column chromatography (silicagel, petroleum ether/EtOAc) to provide the product. |
49% | With ammonium iodide In dimethyl sulfoxide at 100℃; for 10h; Electrochemical reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium carbonate In water at 70 - 80℃; for 2h; | 2-[({4-[(2,4-Dioxo-1,3-thiazolidin-5-ylidene)methyl] phenyl} sulfonyl) amino] alkanoic acidanalogus (3a to 3h) General procedure: An aqueous sodium carbonate solution (10 ml,1.2 mmol) was added drop wise to the stirred solution of amino acid (1 mmol). Compound 2 was added (0.3g,1 mmol) to the above mixture, stirred vigorously and the reaction mixture was heated at 70-80° for 1-2 hr. The resulting solution was allowed to cool and the pH was brought to 2.5 by adding hydrochloric acid under stirring. The product was separated by filtration and washed with cold water. The progress and completion of the reaction was monitored by TLC. The analytical parameters were recorded in Table-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With copper(II) nitrate trihydrate; iodine In dimethyl sulfoxide at 60℃; for 5h; Sealed tube; | II. General procedure for synthesis of 3 (3ac as an example) General procedure: The mixture of phenylacetylene 1a (1.0 mmol), 2-amino-4-methylpentanoic 2c (1.0 mmol) was mixedwith Cu(NO3)2•3H2O (0.5 mmol), and I2(1.0 mmol). The mixture was heated at 60 °C in 4 mL of DMSO in asealed vessel for 5 h till almost completed conversion of the substrates monitored by TLC analysis. Then 50mL water was added to the mixture, which was extracted with EtOAc three times (3 × 50 mL). The extractwas washed with Na2S2O3 solution, dried over anhydrous Na2SO4 then the solvent was removed underreduced pressure. The crude product was purified by column chromatography on silica gel (eluent:petroleum ether/EtOAc = 50/1) to afford the product 3ac |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate In methanol at 60℃; for 8h; diastereoselective reaction; | 3.2. General Procedure for the Synthesis of (S,2S)-6a and (R,2R)-6a General procedure: A suspension of (S)-4 or (R)-4 (100.3 mg, 0.2 mmol, 1 equiv.), rac-phenylalanine 5a (33 mg, 0.2mmol, 1 equiv.), Ni(OAc)2 (35.3 mg, 0.2 mmol, 1 equiv.), and K2CO3 (138.1 mg, 1.0 mmol, 5 equiv.) were refluxed in methanol (4 mL) at 60 °C for 8 h. After cooling to room temperature, the mixture was diluted with 5% aqueous acetic acid (15 mL) and extracted three times with dichloromethane.The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (PE/EA = 4:1 to DCM/MeOH =20:1) to afford two diastereomers (S,2S)-6a and (S,2R)-6a (138 mg, yield 98%) for analysis (dr > 99:1). The mixture was purified again by column chromatography on silica gel (DCM/MeOH = 40:1) to givethe pure diastereomer (S,2S)-6a as a red solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate In methanol at 60℃; for 8h; diastereoselective reaction; | 3.2. General Procedure for the Synthesis of (S,2S)-6a and (R,2R)-6a General procedure: A suspension of (S)-4 or (R)-4 (100.3 mg, 0.2 mmol, 1 equiv.), rac-phenylalanine 5a (33 mg, 0.2mmol, 1 equiv.), Ni(OAc)2 (35.3 mg, 0.2 mmol, 1 equiv.), and K2CO3 (138.1 mg, 1.0 mmol, 5 equiv.) were refluxed in methanol (4 mL) at 60 °C for 8 h. After cooling to room temperature, the mixture was diluted with 5% aqueous acetic acid (15 mL) and extracted three times with dichloromethane.The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (PE/EA = 4:1 to DCM/MeOH =20:1) to afford two diastereomers (S,2S)-6a and (S,2R)-6a (138 mg, yield 98%) for analysis (dr > 99:1). The mixture was purified again by column chromatography on silica gel (DCM/MeOH = 40:1) to givethe pure diastereomer (S,2S)-6a as a red solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.2% | Stage #1: D,L-valine With potassium iodide; sodium hydroxide In water at 60℃; for 2.08333h; Stage #2: chloroacetic acid In water at 45 - 91℃; | 5 Example 5 Preparation method of N,N-bis(carboxymethyl)valine trisodium salt To 1000mL three-necked flask, were added 280.0g of deionized water, 117.1 g of valine,1.0g of potassium iodide, open magnetic stirring, a solution of lye (m / m = 50.0%) adjusted to pH 10.0 to 10.5,After stirring at this temperature for 2.0 h, the temperature was raised to 60.0 ° C, and the remaining aqueous sodium hydroxide solution (m/m = 50.0%) was added dropwise.After 5 minutes, 243.1 g of aqueous chloroacetic acid (m/m = 70.0%) was added dropwise.Maintain the temperature of 45.0-50.0 ° C, about 4.5h all added, continue to stir at this temperature for 5.0h,Then the temperature is raised to 91.0 ° C for the incubation reaction for 2.5 h.After the reaction was completed, the temperature was lowered to room temperature and filtered, and the filtrate was a solution of N,N-bis(carboxymethyl)valine trisodium salt.After testing, the content of N,N-bis(carboxymethyl)valine trisodium salt in the obtained mixture was 25.6%.The yield was 87.2% (calculated as valine). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: copper(ll) sulfate pentahydrate; L-alanin; D,L-valine In water at 20℃; for 3h; Stage #2: With barium dihydroxide In water at 20℃; for 1h; | 2.1.2. Synthesis mixed ligand amino acid copper(II) complexes (method 1) General procedure: The complexes were prepared according to the published method[20]. A solution of mix two of amino acid in ratio 1:1 (on 3.3 mmol) indistilled water (20 ml) was prepared in the 100 ml flask equippedwith a magnetic stirrer. An aqueous solution of CuSO4 (0.82 g,3.3 mmol CuSO4·5H2O in 15 ml) was added to the solution of aminoacids. The reactionmixturewas stirred for 3 h at roomtemperature. Further,Ba(OH)2water solution (3.3mmol)was added to themixture. Thereactionmixture was stirred for 1 h at room temperature. The resultingblue solution was twice filtered and dried over anhydrous CaCl2. Theblue-violet powder containing mainly of trans-isomers 3-6a,b was obtained.The received of complexes were analyzed by XRD and ATRFTIR spectroscopy (br. broad; vs. very strong; s. strong; m. medium;w. weak). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: copper(ll) sulfate pentahydrate; D,L-valine; glycine In water at 20℃; for 3h; Stage #2: With barium dihydroxide In water at 20℃; for 1h; | 2.1.2. Synthesis mixed ligand amino acid copper(II) complexes (method 1) General procedure: The complexes were prepared according to the published method[20]. A solution of mix two of amino acid in ratio 1:1 (on 3.3 mmol) indistilled water (20 ml) was prepared in the 100 ml flask equippedwith a magnetic stirrer. An aqueous solution of CuSO4 (0.82 g,3.3 mmol CuSO4·5H2O in 15 ml) was added to the solution of aminoacids. The reactionmixturewas stirred for 3 h at roomtemperature. Further,Ba(OH)2water solution (3.3mmol)was added to themixture. Thereactionmixture was stirred for 1 h at room temperature. The resultingblue solution was twice filtered and dried over anhydrous CaCl2. Theblue-violet powder containing mainly of trans-isomers 3-6a,b was obtained.The received of complexes were analyzed by XRD and ATRFTIR spectroscopy (br. broad; vs. very strong; s. strong; m. medium;w. weak). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With sodium hydroxide In water at 20℃; for 24h; | 2.1.4. Synthesis mixed ligand amino acid copper(II) complexes (method 2) General procedure: According to the publishedmethods [20,21] a solution ofmix twoof amino acid in ratio 1:1 (on 3.3 mmol) in distilled water (20 ml) was prepared in the 100 ml flask equipped with a magnetic stirrer.1 M solution NaOH (6.6 mmol) was added to an aqueous solutionof mix two of amino acid. Then an aqueous solution of CuCl2(0.56 g, 3.3 mmol CuCl2·2H2O in 10 ml) was added to deprotonatedform of the amino acids. The reaction mixture was stirred for 24 h atroomtemperature and violet powder was formed. The received complexesas a mixture of isomers were analyzed by XRD and ATR-FTIRspectroscopy (br. broad; vs. very strong; s. strong; m. medium; w.weak). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium azide In water at 40℃; for 3h; | General procedure for the synthesis of tetrazoles General procedure: Amino acid (10 mmol), sodium azide (0.65 g, 10 mmol) and the Cu nano catalyst (20 mg) were added to a solution of TEOF (4.4 g, 5 mL, 30 mmol) in H2O (5 mL). The solution was stirred and the mixture heated at 40 C for 1-7 h depending on the substrate. Completion of the reaction was monitored by TLC. Then, H2O (20 mL) was added, the Cu catalyst filtered, the filtrate concentrated and the solvent removed in vacuo. The obtained tetrazoles were recrystallized from ethanol and were fully characterized, including satisfactory elemental analyses. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: D,L-valine With triethylamine; potassium hydroxide In 1,4-dioxane; water at 110℃; for 0.166667h; Microwave irradiation; Stage #2: [1,4]naphthoquinone In 1,4-dioxane; water at 110℃; Microwave irradiation; | 4.2. General Procedure for the Synthesis of Compounds 3a-c and 4a-c General procedure: The obtention and purification of the compounds were carried out under the methodology described by [24]. Briefly, the solution of respective amino acid (1.5-2.5 mmol) in dioxane/water (4:1,15mL for 3a-c derivatives or 20mLfor 4a-c derivatives), was basified with TEA or KOH(Sigma-Aldrich,St. Louis, MO, USA) aq. (pH 9-10) and activated under microwave irradiation under 110 °C, 250W for a time of 10 min (Mars 6, CEM, ISASA Latam, S.A. Alajuela, Costa Rica). Then a solution of naphthoquinone (Sigma-Aldrich, St. Louis, MO, USA) 5 mL (1a) or 2,3-dichloro-1,4-naphthoquinone(1b), 10 mL of dioxane:water mixture was added. The reaction mixture was irradiated with the same parameters by 15-20 min. The progress reaction was monitored by TLC, using MeOH:CHCl3(Sigma-Aldrich, St. Louis, MO, USA) (9:1) as eluent mixture. Finally, 20 mL of HCl (Sigma-Aldrich,St. Louis, MO, USA) (1 N) was added and the precipitated product was filtered and purified by flash column chromatography staring with dichloromethane (DCM) (Sigma-Aldrich, St. Louis, MO, USA)and changing the polarity to finish with methanol (Sigma-Aldrich, St. Louis, MO, USA). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: D,L-valine With triethylamine; potassium hydroxide In 1,4-dioxane; water at 110℃; for 0.166667h; Microwave irradiation; Stage #2: 2,3-Dichloro-1,4-naphthoquinone In 1,4-dioxane; water at 110℃; Microwave irradiation; | 4.2. General Procedure for the Synthesis of Compounds 3a-c and 4a-c General procedure: The obtention and purification of the compounds were carried out under the methodology described by [24]. Briefly, the solution of respective amino acid (1.5-2.5 mmol) in dioxane/water (4:1,15mL for 3a-c derivatives or 20mLfor 4a-c derivatives), was basified with TEA or KOH(Sigma-Aldrich,St. Louis, MO, USA) aq. (pH 9-10) and activated under microwave irradiation under 110 °C, 250W for a time of 10 min (Mars 6, CEM, ISASA Latam, S.A. Alajuela, Costa Rica). Then a solution of naphthoquinone (Sigma-Aldrich, St. Louis, MO, USA) 5 mL (1a) or 2,3-dichloro-1,4-naphthoquinone(1b), 10 mL of dioxane:water mixture was added. The reaction mixture was irradiated with the same parameters by 15-20 min. The progress reaction was monitored by TLC, using MeOH:CHCl3(Sigma-Aldrich, St. Louis, MO, USA) (9:1) as eluent mixture. Finally, 20 mL of HCl (Sigma-Aldrich,St. Louis, MO, USA) (1 N) was added and the precipitated product was filtered and purified by flash column chromatography staring with dichloromethane (DCM) (Sigma-Aldrich, St. Louis, MO, USA)and changing the polarity to finish with methanol (Sigma-Aldrich, St. Louis, MO, USA). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium hydroxide In diethyl ether; water at 20℃; for 20h; | General Procedure for the Synthesis of α-Amino Acid Sulfonamides. General procedure: Following a reported procedure,8 a 50mL drytwo-necked round-bottom flask equipped with a magneticstirrer was charged with valine (0.234 g, 2.0mmol), Et2O (10mL) and aqueous solution of NaOH (5 mL, 1.5 M). To the solutionwas added tosyl chloride (0.572 g, 3.0mmol) in one portion.The mixture was stirred at room temperature overnight(ca. 20 h), then extracted with Et2O. The aqueous layer wasacidified with 1N HCl solution to pH 23,then extracted withethyl acetate. The combined organic layers were dried overNa2SO4 and evaporated under reduced pressure. The crudematerial was then recrystallized from dichloromethane/hexaneto obtain pure sulfonamide 2a quantitatively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With sodium hydroxide In diethyl ether; water at 20℃; for 20h; | General Procedure for the Synthesis of α-Amino Acid Sulfonamides. General procedure: Following a reported procedure,8 a 50mL drytwo-necked round-bottom flask equipped with a magneticstirrer was charged with valine (0.234 g, 2.0mmol), Et2O (10mL) and aqueous solution of NaOH (5 mL, 1.5 M). To the solutionwas added tosyl chloride (0.572 g, 3.0mmol) in one portion.The mixture was stirred at room temperature overnight(ca. 20 h), then extracted with Et2O. The aqueous layer wasacidified with 1N HCl solution to pH 23,then extracted withethyl acetate. The combined organic layers were dried overNa2SO4 and evaporated under reduced pressure. The crudematerial was then recrystallized from dichloromethane/hexaneto obtain pure sulfonamide 2a quantitatively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium hydroxide In diethyl ether; water at 20℃; for 20h; | General Procedure for the Synthesis of α-Amino Acid Sulfonamides. General procedure: Following a reported procedure,8 a 50mL drytwo-necked round-bottom flask equipped with a magneticstirrer was charged with valine (0.234 g, 2.0mmol), Et2O (10mL) and aqueous solution of NaOH (5 mL, 1.5 M). To the solutionwas added tosyl chloride (0.572 g, 3.0mmol) in one portion.The mixture was stirred at room temperature overnight(ca. 20 h), then extracted with Et2O. The aqueous layer wasacidified with 1N HCl solution to pH 23,then extracted withethyl acetate. The combined organic layers were dried overNa2SO4 and evaporated under reduced pressure. The crudematerial was then recrystallized from dichloromethane/hexaneto obtain pure sulfonamide 2a quantitatively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: benzamide; trichloroacetonitrile With zinc(II) oxide In water for 0.75h; Stage #2: D,L-valine In water at 20℃; for 0.5h; Stage #3: ethyl Bromopyruvate In water for 3h; | 2.3. Common process for Generation of Compounds 5 General procedure: The trichloroacetonitrile 1 (2 mmol) and amides 2 (2mmol) mixed with ZnO-NPs (10 mol%) in water (5 mL).after 45 min amino acid 3 (2 mmol) was added to previous mixture at room temperature. After 30 min α-haloketones 4(2 mmol) was added to mixture and stirred for 3 h. After 3 h,the reaction is completed and TLC confirms progress of the reaction. At last, the solid residue was collected by filtration and cleaned with EtOAC to removing ZnO-NPs and after evaporating solvent and washing solid with Et2O compounds 5 afforded as pure product. 2-[4-(ethoxycarbonyl)-2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-yl]propanoic acid (5a) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: benzamide; trichloroacetonitrile With zinc(II) oxide In water for 0.75h; Stage #2: D,L-valine In water at 20℃; for 0.5h; Stage #3: 2-Bromo-4'-methoxyacetophenone In water for 3h; | 2.3. Common process for Generation of Compounds 5 General procedure: The trichloroacetonitrile 1 (2 mmol) and amides 2 (2mmol) mixed with ZnO-NPs (10 mol%) in water (5 mL).after 45 min amino acid 3 (2 mmol) was added to previous mixture at room temperature. After 30 min α-haloketones 4(2 mmol) was added to mixture and stirred for 3 h. After 3 h,the reaction is completed and TLC confirms progress of the reaction. At last, the solid residue was collected by filtration and cleaned with EtOAC to removing ZnO-NPs and after evaporating solvent and washing solid with Et2O compounds 5 afforded as pure product. 2-[4-(ethoxycarbonyl)-2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-yl]propanoic acid (5a) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: benzamide; trichloroacetonitrile With zinc(II) oxide In water for 0.75h; Stage #2: D,L-valine In water at 20℃; for 0.5h; Stage #3: para-bromophenacyl bromide In water for 3h; | 2.3. Common process for Generation of Compounds 5 General procedure: The trichloroacetonitrile 1 (2 mmol) and amides 2 (2mmol) mixed with ZnO-NPs (10 mol%) in water (5 mL).after 45 min amino acid 3 (2 mmol) was added to previous mixture at room temperature. After 30 min α-haloketones 4(2 mmol) was added to mixture and stirred for 3 h. After 3 h,the reaction is completed and TLC confirms progress of the reaction. At last, the solid residue was collected by filtration and cleaned with EtOAC to removing ZnO-NPs and after evaporating solvent and washing solid with Et2O compounds 5 afforded as pure product. 2-[4-(ethoxycarbonyl)-2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-yl]propanoic acid (5a) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.3% | Stage #1: D,L-valine With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 5-amino-N-(5-(3-aminoprop-1-yn-1-yl)-2-(4-methylpiperazin-1-yl)phenyl)-2-chloro-4-fluoro-3-methylbenzamide In N,N-dimethyl-formamide at 20℃; | 4.1.2 General procedure for the synthesis of 10-17 General procedure: To a solution of acid (0.46mmol) in DMF (10mL) at room temperature was added BOP reagent (0.12g, 0.28mmol), followed by TEA (0.06mL, 0.46mmol). The mixture was stirred for 0.5h before compound 9 (0.1g, 0.23mmol) was added. Then the resulting solution was stirred at room temperature for 4-8h. The aqueous solution was diluted with EA (50mL) and the mixture was washed with saturated sodium chloride solution (3×30mL). The organic phase was then separated, dried (Na2SO4), filtered, and concentrated to provide crude product. Then purified by column chromatography on silica gel using a common 2-5% MeOH/DCM gradient to afford compounds 10-17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium hydroxide In dichloromethane at 0 - 20℃; for 1.5h; | 4.2.1. Synthesis of 2-{4-[(4-Chlorophenyl)sulfonyl]benzamido}-3-methylbutanoic Acid 3 Valine (2.34 g, 20 mmol) was dissolved in 20 mL (20 mmol) of 1 N NaOH solution.To this solution, cooled in an ice bath (0-5 °C), a solution of raw 4-[(4-chlorophenyl)sulfonyl]benzoyl chloride 2 (6.30 g, 20 mmol) in 45 mL of anhydrous CH2Cl2, and a 2 N NaOHsolution (10 mL, 20 mmol), respectively, were added simultaneously, dropwise, undermagnetic stirring, for 30 min. Stirring of the reaction mixture was continued for another 1h at room temperature, then, the aqueous phase was separated and acidified with 2 NHCl. The precipitated solid was filtered off, washed with water, dried, and recrystallizedfrom water, when white acicular crystals were obtained; yield = 93% (7.36 g); m.p. = 191-193 °C.UV-Vis (CH3OH, λ nm) (lg ε): 202.6 (4.48); 248.5 (4.08).FT-IR (KBr, ν cm-1): 3358 s; 3090 m; 3074 m; 2964 s; 2937 m; 2876 m; 2615 w; 2577 w;2563 w; 1737 vs; 1641 vs; 1601 m; 1555 s; 1478 m; 1468 m; 1320 vs; 1303 s; 1290 s; 1283 s;1160 vs; 849 s; 759 vs.1H-NMR (DMSO-d6, δ ppm, J Hz): 0.94 (d, 6.9, 3H, H-19); 0.95 (d, 6.9, 3H, H-20); 2.18(oct, 6.9, 1H, H-18); 4.29 (dd, 8.1, 6.9, 1H, H-4); 7.71 (d, 8.5, 2H, H-14, H-16); 8.00 (d, 8.5,2H, H-13, H-17); 8.05 (d, 8.8, 2H, H-8, H-10); 8.09 (d, 8.8, 2H, H-7, H-11); 8.73 (d, 8.0, 1H,H-3).13C-NMR (DMSO-d6, δ ppm): 18.61 (C-19); 19.25 (C-20); 29.48 (C-18); 58.43 (C-4);127.49 (C-8, C-10); 129.08 (C-13, C-17); 129.46 (C-7, C-11); 130.01 (C-14, C-16); 139.03 (C-6);139.10 (C-15); 139.51 (C-12); 142.70 (C-9); 165.78 (C-2); 172.80 (C-5).RP-HPLC (methanol/water 30:70, v/v; 1 mL/min; 250 nm): purity = 99.99%; tR = 4.38min.Elemental analysis (%): calculated for C18H18ClNO5S (395.86 g/mol): C, 54.61; H, 4.58;N, 3.54; S, 8.10 and found: C, 54.66; H, 4.57; N, 3.54; S, 8.13. |
Tags: 516-06-3 synthesis path| 516-06-3 SDS| 516-06-3 COA| 516-06-3 purity| 516-06-3 application| 516-06-3 NMR| 516-06-3 COA| 516-06-3 structure
[ 20859-02-3 ]
(S)-2-Amino-3,3-dimethylbutanoic acid
Similarity: 0.97
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P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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