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CAS No. : | 826-55-1 | MDL No. : | MFCD00014332 |
Formula : | C10H12O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YYEROYLAYAVZNW-UHFFFAOYSA-N |
M.W : | 164.20 | Pubchem ID : | 13222 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.3 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 47.48 |
TPSA : | 37.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.19 cm/s |
Log Po/w (iLOGP) : | 1.38 |
Log Po/w (XLOGP3) : | 1.57 |
Log Po/w (WLOGP) : | 2.05 |
Log Po/w (MLOGP) : | 2.29 |
Log Po/w (SILICOS-IT) : | 1.91 |
Consensus Log Po/w : | 1.84 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.09 |
Solubility : | 1.35 mg/ml ; 0.00822 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.96 |
Solubility : | 1.79 mg/ml ; 0.0109 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.58 |
Solubility : | 0.427 mg/ml ; 0.0026 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.11 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: With thionyl chloride In dichloromethane for 15 h; Reflux |
Example 1: Synthesis of 2,2-dimethylphenylacetic acid ethyl ester In a 10L reaction flask, add 2,2-dimethylphenylacetic acid(500g, 3.1mol), 2.5L methylene chloride solution. Stir at room temperature. Add thionyl chloride (750g, 6.3mol). Warmed the reaction system to reflux and react for 15H. Then slowly add dropwise 400mL of absolute ethanol and stir for some time. until the reaction was complete by TLC after adjusted to pH 9-10 with NaOHsolution, divided the organic layer was washed twice with saturated sodiumbicarbonate, and saturated sodium chloride twice and dried and concentrated togive 2,2-dimethylphenylacetic acid ethyl ester 560g, 96percent). |
31 g | Reflux | 1) the α,α-dimethyl-phenylacetic acid is dissolved in ethanol in water-free, α, α-dimethylphenyl acetic acid in the molar concentration of anhydrous ethanol is 1.5-2mol/L, then adding equivalent to α, α-dimethyl benzyl acetic acid weight 2-3percent solid loading a heteropolyacid catalyst PW12/SiO2, reflux reaction 2-3h, separating the catalyst, reducing pressure and evaporating ethanol filtrate, the residue is dissolved in dichloromethane, are sequentially water, saturated sodium bicarbonate aqueous solution and water, anhydrous magnesium sulphate dried after-filtration, filtrate reducing pressure and evaporating the solvent, the residue is distilled under reduced pressure to continue, collecting the fraction 130-133° C/85kPa, shall be colorless transparent liquid α, α-dimethylphenyl acetic acid ethyl ester; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With dimethylsulfide borane complex; In tetrahydrofuran; at 0℃; for 1.5h;Reflux; | To a solution of 2-methyl-2-phenyl-propionic acid (82 g, 0.5 mol) in THF (200 mL) was added dropwise borane-dimethyl sulfide (2M, 100 mL) at 0-5 C. The mixture was stirred at this temperature for 30 min and then heated at reflux for 1 h. After cooling, methanol (150 mL) and water (50 mL) were added. The mixture was extracted with EtOAc (100 mL*3), and the combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to give 2-methyl-2-phenyl-propan-1-ol as an oil (70 g, 77%). |
72.7% | To a suspension of LiAIH4 (4.64 g, 123.0 mmol) in dry THF (500 mL) was added 2- methyl-2-phenyl-propionic acid (20.0 g, 123.0 mmol) in dry THF (250 mL) dropwise at 55C over 10 min. The mixture was quenched with sodium hydroxide aqueous solution (60 mL, 15%). The mixture was filtered and the filtrate was dried over anhydrous sodium sulfate, filtered and evaporated to yield 2-methyl-2-phenyl-propan-1-ol (13.3 g, 72.7%), which was used to the next step without further purification. | |
With sodium tetrahydroborate;boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃; for 5.08333h; | To a suspension of NaBH4 (0.70 g, 18.3 MMOL) in dry THF (20 mL) was added BF3. Et20 (0.25 mL, 20.1 MMOL) drop wise at 0C over 5 min and the mixture was stirred for 30 min. A solution of 2-methyl-2- PHENYL-PROPIONIC ACID (1.0 g, 6.1 MMOL) in dry THF (10 mL) was added drop wise at 0C over 30 min, and the mixture was stirred at room temperature for 4 h. Methanol was slowly added to the reaction mixture until hydrogen evolution stopped. The mixture was diluted with 10% HCI and extracted twice with EtOAc. The organic layer was dried over NA2SO4 and then under vacuum to yield colorless oil. [00202] This material was dissolved in DCM (25 mL), pyridine (1.2 mL, 15.3 MMOL) and acetyl chloride (2.2 mL, 30.5 MMOL) added, and the reaction mixture left to stir at room temperature overnight. The reaction mixture was washed with 10% HCI and the organic layer was dried over MGS04. [00203] The material was then dissolved in DCM (25 mL) and cooled to 0C. CHLOROSULFONIC acid (1.2 mL, 18 MMOL) was added drop wise over 15 minutes and the mixture was stirred at the same temperature for 3 H. The volatiles were evaporated and SOC12 (10 mL) was added and the mixture stirred at room temperature for 3 h. The excess SOC12 was evaporated and the residue was treated with ice-water and extracted with ether. The organic layer was washed with water and brine, dried over MGS04 and concentrated in vacuo to afford the aryl sulfonyl chloride as a yellowish oil. [00204] This oil was treated with a solution of (2-amino-5-chloro- PHENYL)-PYRIDIN-4-YL-METHANONE (1.2 g, 5 MMOL) in 10 mL pyridine and heated at 60 C for 4 h. The solvent was evaporated and the residue suspended in 3M HCI (10 mL) and stirred at room temperature for 16 h. The reaction mixture was put in an ice bath and neutralized with concentrated NAOH solution. The white precipitate formed was collected by filtration, washed with water and DRIED IN VACUO and purified by flash chromatography to yield 320 mg of N- [4-CHLORO-2- (PYRIDINE-4-CARBONYL)-PHENYL]-4- (2-HYDROXY-1, 1-DIMETHYL- ethyl)-benzenesulfonamide. [00205] Oxidation of this intermediate with MCPBA according to the general procedure gave N- [4-CHLORO-2- (1-OXY-PYRIDINE-4-CARBONYL)-PHENYL]- 4-(2-HYDROXY-1, 1-DIMETHYL-ETHYL)-BENZENESULFONAMIDE. 1H-NMR (400 MHz, CDC13) : B 1.24 (s, 6H), 3.58 (s, 2H), 7.29 (d, 1 H, J = 2.4 Hz), 7.37 (m, 4H), 7.53 (m, 2H), 7.62 (m, 2H), 7.78 (d, 1 H, J = 8.8 Hz), 8.23 (d, 2H, J = 6.8 Hz), 9.51 (s, 1 H). MS : M/Z 461. 1 (M+ + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; benzene | ||
With thionyl chloride | ||
With phosphorus trichloride |
With thionyl chloride for 1h; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 4h; | ||
With phosphorus pentachloride | ||
With thionyl chloride for 3h; Heating; | ||
With oxalyl dichloride In dichloromethane for 2h; | ||
With thionyl chloride In toluene for 1h; Heating / reflux; | ||
With oxalyl dichloride | ||
With oxalyl dichloride; N,N-dimethyl-formamide In hexane | ||
With oxalyl dichloride | ||
With oxalyl dichloride In dichloromethane at 0℃; for 3h; | 208.A 5-chloro-N-(5-chloro-pyridin-2-yl)-2-[4-(2-dimethylamino-1,1-dimethylethyl)benzylamino]benzamide Step A. To a solution of 2-methyl-2-phenylpropionic acid (5.0 g, 30.49 mmol) inCH2C12 at 0 C was added oxalyl chloride (4.0 ml, 45.7 mmol). The mixture was stirred at 0 C for 3 hr. Solvent was evaporated and the residue was dried. The above residue was dissolved inCH2Cl2, and dimethylamine was purged for 20 min. or until saturated. The mixture was stirred rt for lhr. The reaction mixture was washed with water, 1N HC1, sat'dNaHC03, and brine. Chromatography purification gave N, N-dimethyl-2-phenyl-isobutyramide as white solid. MS found:(M+1) +=192. 2. | |
With oxalyl dichloride In dichloromethane for 2h; | B6; B9 2,2-dimethylphenyl acetic acid (CAS 826-55-1) (2.5 g, 15 mmol) was dissolved in dry CH2C12 (50 mL), oxalyl chloride (1.5 mL, 0.017 mol) was added and one drop of DMF. After stirring for two hours, the solution was evaporated till dryness, redissolved in 50 mL of CH2C12, and added to a solution of 2-amino adamantane (CAS 13074-39-0) (2.5 g, 15 mmol) and triethylamine (3. 0 g, 30 mmol) in CH2C12 (50 mL). The mixture was stirred overnight, extracted with 15% citric acid, SAT. NAHCO3 and brine, dried over MGS04, and evaporated in vacuo. The residue was chromatographed over silicagel (eluens 3-5% MEOH in CH2C12), yielding the title compounds. 1.8 g of trans-, NMR : (CDC13) 8 1.2-1. 85 (m, CH), 1.59 (s, 6H, (CH3) 2), 1.95-2. 00 (m, 2H, CH), 3.91 (dt, 1H, CH), 5.32 (d, 1H, NH), 7.25-7. 47 (m, 5H, Ar-H). And 1.8 g of cis isomer. NMR: (CDC13) 5 1.2-1. 7 (m, CH), 1.56 (s, 6H, (CH3) 2), 2.05-2. 10 (m, 2H, CH), 3.83 (dt, 1H, CH), 5.32 (d, 1H, NH), 7.25-7. 50 (m, 5H, Ar-H) | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Inert atmosphere; | ||
With thionyl chloride for 3h; Inert atmosphere; Reflux; | ||
With thionyl chloride for 1h; Reflux; | 4 A solution of α,α dimethyl phenylacetic acid (2 g, 12.18 mmol) in thionyl chloride (20 ml) is heated to reflux for 1 hour after which time all of the starting acid has been consumed. The reaction mixture is concentrated in vacuo and the resulting acid chloride is used directly for the synthesis of [(tert-butoxy)carbonyl]amino 2-methyl-2-phenylpropanoate, which is prepared from the described acid chloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1. (2.76 g, 81%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.64 (1H, s), 7.29 (4H, dt, 15.6, 7.8 Hz), 7.12-7.23 (1H, m), 1.60 (6H, s), 1.38 (9H, s). | |
With thionyl chloride at 85℃; for 3h; Inert atmosphere; | ||
With thionyl chloride for 5h; Reflux; | ||
With oxalyl dichloride In dichloromethane | 10 Compound 1-236[00516] To a solution of 2-methyl-2-phenylpropanoic acid (11 equiv) in dichloromethane was added oxalyl chloride (33 equiv) and catalytic N,N-dimethylformamide. Once gas evolution ceased, this solvent was removed in vacuo. The crude acid chloride was redissolved in dichloromethane and added portion- wise to a suspension of Compound 1-107 (1 equiv) in dichloromethane/pyridine (2:1) until the absence of starting material was observed by LC/MS. Following an aqueous ammonium chloride and dichloromethane workup, purification via silica gel chromatography (0-10% methanol in dichloromethane) did not provide sufficiently pure material. Repurification using ethyl acetate in hexanes as an eluent provided the desired compound as a white solid (57%). 1H NMR (400 MHz, CD3OD) δ 8.74 (m, IH), 8.03 (s, IH), 7.48-7.46 (m, 2H), 7.41-7.36 (m, 3H), 7.30-7.21 (m, 2H), 7.09-7.04 (m, IH), 7.01 (t, IH), 6.85-6.79 (m, 2H), 5.93 (s, 2H), 1.67 (s, 6H). | |
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 3h; Inert atmosphere; | ||
With thionyl chloride In tetrahydrofuran at 25℃; for 1h; Inert atmosphere; | ||
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 25 - 45℃; for 12h; | 2 Example-2: Preparation of 2-methyl-2-phenylpropanoyl chloride (FormuIa-4) Example-2: Preparation of 2-methyl-2-phenylpropanoyl chloride (FormuIa-4) Thionyl chloride (217.2 gm) was slowly added to a mixture of 2-methyl-2- phenylpropanoic acid compound of formula-3 (100 gm), dichloromethane (500 ml) and dimethylformamide (8.9 gm) at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 12 hrs at the same temperature. Distilled off the solvent completely form the reaction mixture under reduced pressure and the obtained compound is utilized in the next step. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 17h; | ||
With thionyl chloride for 3h; Reflux; | ||
With oxalyl dichloride | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 17h; Inert atmosphere; Schlenk technique; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 5h; Inert atmosphere; | ||
With oxalyl dichloride | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 17h; Inert atmosphere; Schlenk technique; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; | 207E 207E N-methoxy-N-methyl-2-phenyl-isobutyramide To a solution of 2-methyl-2-phenyl-propionic acid (24.06g, 150 mmoles) in CH2Cl2 (150 mL) is added oxalyl chloride(21 g, 0.165 mmoles) and 5 drops of DMF. The reactionmixture is stirred overnight at room temperatures (reactionvessel connected to a bubbler to remove gases formed duringthe reaction). The solvent and volatiles are removed underreduced pressure to afford the acylchloride.A part of the residual oil (16 g, 87.6 mmoles) is dissolvedin CH2Cl2 (20 ml) and N,O-dimethylhydroxylamine.hydrochloride(9.0 g, 90 mmoles) and NEt3 (22.7 g, 219 mmoles)are added. The reaction mixture is stirred overnight at roomtemperature. CH2Cl2 is added to dilute the mixture and theorganic phase is washed with water, O.lN HCl, brine, driedover MgS04 , filtered and the solvent is removed underreduced pressure to give N-methoxy-N-methyl-2-phenylisobutyramide. | |
With thionyl chloride In toluene for 2h; Reflux; | 2.6 Example 6 500 mL reaction flask, 63 g of 2-methyl-2-phenylpropionic acid (II), 250 mL of toluene and 150 g of thionyl chloride were added, Heating reflux reaction 2h, HPLC monitoring reaction is complete, Vacuum dry solvent and excess of thionyl chloride, Plus 100mL toluene dissolved, Cooling to 0 ~ 5 , A solution of cesium carbonate (375 g) / water (180 g) was slowly added dropwise, Add insulation for 10min, A solution of N, O-dimethylhydroxylamine hydrochloride (40 g) in water (80 g) was added dropwise, Plus, Natural temperature to room temperature reaction 2h, HPLC monitoring reaction is complete, Separate the organic layer, The aqueous layer was extracted with dichloromethane 200 mL * 2, Combined organic layer, Were washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated brine, respectively, Dried over anhydrous sodium sulfate, Filtered to give an oil, Vacuum distillation, The bp: 112 ~ 115 ° C / 3 mmHg fraction was collected, To give 75 g of N-methoxy-N, 2-dimethyl-2-phenylpropionamide (III) Purity 98%, yield 94.3%. among them, 2-methyl-2-phenylpropionic acid (II), N, O-dimethylhydroxylamine hydrochloride, the molar ratio of base is 1: 1.1: 3. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; | ||
With N,N-dimethyl-formamide In chloroform at 80℃; for 3h; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 17h; Schlenk technique; Inert atmosphere; | ||
With thionyl chloride for 5h; Heating / reflux; | 24 Synthesis 24 3-(-1 -Phenyl-1 -methylethyl)-8-carbamoylimidazotetrazin-4-one (BB-006); Thionyl chloride (1.33 ml_, 18.27 mmol) was added drop wise to α,α-dimethylphenylacetic acid (Alfa Lancaster) (2.0 g, 12.18 mmol) and the mixture heated at reflux. After 5 hours, the thionyl chloride was removed by distillation at 78°C, then by co-evaporation with toluene at 1100C. The residue (α,α-dimethylphenylacetyl chloride) was used in the next step without further purification. | |
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 25 - 30℃; for 2h; Inert atmosphere; Large scale; | 13.1 Step-1 A mixture of 2-methyl-2-phenylpropanoic acid (50 Kg) and dichloromethane (250 Lt) was stirred for 15 min at 25-30°C. N,N-dimethylformamide (2.5 Lt) was added to the obtained solution at 25-30°C. Thionyl chloride (54.5 Kg) was slowly added to the reaction mixture at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 2 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture and co-distilled with dichloromethane. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 17h; | General procedure: Oxalyl chloride (1.75 mL, 20 mmol) was added dropwise to a stirred solution of thecarboxylic acid in CH2Cl2 (20 mL) and DMF (0.1 mL) at 0 C. The mixture wasstirred for 1 h at 0 C and another 16 h at room temperature, and evaporated in vacuoto give the crude acid chloride IV, which was used directly for the next step withoutfurther purification. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 23℃; for 2h; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 17h; | ||
With thionyl chloride In N,N-dimethyl-formamide at 80℃; for 2h; Inert atmosphere; | ||
With thionyl chloride at 65℃; for 1h; | 63.A Step A: Preparation of Diethyl 2-(2-methyl-2- phenylpropanoyl)malonate; [0766] EtOH (31.9 mL) and CCl4 (0.441 mL) were added to magnesium(2.22 g, 91.3 mmol) and diethyl malonate (13.8 mL, 91.3 mmol) at ambient temperature. THF (91.3 mL) was added slowly to control the reaction and maintain the temperature under reflux. The reaction mixture was then heated to 700C for 2 hours and cooled to room temperature. Meanwhile, the acid chloride of alpha^lpha-dimethylphenylacetic acid (10.0 g, 60.9 mmol) was formed by addition of thionyl chloride (3OmL) followed by heating to 65°C for 1 hour. The mixture was cooled, concentrated and redissolved in ether (2OmL). The resulting acid chloride solution was added dropwise via addition funnel to the magnesium enolate as prepared above. The reaction mixture was stirred for 1 hour and then quenched with IN HCl, diluted with 200 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed 2 times with 50 mL of water, separated, dried over Na2SC^, and concentrated in vacuo to give the title compound (22.1 1 g). MS (m/z) = 307 (M+H)+. | |
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20℃; | 3.1.1. 2-(4-(2-Chloroacetyl)phenyl)-N-Methoxy-N,2-Dimethylpropanamide (19) To a stirred solution of 2-methoxy-2-phenylpropionic acid (1.0 Kg, 6.1 mol) in dichloromethane (5 L) and dimethyl formamide (50 mL) was slowly added thionylchloride (1.08 Kg, 9.1 mol) at ambient temperature. The mixture was stirred at that temperature for 10-12h and after completion of reaction,the reaction mass was distilled and added with dichloromethane (5 L) to make 2-methoxy-2-phenylpropionyl chloridesolution (X). In another RBF N-methyl-O-methyl hydroxylamine hydrochloride (0.66 Kg, 7.3 mol) was added tothe stirred solution of sodium carbonate (0.77 Kg, 7.3 mol) and water (5 L) at 0°C. At the same temperature acid chloride solution (X) was added to reaction mixture and stirred for 2-3 h. After completion of reaction, organic layer was separated from reaction mass and distilled to get N-methoxy-N,2-dimethylpropanamide as residue. This residue was dissolved in dichloromethane (2.5 L) and added to the stirred solution of aluminium trichloride (1.62 Kg, 12.1 mol), dichloromethane (3.7 L) and chloroacetyl chloride (0.82 Kg, 7.3 mol) at 0°C. The mixture was stirred at ambient temperature for 4-5 h. After completion of reaction, chilled water (5 L) was added to mass and extracted the organic mass withdichloromethane (5 L). The organic layer was washed with5% brine solution (5 L) and solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate (100 mL). Cyclohexane was added to the resulting mass and stirred at 0°C for 1 hr. The precipitated solid was filtered and washed with cyclohexane (1 L) and dried inthe oven to afford title compound 19 as a white solid (1.06 Kg, 61%). | |
With phosphorus pentachloride In chloroform-d1 at 20℃; for 2h; | ||
With phosphorus pentachloride In dichloromethane at 20℃; for 2h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; | ||
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 0.5h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 2h; | ||
With chlorinating agent In dichloromethane at 0℃; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3h; | ||
With thionyl chloride at 85℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Example 3:; 2-Methyl-2-phenylpropanoic acid (5 g, 0.0304 moles) and water (50 ml) were added to three-necked round bottomed flask at ambient temperature (25 C to 30 C). To the resulting mixture, sodium carbonate solution (20% in water) was added dropwise until the pH was about 7. To the resulting solution 8.7 g of bromine was added dropwise while maintaining the pH of reaction solution at about 7 by addition of sodium carbonate solution. The reaction mixture was stirred until complete consumption of 2-methyl-2-phenylpropanoic acid as determined by gas chromatographic analysis. The neutral reaction solution was acidified with 5N hydrochloric acid to pH 1 to 2. The aqueous solution was extracted with dichloromethane (3x50 ml). All organic layers were combined, dried with anhydrous sodium sulphate and evaporated to dryness. The resulting solid product was suspended in hexanes (50 ml) and filtered to recover the product, 6.0 g, 81% yield, GC purity 98.5% of 2-(4-bromophenyl)-2-methylpropanoic acid and 1.25% of 2-(3-bromophenyl)-2-methylpropanoic acid. | |
46.6% | Step-2: Preparation of 2-(4-bromophenyl)-2-methylpropanoic acidThe wet material (on dry basis) from step-1 (275 Kg, assay 98%) was charged into a reactor containing 6875 L of water and 660 Kg of sodium bicarbonate. Bromine (330 Kg) was fed slowly into the reactor during 3 hours at 25-35 C. and maintained for 10 hours at 25-35 C. Toluene (275 L) was charged into reactor and stirred for 15 minutes. The aqueous phase was discharged into another reactor and pH adjusted to about 5 with dilute hydrochloric acid (880 L of water and 440 L of hydrochloric acid) at 0-10 C. The resultant material was filtered and washed with water. The obtained wet product was treated with heptanes (700 L) to recover 190 Kg (46.6% yield) of 2-(4-bromophenyl)-2-methylpropanoic acid, GC purity: 99.28% of 2-(4-bromophenyl)-2-methylpropanoic acid and 0.72% of 2-(3-bromophenyl)-2-methylpropanoic acid, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With water; sodium hydroxide In methanol at 80℃; for 12h; | |
73% | With water; potassium hydroxide In ethylene glycol at 100℃; for 48h; Inert atmosphere; | |
In ethylene glycol (hydrolysis); |
With potassium hydroxide In ethylene glycol Heating; | ||
(hydrolysis); | ||
With potassium hydroxide In methanol | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: sodium nitrite; hydrochloric acid | ||
Stage #1: 2-methyl-2-phenylpropionitrile With sodium hydroxide In water for 6h; Heating / reflux; Stage #2: With hydrogenchloride In water at 20℃; | 1 Benzyl cyanide (0.5 kg), potassium hydroxide (1.4 kg) and DMSO (2.5 ITR) were initially charged to a reactor and dimethyl sulphate (1.20 kg) was slowly added thereto over a period of one hour. The mixture was stirred for 3-4 hours at room temperature. The mass was slowly quenched in water with stirring. The pH was adjusted to 1-2 with conc HC1. The solution was filtered, the solids washed with water and the resulting material was dried under vacuum in an oven. The resulting product was suspended in water (3.0 LTR), sodium hydroxide (0.5 kg) added thereto and the mixture refluxed for 6 hours. After completion of the reaction, the reaction mass was cooled to room temperature and acidified with HC1 to pH 2-3. The resulting precipitated material was filtered, washed with water and dried to obtain the title product. | |
1.6 g | With potassium hydroxide In ethanol; water at 110℃; | Intermediate 39b: 2-Methyl-2-phenylpropanoic acid To a solution of 39a (2.0 g, 13.7 mmol) in ethanol: water (10 mL: 1 mL), KOH (4.63 g, 6.0 eq) was added and heated at 110 00 over night. After cooling, the reactionmixture was acidified with iN HCI (pH=2) and extracted with ethyl acetate, washed with water, dried and concentrated to yield the title compound (1 .6 g) as a white solid.LCMS: (M-H) = 163.0; 1H NMR: (DMSO-d6, 300MHz) 6 12.31(s, 1H), 7.33-7.34 (m, 4H), 7.22-7.27 (m, 1 H), 1.47 (5, 6H). |
1.6 g | With potassium hydroxide In ethanol; water at 110℃; | 39b Intermediate 39b: 2-Methyl-2-phenylpropanoic acid To a solution of Intermediate 39a (2.0 g, 13.7 mmol) in ethanol: water (10 mL: 1 mL), KOH (4.63 g, 6.0 eq) was added and heated at 110 00 over night. After cooling, the reaction mixture was acidified with 1 N HCI (PH=2) and extracted with ethyl acetate,washed with water, dried and concentrated to yield the title compound (1 .6 g) as a white solid. LCMS: (M-H) = 163.0; 1H NMR: (DMSO-d6, 300MHz ) 6 12.31(s, 1H), 7.33-7.34 (m, 4H), 7.22-7.27 (m, 1 H), 1 .47 (5, 6H). |
With potassium hydroxide In water; ethylene glycol at 100℃; for 48h; | ||
With sodium hydroxide In water for 48h; Reflux; | 1.1 Example 1 1000 mL reaction flask, Adding 50 g of phenylacetonitrile, 140 g of potassium hydroxide and 250 mL of dimethylsulfoxide, Stirred at room temperature for 1 h, 132 g of dimethyl sulfate was added dropwise, Temperature control 35 ~ 40, Plus, At this temperature for 1 h, HPLC monitoring; After the reaction is complete, The reaction solution was poured into 1000 g of stirred ice-water mixture, Dichloromethane extraction 200 mL * 2, Combine organic phase, Followed by water, saturated salt water wash, Dried over anhydrous sodium sulfate, Concentrated to get red liquid; The resulting red liquid is added to the reaction flask, 250 ml of water and 85 g of sodium hydroxide were added successively, Heat at reflux for 48h, HPLC monitoring, After the reaction is complete, Cooling to 20 ~ 25 , The impurities were extracted with dichloromethane 100 mL * 2, Toss, The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 1 to 2, Precipitation of a large number of solid, filter, Washed, dry, To give 63 g of a pale yellow solid 2-methyl-2-phenylpropionic acid (II) Purity 96% Two-step yield of 90%. among them, The molar ratio of phenylacetonitrile, dimethyl sulfate to base was 1: 2.4: 5.6. | |
With potassium hydroxide In ethylene glycol for 4h; Reflux; | ||
With potassium hydroxide at 160℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Example 1: Synthesis of 2,2-dimethylphenylacetic acid ethyl esterIn a 10L reaction flask, add 2,2-dimethylphenylacetic acid(500g, 3.1mol), 2.5L methylene chloride solution. Stir at room temperature. Add thionyl chloride (750g, 6.3mol). Warmed the reaction system to reflux and react for 15H. Then slowly add dropwise 400mL of absolute ethanol and stir for some time. until the reaction was complete by TLC after adjusted to pH 9-10 with NaOHsolution, divided the organic layer was washed twice with saturated sodiumbicarbonate, and saturated sodium chloride twice and dried and concentrated togive 2,2-dimethylphenylacetic acid ethyl ester 560g, 96%). | |
31 g | With heteropolyacid catalyst PW12/SiO2;Reflux; | 1) the alpha,alpha-dimethyl-phenylacetic acid is dissolved in ethanol in water-free, alpha, alpha-dimethylphenyl acetic acid in the molar concentration of anhydrous ethanol is 1.5-2mol/L, then adding equivalent to alpha, alpha-dimethyl benzyl acetic acid weight 2-3% solid loading a heteropolyacid catalyst PW12/SiO2, reflux reaction 2-3h, separating the catalyst, reducing pressure and evaporating ethanol filtrate, the residue is dissolved in dichloromethane, are sequentially water, saturated sodium bicarbonate aqueous solution and water, anhydrous magnesium sulphate dried after-filtration, filtrate reducing pressure and evaporating the solvent, the residue is distilled under reduced pressure to continue, collecting the fraction 130-133 C/85kPa, shall be colorless transparent liquid alpha, alpha-dimethylphenyl acetic acid ethyl ester; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(i) SOCl2, (ii) Li<AlH(OtBu)3>, THF; Multistep reaction; | ||
Multi-step reaction with 2 steps 1: (μ3,η2,η3,η5-acenaphthylene)Ru3(CO)7 / TETRAHYDROPYRANE / 18 h / 70 °C 2: tetrabutyl ammonium fluoride; water | ||
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 1.5 h / -78 - 0 °C / Inert atmosphere 2: Dess-Martin periodane / dichloromethane / 1 h / 20 °C / Inert atmosphere |
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / diethyl ether / 2 h / 0 °C / Inert atmosphere; Schlenk technique 2: N-(2,2,6,6-tetramethyl-1-oxopiperidin-1-ium-4-yl)acetamide tetrafluoroborate; 2,6-dimethylpyridine / dichloromethane / 20 °C | ||
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2: Dess-Martin periodane / dichloromethane / 10 h / 0 - 25 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / diethyl ether / 20 °C / Inert atmosphere 2: pyridinium chlorochromate; potassium acetate / dichloromethane / 2 h / 0 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0.17 h / 55 °C 2: sulfur trioxide pyridine complex; triethylamine / dimethyl sulfoxide / 2.5 h / 20 °C | ||
2.48 g | Stage #1: 2-methyl-2-phenylpropionic acid With lithium aluminium tetrahydride In diethyl ether for 0.333333h; Stage #2: With potassium acetate; pyridinium chlorochromate In dichloromethane at 20℃; for 3h; Inert atmosphere; | |
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / diethyl ether / 1.5 h / 20 °C / Inert atmosphere 2: 4-methylmorpholine N-oxide; tetrapropylammonium perruthennate / dichloromethane / 20 h / 20 °C / Inert atmosphere; Molecular sieve | ||
Multi-step reaction with 2 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.5 h / 20 °C 1.2: 0.25 h / 20 °C 2.1: diisobutylaluminium hydride / toluene / 0.25 h / 0 °C 2.2: 2 h / 20 °C | ||
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / 0 °C 2: pyridinium chlorochromate / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 2-methyl-2-phenylpropionic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 9h; Stage #2: With ammonium hydroxide In dichloromethane; N,N-dimethyl-formamide for 9h; | 1 Amide formation 1.26 mL of oxalyl chloride (14.70 mmol, 3.2 equiv) was added dropwise to the solution of 0.750 g (4.57 mmol) of 2-methyl-2-phenylpropanoic acid in 10 mL dichloromethane at 0 °C. This was followed by the addition of 1 drop of DMF. The reaction mixture was brought to room temperature, and after 9 hours of stirring was slowly added to 20 mL of 30% aqueous NfL solution upon vigorous stirring. The stirring continued for 9 more hours. The reaction mixture diluted with water (20 mL), filtered from white precipitate into a separatory funnel, and washed with dichloromethane (3 x 30 mL). Combined organic fractions were washed with brine (30 mL), filtered through cotton and concentrated under reduced pressure to yield a crude amide, which was purified by flash chromatography (hexanes/ethyl acetate), 0.588 g of 2-methyl-2-phenylpropanamide (3.60 mmol, 78% yield). Melting point: 162.0 °C. |
(i) SOCl2, (ii) aq. NH3; Multistep reaction; | ||
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 23 °C 2: ammonia / ethyl acetate / 0.25 h / 23 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; at 20℃; for 12h;Heating / reflux; | Methanol (2.5 LTR), 2,2-dimethyl-2-phenyl-acetic acid (Intermediate 1) (0.5 kg), and conc. sulphuric acid (50 ml) were charged to a reactor at room temperature. The temperature was raised to reflux and maintained for 12 hours. The pH was adjusted to 7-8 using aqueous ammonia and the methanol concentrated completely. The reaction mass was quenched in water (1 LTR) and extracted with MDC (750 ml). The MDC layer was dried over sodium sulphate and concentrated to obtain 500 gms of the title compound as an oil having 98% purity | |
With sulfuric acid; at 25 - 45℃; for 4h;Heating / reflux; | (a) Reaction of alpha,alpha-Dimethyl phenyl acetic acid and methanol alpha,alpha-Dimethylphenyl acetic acid was reacted with methanol in presence of cone, sulfuric acid between about 25 to 45C. Reaction mixture was refluxed for about 4 hours. Methanol was distilled off after the said time to give thick oily slurry of Methyl-alpha,alpha-dimethylphenyl acetic acid. Water was added to the pre-cooled reaction mixture and extracted with chloroform EPO <DP n="8"/>followed by washing with aqueous sodium bicarbonate solution and finally with potable water. Removal of chloroform under reduced pressure yielded title compound as oily mass in about 98 % HPLC purity.EXAMPLE 1Methyl- a, a-Dimethyl phenyl acetate (ester)51 Kg (0.3109 Kmole) of alpha,alpha-Dimethyl acetic acid was dissolved in 100 to 150 Ltr methanol and to it was added concentrated sulfuric acid, 6 to 9 Kg maintaining temperature 25 to 450C. After complete addition of sulfuric acid reaction mixture was refluxed for 4 hours. After completion of the reaction methanol was distilled off under vacuum to obtain thick slurry which was cooled to room temperature and to it was added water. Reaction mixture was then extracted with chloroform and washed with 10% w/v sodium bicarbonate aqueous solution. Finally, chloroform layer was washed with potable water. On removal of chloroform under vacuum, Methyl-alpha,alpha-Dimethyl phenyl acetate as oily mass was obtained. HPLC Purity = 98%. Yield = 40 to 50 Kg | |
1 g | With methanesulfonic acid; for 2h;Sealed tube; Reflux; | A 100 mL sealed tube was charged with intermediate 39b (1.6 g, 9.7 mmol) and methanol (10 mL). To the above stirred solution CH3SO3H (1 .6 mL) was added drop wise and refluxed for 2 h. The reaction mixture concentrated and was diluted with ice- water and neutralized with NaHCO3, extracted with ethyl acetate, washed with water and dried. The product was obtained by concentrating under vacuo, which was further purified by combiflash to yield the title compound (1 .0 g) as a colourless liquid.H NMR: (ODd3, 300MHz) 6 7.25-7.27(d, 4H) 7.17-7.20 (m, 1H), 3.58 (5, 3H),1 .51 (5, 6H). |
2 g | With sulfuric acid; at 0℃;Reflux; | To a stirred solution of 2-methyi-2-phenyipropanoic acid (2 g, 12.18 mmol) in methanol (30m1) at 0 was added drop wise solution of H2S04 (2 ml, 37.5 mmol), The reaction mixture was heated torefiux for overnight. After completion of reaction, methanol was evaporated under reduced pressure and the residue was diluted with dichioromethane. The organic portion was washed with saturatedsodium bicarbonate solution, brine and evaporated under reduced pressure to give methyl 2-methyl-2-phenyipropanoate (2 g) as oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With water; sodium hydroxide; In 1,4-dioxane; for 24h; | Methyl 2-methyl-2-phenylpropanoate (0.840 g, 4.71 mmol) was dissolved in 5 mL of l,4-dioxane and 10 mL of 1.0 M NaOH (10.0 mmol, 2.1 equiv) was added. The mixture was heated at 95 C for 24 h. 20 mL of 1.0 M HC1 was added and the mixture was extracted with dichloromethane (3 x 20 mL). Combined organic fractions were washed with brine (30 mL), filtered through cotton and concentrated under reduced pressure to yield a crude mixture which was purified by flash chromatography (hexanes/ethyl acetate), 0.758 g of 2-methyl-2-phenylpropanoic acid (4.62 mmol, 98%). |
89 g | With water; sodium hydroxide; In methanol; at 10℃; for 3h;Reflux; | Example-l: Preparation of 2-methyl-2-phenylpropanoic acid (FormuIa-3) Methyl 2-methyl-2-phenylpropanoate compound of formula-2 (100 gm) and methanol (500 ml) were added to a pre-cooled mixture of sodium hydroxide (45 gm) and water (500 ml) at 10-15C. Heated the reaction mixture to reflux temperature and stirred for 3 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure and cooled the reaction mixture to 25-30C. Water was added to the reaction mixture and cooled to 5-10C. Acidified the reaction mixture using dil.HCl solution at 5-10C. Raised the temperature of the reaction mixture to 25-30C and stirred for 30 rhin at the same temperature. Filtered the solid, washed with water and dried the material to get the title compound. Yield: 89.0 gm. |
With water; sodium hydroxide; In methanol; at 65℃; | General procedure: The ester II was added to a mixture of NaOH (2.0 M, 8 mL) and methanol (10 mL)and stirred overnight at 65 C. After removal of methanol in vacuo, the residue wasdiluted with water and extracted with EtOAc (10 mL × 3). Then the pH value of thewater layer was adjusted to 2.0 with HCl (2.0 M) and extracted with EtOAc (30 mL ×3). The combined organic phases were evaporated in vacuo to give the crudecarboxylic acid III, which was used directly for the next step without furtherpurification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With Rh/Al<SUB>2</SUB>O<SUB>3</SUB>; hydrogen In acetic acid | 3.11b 2-cyclohexyl-2-methylpropanoic acid 2-methyl-2-phenylpropanoic acid (10 g, 61 mmol), acetic acid (60 mL) and 5 wt % Rh/Al2O3 (2.0 g) were combined in a glass beaker. The beaker was placed in the stainless steel pressure reactor and the reaction medium was stirred under H2 atmosphere (110 psi) overnight. The reaction mixture was filtered thru celite and washed with ethyl acetate then concentrated. The residue was dissolved in diethyl ether, washed with water (50 mL×4), and brine (50 mL×2), dried over MgSO4 and concentrated to give 2-cyclohexyl-2-methylpropanoic acid as a white solid (10 g, 95% yield). UPLC MS (M-H)=169; 1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 1.72 (dt, J=12.2, 2.7 Hz, 2H), 1.67-1.51 (m, 3H), 1.47 (dt, J=11.9, 3.0 Hz, 1H), 1.25-1.01 (m, 3H), 1.00 (s, 6H), 0.98-0.87 (m, 2H). |
With hydrogen |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With water In butanone at 115℃; for 5.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 99 percent / LiAlH4 / diethyl ether 2: 97 percent / Et3N; 4-pyrrolidinopyridine / 0.33 h / 20 °C 3: 63.5 percent / AlCl3 / CS2 / 1.5 h / 0 - 5 °C 4: 68 percent / p-TsOH*H2O / benzene / 24 h / Heating 5: 99 percent / NaOH; MeOH / 0.5 h / 20 °C 6: 89 percent / Jones reagent / acetone / 0 °C 7: 92 percent / diethyl ether / 0 °C 8: 89 percent / HCl; H2O / tetrahydrofuran / 15 h / 20 °C 9: 95 percent / NaBH4 / methanol; tetrahydrofuran / 0.5 h / 0 °C 10: 44 percent / K2CO3; KI / dimethylformamide; toluene / 7 h / Heating | ||
Multi-step reaction with 3 steps 1.1: sodium hydrogencarbonate; bromine / water / 13 h / 25 - 35 °C / Industry scale 1.2: 0 - 10 °C / pH 5 2.1: sulfuric acid / toluene / 16 h / 63 - 67 °C / Industry scale 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0); copper(l) iodide / toluene / 24 h / Reflux 3.2: 2 h / 25 - 35 °C | ||
Multi-step reaction with 3 steps 1.1: bromine; sodium carbonate / water / 25 - 30 °C / pH 7 1.2: pH 1 - 2 2.1: sulfuric acid / toluene / 16 h / 63 - 67 °C / Industry scale 3.1: potassium carbonate / copper(l) iodide / toluene / 24 h / Reflux 3.2: 2 h / 25 - 35 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: SOCl2 / 1 h 2: 1 h / Heating 3: 81 percent / magnesium / diethyl ether / 3 h / Heating | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 0 °C / Reflux 2: tetrahydrofuran / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Stage #1: tert-butyl 4-((R)-(3-aminophenyl){4-[(diethylamino)carbonyl]phenyl}methyl)piperazine-1-carboxylate; 2-methyl-2-phenylpropionic acid With N-ethyl-N,N-diisopropylamine; HATU In DMF (N,N-dimethyl-formamide) at 20℃; for 18h; Stage #2: With trifluoroacetic acid In dichloromethane for 18h; | 38 COMPOUND 38: N, N-DIETHYL-4-[(R)-{3-[(2-METHYL-2- phenylpropanoyl) amino] phenyl} (PIPERAZIN-L-YL) methyl] benzamide To a solution of INTERMEDIATE 5b (105 mg) in dimethylformamide (4 mL) was added oc, OC-DIMETHYLPHENYLACETIC acid (74 g; 2 eq), HATU (156 g; 4eq) and N, N- diisopropylethylamine (173 1L ; 4eq). The reaction was stirred at room temperature under nitrogen. After 18 hours, the reaction was concentrated and the crude dissolved in dichloromethane (5 ML) and trifluoroacetic acid (0.5 mL) was added to the reaction and stirred for 18 hours until complete removal of the boc group. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The aqueous was extracted with two portions of dichloromethane and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase chromatography, eluting 10% to 45% acetonitrile in water containing 0. 1 % trifluoroacetic acid. The product was obtained as the trifluoroacetic acid salt and was lyophilized to give COMPOUND 38 (51 mg, 31% yield) as a colourless solid. Purity (HPLC): > 99%; Optical purity (Chiral HPLC): > 99% ; 1H NMR (400MHZ, CD30D) 1.06 (t, J = 7.66Hz, 3H), 1.19 (t, J = 6.92Hz, 3H), 1.58 (s, 6H), 2.53-2. 68 (m, 4H), 3.17-3. 25 (m, 6H), 3.44-3. 53 (m, 2H), 4.40 (s, 1H), 7.11-7. 17 (m, 1H), 7.18-7. 24 (m, 3H), 7.29 (d, J = 8.34Hz, 2H), 7.31- 7.38 (m, 4H), 7.52 (d, J = 8.22Hz, 2H), 7.71-7. 73 (m, 1H). Found: C, 60.46 ; H, 6.23 ; N, 8.18. C32H40N402 X 0. 6H20 X 1.5CF3COOH has C, 60.53 ; H, 6.20 ; N, 8.07%. [a] D20=-8. 58 deg [c 0.792, MeOH]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 23℃; for 16h; | 1 EXAMPLE 1 N-2-adamantyl-2-methyl-2-phenylpropanamide A solution of 2-adamantanamine hydrochloride (38 mg, 0.20 mmol), 2-phenylisobutyric acid (30 mg, 0.19 mmol), and O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (65 mg, 0.20 mmol) in N,N-dimethylacetamide (DMA) (2 mL) and DIEA (80 μL, 0.46 mmol) was stirred for 16 hours at 23° C. The reaction mixture was analyzed by LC/MS and determined to be near completion. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm*100 mm, 7 um particle size) using a gradient of 10% to 100% acetonitrile: aqueous ammonium acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40 mL/min on reverse phase HPLC to afford the title compound upon concentration under reduced pressure (11 mg, 20%). 1H NMR (300 MHz, DMSO-d6) δ 7.35 (m, 4H), 7.24 (m, 1H), 6.16 (d, J=6.9 Hz, 1H), 3.78 (m, 1H), 1.74 (m, 7H), 1.64 (m, 3H), 1.55 (m, 2H), 1.48 (s, 6H), 1.41 (m, 2H); MS (DCI+) m/z 298 (M+H)+. |
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 23℃; for 16h; | 7 N-2-adamantyl-2-methyl-2-phenylpropanamide A solution of 2-adamantanamine hydrochloride (38 mg, 0.20 mmol), 2-phenylisobutyric acid (30 mg, 0.19 mmol), and O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (65 mg, 0.20 mmol) in N,N-dimethylacetamide (DMA) (2 mL) and DIEA (80 μL, 0.46 mmol) was stirred for 16 hours at 23° C. The reaction mixture was analyzed by LC/MS and determined to be near completion. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 um particle size) using a gradient of 10% to 100% acetonitrile:aqueous ammonium acetate (10 mM) over 8 minutes (10 minute run time) at a flow rate of 40 mL/minute on reverse phase HPLC to afford the title compound upon concentration under reduced pressure. 1H NMR (300 MHz, DMSO-d6) 67.35 (m, 4H), 7.24 (m, 1H), 6.16 (d, J=6.9 Hz, 1H), 3.78 (m, 1H), 1.74 (m, 7H), 1.64 (m, 3H), 1.55 (m, 2H), 1.48 (s, 6H), 1.41 (m, 2H); MS (DCI+) m/z 298 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With hydrogenchloride; thionyl chloride; potassium carbonate In water; toluene | 22.h Step h: Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid, N-methoxy-N-methylamide Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) in toluene (80 mL) and add, by dropwise addition5 minutes, thionyl chloride (15 mL, 206 mmol). Stir at room temperature overnight, add additional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40 mL). Add toluene (20 mL) to the reaction mixture along with a solution of potassium carbonate (28.0 g, 203 mmol) in water (40 mL). Add, by dropwise addition, a solution of N,O-dimethylhydroxylamine hydrochloride (8.9 g, 91.2 mmol) in water (20 mL) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75 mL) following by slow addition of aqueous HCl (2N, 75 mL) with vigorous stirring. Separate the organic layer and wash with aqueous HCl (2N, 75 mL), saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry the organic layer(Na2 SO4), filter, evaporate the filtrate in vacuo and purify by vacuum distillation to give 2-methyl-2-phenyl-propionic acid, N-methoxy-N-methylamide (18.0 g, 95%); bp 91-103° C./5 mm Hg. MS (CI, CH4) m/e 208 (M+ +1, 100), 119. |
95% | With hydrogenchloride; thionyl chloride; potassium carbonate In water; toluene | 22.h 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, N-methoxy-N-methylamide Step h 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, N-methoxy-N-methylamide Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) in toluene (80 mL) and add, by dropwise addition5 minutes, thionyl chloride (15 mL, 206 mmol). Stir at room temperature overnight, add additional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40 mL). Add toluene (20 mL) to the reaction mixture along with a solution of potassium carbonate (28.0 g, 203 mmol) in water (40 mL). Add, by dropwise addition, a solution of N,O-dimethylhydroxylamine hydrochloride (8.9 g, 91.2 mmol) in water (20 mL) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75 mL) following by slow addition of aqueous HCl (2N, 75 mL) with vigorous stirring. Separate the organic layer and wash with aqueous HCl (2N, 75 mL), saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry the organic layer(Na2SO4), filter, evaporate the filtrate in vacuo and purify by vacuum distillation to give 2-methyl-2-phenyl-propionic acid, N-methoxy-N-methylamide (18.0 g, 95%); bp 91-103° C./5 mm Hg. MS (CI, CH4) m/e 208 (M++1, 100), 119. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With hydrogenchloride; thionyl chloride; potassium carbonate In water; toluene | 23.h Step h: Step h: 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic Acid, Dimethylamide Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) in toluene (80 mL) and add, by dropwise addition5 minutes, thionyl chloride (15 mL, 206 mmol). Stir at room temperature overnight, add additional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40 mL). Add toluene (20 mL) to the reaction mixture along with a solution of potassium carbonate (28.0 g, 203 mmol) in water (40 mL). Add, by dropwise addition, a 40% aqueous solution of dimethylamine hydrochloride (20 mL, 0.18 mol) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75 mL) following by slow addition of aqueous HCl (2N, 75 mL) with vigorous stirring. Separate the organic layer and wash with aqueous HCl (2N, 75 mL), saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry the organic layer(Na2 SO4), filter, evaporate the filtrate in vacuo and purify by crystallization to give 2-methyl-2-phenyl-propionic acid, dimethylamide (15.35 g, 88%) as a white solid; mp 57-59° C. Anal. Calcd for C12 H17 NO: C, 75.35; H, 8.96; N, 7.32; Found: C, 75.12; H, 8.86; N, 7.26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 6 Following the procedure of Example 1, the enol ether of isobutyrophenone of the formula STR10 is reacted with thallium (III) acetate to give methyl 2-methyl-2-phenylpropionate. This ester is hydrolyzed to yield 2-methyl-2-phenylpropionic acid. | ||
EXAMPLE 6 Following the procedure of Example 1, the enol ether of isobutyrophenone of the formula STR3 is reacted with thallium (III) aceetate to give methyl 2-methyl-2-phenylpropionate. This ester is hydrolyzed to yield 2-methyl-2-phenylpropionic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With hydrogenchloride; thionyl chloride; potassium carbonate In water; toluene | 23.h 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, dimethylamide Step h 2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, dimethylamide Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) in toluene (80 mL) and add, by dropwise addition5 minutes, thionyl chloride (15 mL, 206 mmol). Stir at room temperature overnight, add additional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40 mL). Add toluene (20 mL) to the reaction mixture along with a solution of potassium carbonate (28.0 g, 203 mmol) in water (40 mL). Add, by dropwise addition, a 40% aqueous solution of dimethylamine hydrochloride (20 mL, 0.18 mol) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75 mL) following by slow addition of aqueous HCl (2N, 75 mL) with vigorous stirring. Separate the organic layer and wash with aqueous HCl (2N, 75 mL), saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry the organic layer(Na2SO4), filter, evaporate the filtrate in vacuo and purify by crystallization to give 2-methyl-2-phenyl-propionic acid, dimethylamide (15.35 g, 88%) as a white solid; mp 57-59° C. Anal. Calcd for C12H17NO: C, 75.35; H, 8.96; N, 7.32; Found: C, 75.12; H, 8.86; N, 7.26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃; for 40h; | 2-Methyl-2-phenyl-propionic acid methyl ester: 9.00 g (55 mmol) 2-methyl-2-phenyl-propionic acid was dissolved in 90 ml N,N-dimethylformamide, 11.51 g (2.5 eq.) of sodium hydrogencarbonate was added followed by 6.89 mL (15.72 g 2 eq.) of methyl iodide. The mixture was stirred at rt for 40 hours, then poured into ice water, the pH was adjusted to 3.0 with aq. HCl (1N) and the mixture extracted 3 times with ether; the organic phases were washed with water, dried over MgSO4, filtered and evaporated to give 7.34 g of the crude title compound as yellow oil. MS: 178.1 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: 2-methyl-2-phenylpropionic acid With oxalyl dichloride In dichloromethane at 20℃; Stage #2: diazomethane In tetrahydrofuran; diethyl ether at 0 - 20℃; for 12h; Stage #3: With hydrogenchloride In tetrahydrofuran; diethyl ether at 0℃; for 0.0833333h; | To a 250 mL round-bottom flask under a nitrogen atmosphere was added 2-methyl-2-phenylpropanoic acid (5.0 g, 30.9 mmol, 1.0 eq.) and 100 mL of methylene chloride. To the resulting stirred solution was added oxalyl chloride (3.2 mL, 37.04 mmol, 1.2 eq.) and 3 drops of dimethylformamide (DMF). The mixture was stirred at room temperature until all gas evolution ceased. All volatile materials were removed in vacuo to give an oily solid. This material was redissolved into 50 mL of anhydrous tetrahydrofuran (THF) and added dropwise to 100 mL of an ethereal solution of diazomethane at 0° C. The resulting solution was allowed to warm slowly to room temperature and stirred for an additional 12 hours. The solution was cooled to 0° C. and hydrogen chloride (HCl) gas was bubbled through the solution for 5 minutes. Crushed ice was added to the mixture and stirring was continued for 15 minutes. The layers were separated and the aqueous layer was extracted with two 50 mL-portions of diethyl ether. The combined organic layers were washed with three 100 mL-portions of saturated sodium bicarbonate solution, three 100 mL-portions of water, and 100 mL of saturated sodium chloride solution. The solution was dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to give intermediate 1 as a colorless oil (5.73 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ 1.55 (s, 6H), 4.03 (s, 2H), 6.57-7.64 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 2-methyl-2-phenylpropionic acid With thionyl chloride In toluene at 20℃; Heating / reflux; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With potassium carbonate In water; toluene for 2h; | 22.h.1 EXAMPLE 22 Step h Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) in toluene (80 mL) and add, by dropwise addition5 minutes, thionyl chloride (15 mL, 206 mmol). Stir at room temperature overnight, add additional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40 mL). Add toluene (20 mL) to the reaction mixture along with a solution of potassium carbonate (28.0 g, 203 mmol) in water (40 mL). Add, by dropwise addition, a solution of N,O-dimethylhydroxylamine hydrochloride (8.9 g, 91.2 mmol) in water (20 mL) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75 mL) following by slow addition of aqueous HCl (2N, 75 mL) with vigorous stirring. Separate the organic layer and wash with aqueous HCl (2N, 75 mL), saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry the organic layer(Na2SO4), filter, evaporate the filtrate in vacuo and purify by vacuum distillation to give 2-methyl-2-phenyl-propionic acid, N-methoxy-N-methylamide (18.0 g, 95%); bp 91-103° C./5 mm Hg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 2-methyl-2-phenylpropionic acid With thionyl chloride In toluene at 20℃; Heating / reflux; Stage #2: pyrrolidine With potassium carbonate In water; toluene for 2h; | 24.h.1 EXAMPLE 24 Step h Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) in toluene (80 mL) and add, by dropwise addition5 minutes, thionyl chloride (15 mL, 206 mmol). Stir at room temperature overnight, add additional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40 mL). Add toluene (20 mL) to the reaction mixture along with a solution of potassium carbonate (28.0 g, 203 mmol) in water (40 mL). Add, by dropwise addition, pyrrolidine (7.61 mL, 91 mmol) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75 mL) following by slow addition of aqueous HCl (2N, 75 mL) with vigorous stirring. Separate the organic layer and wash with aqueous HCl (2N, 75 mL), saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry the organic layer(Na2SO4), filter, evaporate the filtrate in vacuo and purify by crystallization to give 2-methyl-2-phenyl-propionic acid, pyrrolidineamide (18.28 g, 92%) as a solid; mp 96-97° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 2-methyl-2-phenylpropionic acid With thionyl chloride In toluene at 20℃; Heating / reflux; Stage #2: N,N-dimethylammonium chloride With potassium carbonate In water; toluene for 2h; | 23.h.1 EXAMPLE 23 Step h Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) in toluene (80 mL) and add, by dropwise addition5 minutes, thionyl chloride (15 mL, 206 mmol). Stir at room temperature overnight, add additional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40 mL). Add toluene (20 mL) to the reaction mixture along with a solution of potassium carbonate (28.0 g, 203 mmol) in water (40 mL). Add, by dropwise addition, a 40% aqueous solution of dimethylamine hydrochloride (20 mL, 0.18 mol) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75 mL) following by slow addition of aqueous HCl (2N, 75 mL) with vigorous stirring. Separate the organic layer and wash with aqueous HCl (2N, 75 mL), saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry the organic layer(Na2SO4), filter, evaporate the filtrate invacuo and purify by crystallization to give 2-methyl-2-phenyl-propionic acid, dimethylamide (15.35 g, 88%) as a white solid; mp 57-59° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 45% 2: 30% | With sodium acetate; palladium diacetate; silver carbonate In 1,4-dioxane at 150℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylsilane; water In butanone at 90℃; Sealed vial; Inert atmosphere; Autoclave; | 12 Example 12: Hydroxycarbonylation of alpha-methyl-styrene using [Pd2(Xyl- Phanephos)CI4]LiCI (4.2 mg, 0.1 mmol), p-TsOH (17.2 mg, 0.1 mmol) and [(Xyl-(S)- Phanephos)Pd2CI4] (0.005 mmol) were weighed into a 5 ml microwave vial. A magnetic stirrer bar was added, the vial was sealed with a crimp cap and put under an inert atmosphere, a-methylstyrene (65 μΙ, 0.5 mmol), water (22.5 μΙ, 1.25 mmol) and butanone (1.5 ml) were then added by syringe, as was the internal standard Et4Si (23.5μΙ, 0.125 mmol). The caps were pierced with two needles and the vials placed into an autoclave, under an inert atmosphere, and the autoclave quickly sealed. The autoclave was purged three times with CO, then pressurised to 30 bar and heated in a preheated oil bath to 90 °C. After 20 hours the autoclave was cooled to room temperature and the pressure released slowly. A sample of the crude product was removed for analysis by 1H NMR spectroscopy. The solvent was removed from the remaining reaction mixture under vacuum and the residue dissolved in toluene. The product was extracted 3 times with saturated NaHC03 solution and the combined aqueous phases were acidified with cone. HCI. The solution was then extracted 3 times with EtOAc. The combined organic layers were dried over MgS04, filtered and the solvent removed under vacuum, to give the carboxylic acid product as a 4:94 mixture of quaternary and linear isomers (84% conversion, 77 % isolated yield). | |
With toluene-4-sulfonic acid; lithium chloride In water; butanone at 90℃; for 20h; Inert atmosphere; | 12 LiCl (4.2 mg, 0.1 mmol), p-TsOH (17.2 mg, 0.1 mmol) and [(Xyl-(S)-Phanephos)Pd2Cl4] (0.005 mmol) were weighed into a 5 ml microwave vial. A magnetic stirrer bar was added, the vial was sealed with a crimp cap and put under an inert atmosphere. α-methylstyrene (65 μl, 0.5 mmol), water (22.5 μl, 1.25 mmol) and butanone (1.5 ml) were then added by syringe, as was the internal standard Et4Si (23.5 μl, 0.125 mmol). The caps were pierced with two needles and the vials placed into an autoclave, under an inert atmosphere, and the autoclave quickly sealed. The autoclave was purged three times with CO, then pressurised to 30 bar and heated in a preheated oil bath to 90° C. After 20 hours the autoclave was cooled to room temperature and the pressure released slowly. A sample of the crude product was removed for analysis by 1H NMR spectroscopy. The solvent was removed from the remaining reaction mixture under vacuum and the residue dissolved in toluene. The product was extracted 3 times with saturated NaHCO3 solution and the combined aqueous phases were acidified with conc. HCl. The solution was then extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4, filtered and the solvent removed under vacuum, to give the carboxylic acid product as a 4:94 mixture of quaternary and linear isomers (84% conversion, 77% isolated yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | In tetrahydrofuran; methanol; water; | Example 14 2-Methyl-2-phenyl-propan-1-ol To a solution of 2-methyl-2-phenyl-propionic acid (82 g, 0.5 mol) in THF (200 mL) was added dropwise borane-dimethyl sulfide (2M, 100 mL) at 0-5 C. The mixture was stirred at this temperature for 30 min and then heated at reflux for 1 h. After cooling, methanol (150 mL) and water (50 mL) were added. The mixture was extracted with EtOAc (100 mL*3), and the combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to give 2-methyl-2-phenyl-propan-1-ol as an oil (70 g, 77%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With [bis(acetoxy)iodo]benzene; potassium acetate; palladium diacetate; N-acetylglycine In <i>tert</i>-butyl alcohol at 100℃; for 12h; Sealed tube; | |
51% | With isopropylmagnesium bromide; triphenylphosphine; cobalt(II) chloride In tetrahydrofuran at 20℃; for 18h; Green chemistry; | Sample procedure of cobalt-catalyzed carboxyl-directed C-H activation/C-O cyclization General procedure: The iPrMgBr (excess in THF) was added to a mixture of α,α-dimethyl phenylacetic acids (1 mmol), cobalt salt (10 mol%), ligand (20 mol%) in dried THF (3 mL), the reaction mixture was stirred at room temperature for 18 h. After that, the mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel with a gradient eluent of petroleum ether and dichloromethane to give the corresponding products. |
47% | With [bis(acetoxy)iodo]benzene; silver(I) acetate; cesium acetate; sodium acetate; palladium diacetate In chlorobenzene; <i>tert</i>-butyl alcohol at 100℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With Bromotrichloromethane; 4-(diphenylphosphino)-benzyltrimethylammonium bromide; triethylamine In tetrahydrofuran at 60℃; for 15h; Inert atmosphere; | 4.3 Typical experimental procedure for amidation with IS-PPh3 General procedure: IS-PPh3 (746 mg, 1.8 mmol) was dried by a vacuum pump for 2 h at 70 °C. To a flask containing IS-PPh3 were added 4-methoxycarboxylic acid (152 mg, 1.0 mmol), BrCCl3 (357 mg, 1.8 mmol), benzylamine (129 mg, 1.2 mmol), triethylamine (0.14 mL, 1.0 mmol), and THF (4 mL). The obtained mixture was stirred for 6 h at 60 °C under Ar atmosphere. After the reaction, diethyl ether (10 mL) and aq HCl (1 M, 2 mL) were added at 0 °C and the obtained mixture was stirred for 15-30 min at room temperature. Then, the reaction mixture was poured into water (8 mL) and the obtained mixture was extracted with diethyl ether (10 mL×4). The combined organic layer was washed with water (10 mL) and brine (10 mL), and then dried over Na2SO4. After removal of the solvent under reduced pressure, N-benzyl-4-methoxybenzamide was obtained in 93% yield with 99% purity, as estimated by 1H NMR measurement. For cinnamic and aliphatic amides (entries 18-25 in Table 2) and indole-2-carboxamide (entry 16 in Table 2), the reaction mixture was poured into water (8 mL) and the obtained mixture was extracted with chloroform (10 mL×4). The combined organic layer was washed with water (10 mL) and brine (10 mL), and then dried over Na2SO4. After removal of the solvent under reduced pressure, N-benzylamide was obtained. or the recovery of IS-Ph3PO, NaCl (5.0 g) was added to the aqueous layer. The aqueous solution was extracted with CHCl3 (10 mL×5) and the combined organic layer was dried over NaSO4. After removal of the solvent, IS-Ph3PO containing a trace amount of IS-Ph3P was obtained in 95% yield. |
92% | With 4-(2-(1,3-dioxa-3a1,8,10-triaza-2,3a,14b-triboradibenzo[fg,op]tetracen-2-yl)phenyl)benzo[c]pyrimido[4,5-e][1,2]azaborinin-6(5H)-ol In fluorobenzene at 85℃; for 8h; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 2-methyl-2-phenylpropionic acid With N-ethyl-N,N-diisopropylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one In dichloromethane at 20℃; for 0.0833333h; Stage #2: (S)-2-amino-N-(2-morpholin-4-yl-ethyl)-2-phenyl-acetamide In dichloromethane at 20℃; for 16h; | (S)-N-[(2-Morpholin-4-yl-ethylcarbamoyl)-phenyl-methyl]-2-phenyl-isobutyramide chloride 15e To a solution of 10e (0.27 g, 1.7 mmol) in DCM (15 mL), DEPBT (0.50 g, 1.7 mmol) and DIPEA (0.58 mL, 3.3 mmol) were added and reaction mixture was stirred at room temperature for 5 min. 14a (0.44 g, 1.7 mmol) was added to the reaction mixture and it was stirred at room temperature for 16 H. Mixture was quenched with H2O (15 mL) and organic layer was washed with brine (2x15 mL), dried over Na2SO4 filtered and evaporated. The residue was purified by flash column chromatography eluting with CHCl3 : MeOH (95 : 5) and dissolved in 1 mL of acetonitrile. 0.5M HCl (2.4 mL) was added dropwise at 0 °C and mixture was lyophilized to afford 0.56 g of the titled compound 15e as a white solid (76 %): mp 83-84 °C; [α]D20+ 45.2 (c 1, MeOH); δH (400 MHz; DMSO d6) 8.73 (1H, t, J = 5.5), 7.41-7.29 (11H, m), 5.40 (1H, d, J = 7.0), 3.92-3.81 (4H, m), 3.56-3.36 (4H, m), 3.13-3.00 (4H, m), 1.55 (3H, s), 1.51 (3H, s); 13C NMR (300 MHz; DMSO d6) 176.5, 171.3, 146.7, 139.7, 129.6, 128.9, 128.3, 127.8, 127.4, 64.3, 60.0, 56.0, 52.3, 47.5, 34.7, 28.2, 27.8; HR-MS [M + H]+ observed = 410.2446, calculated = 410.2438. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In dichloromethane at 20℃; for 24h; Inert atmosphere; | |
82% | In dichloromethane at 20℃; for 48h; Inert atmosphere; | The carboxylic acid (1.50 mmol) was dissolved in anhydrous CH2Cl2 (6 mL, to provide a 0.25M solution). 4-Methoxybenzyl-2,2,2-trichloroacetimidate (430 mg, 3.00 mmol, 2.0 equiv) was then added. After 24 hTLC indicated that all of the starting material had been consumed. The reaction mixture was taken up inethyl acetate and washed with sodium bicarbonate (sat. aq., 3x). The organic layer was dried (Na2SO4),filtered and concentrated. The residue was adsorbed on silica gel and purified by silica gelchromatography to provide the corresponding PMB ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.0 g | In methanol; for 2h;Sealed tube; Reflux; | A 100 mL sealed tube was charged with intermediate 39b (1.6 g, 9.7 mmol) and methanol (10 mL). To the above stirred solution, CH3SO3H (1.6 mL) was added drop wise and refluxed for 2 h. The reaction mixture concentrated and was diluted with ice-water and neutralized with NaHCO3, extracted with ethyl acetate, washed withwater and dried. The product was obtained by concentrating under vacuo, which wasfurther purified by combiflash to yield the title compound (1 .0 g) as a colourless liquid.1H NMR: (ODd3, 300MHz) 6 7.25-7.27(d, 4H) 7.17-7.20 (m, 1H), 3.58 (5, 3H),1 .51(s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sodium periodate; sulfuric acid; acetic acid In water | 1 Bis(4-(2-carboxypropan-2-yl)phenyl)iodonium bromide Example 1 Bis(4-(2-carboxypropan-2-yl)phenyl)iodonium bromide 2-methyl-2-phenylpropanoic acid (10 g, 60.9 mmol) was suspended in a 1:1 mixture of sulfuric acid and acetic acid (90 mL) and heated to 55° C. where NaIO4 (23.4 mmol, 5.00 g) was slowly added in portions over 90 minutes followed by additional heating for 1 h. The reaction mixture was cooled, poured onto ice water (1 L) and extracted with methyl t-butyl ether (MTBE) (3*350 mL). KBr (0.609 mol, 72.4 g) in water (100 mL) was added to the aqueous layer and extracted with dichloromethane (DCM) (3*300 mL). The combined organic layers concentrated and the crude residue recrystallized from heptanes, ethyl acetate and acetone to afford the title compound (5.27 g, 42%) as a white solid. 1H NMR (300 MHz, (CD3)2SO) δ: 12.6 (brs, 2COOH), 8.16 (d, J=8.1 Hz, 4H), 7.45 (d, J=8.1 Hz, 4H), 1.43 (2, 12H). |
42% | Stage #1: 2-methyl-2-phenylpropionic acid With sodium periodate; sulfuric acid at 55 - 90℃; for 2.5h; Stage #2: With potassium bromide | 1 bis(4-(2-carboxypropane-2-yl)phenyl)iodonium bromide 2-methyl-2-phenyl propanoyl acid (10g, 60.9 mmol) and the sulfuric acid of 1:01 mixture (90mL) and the suspension was heated to 55 , hereNaIO4 (23.4 mmol, 5.00g)for 90 It was added slowly over a dividing minutes followed by further heating for 1 hour.The reaction mixture was cooled, poured onto ice water after (1L), and extracted with methyl t- butyl ether (MTBE) (3 x 350mL).KBr was added to (0.609 mol, 72.4 g) solution (100 mL) to the aqueous layer extracted with dichloromethane (DCM) (3x 300mL).The collected organic layer was concentrated and the crude residue (crude residue) of heptane, ethyl acetate, and recrystallized from acetone to give the title compound (5.27g, 42%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 2h; | 1136.D Step D 4,4-Dimethyl-2-phenyl-1,2,3,4-tetrahydro-pyrrolo[1,2,-a]pyrimidine-8-carboxylic acid N-(2-methyl-2-phenyl-propionyl)-hydrazide (4): Compound 3 (0.085 g, 0.30 mmol) was dissolved in THF (2 mL). HBTU (0.136 g, 0.36 mmol), α,α-dimethyl-phenylacetic acid (0.059 g, 0.36 mmol), and DIEA (0.10 mL, 0.60 mmol) were added. The reaction stirred for 2 h. and was concentrated. Flash chromatography (50% AcOEt/hexanes) gave the desired product. 0.123 g obtained (96% yield). 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 3H), 1.50 (s, 3H), 1.60 (s, 3H), 1.61 (s, 3H), 1.95-2.10 (m, 2H), 4.56 (dd, J=3.1, 11.3 Hz, 1H), 6.13 (d, J=3.5 Hz, 1H), 6.17 (d, 3.5 Hz, 1H), 6.65 (brs, 1H), 7.22-7.43 (m, 10H), 7.81 (brs, 1H), 7.92 (brs, 1H). MS Calcd.: 430. Found 431 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; | Step a General procedure: A mixture of 2-phenylacetic acid (2.72 g, 20.0 mmol), methyl 4-aminobenzoate(3.02 g, 20.0 mmol), triethylamine (6.07 g, 60 mmol), and HATU (7.60 g, 20.0 mmol)in dimethylformamide (40.0 mL) was flushed with argon, and stirred at r.t. for 12hours. The reaction mixture was extracted with ice water (200.0 mL) and ethyl acetate(50.0 mL x 3). The combined organic extracts were washed with 2M HCl(aq) (50.0mL), NaHCO3(sat) (50.0 mL), dried with Na2SO4, filtered, and evaporated. The crudeproduct was purified with flash column chromatography on silica gel, and using 20%Ethyl acetate/Hexanes to afford 46 [methyl 4-(2-phenylacetamido)benzoate] (5.027 g,18.7 mmol, 93%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1-methyl-1H-imidazole; N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate In acetonitrile at 23℃; for 0.166667h; | |
89% | With C36H24B4N2O3 In toluene at 80℃; for 14h; Molecular sieve; | To a test tube equipped with a magnetically stirred chip was added powdered MS4Å(240 mg, 800 mg mmol-1), and the tube was flame-dried under reduced pressure. Tothis, acid 10a (49.3 mg, 0.30 mmol, 1.0 equiv.), amine 11c (34.5 μl, 0.30 mmol, 1.0equiv.), catalyst 8a (8.6 mg, 0.015 mmol, 5 mol%), and toluene (3.0 ml, 0.1 M) wereadded successively. The suspension was stirred for 14 h at 80 °C. After the additionof H2O, the aqueous phase was extracted with EtOAc (3×). The combined organicphases were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered,and removed under reduced pressure. The obtained material was purified by flashcolumn chromatography to give 17 (71.9 mg, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With Ag nano wire core encapsulated by a N-doped carbon shell at 700 °C In acetonitrile at 25℃; Electrochemical reaction; | |
92 %Chromat. | With nitrogen-doped carbon nanofibers embedded with platinum nanoparticles onto flexible carbon cloth In acetonitrile at 25℃; Electrochemical reaction; | |
15 %Spectr. | With magnesium bromide In N,N-dimethyl-formamide for 3.5h; Electrochemical reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(II) bis(trifluoromethanesulfonate) In acetonitrile at 80℃; for 12h; | 11 α,α-dimethylphenylacetic acid (32.8 mg, 0.2 mmol, 1 equiv)And Cu(OTf) 2 (3.6 mg, 0.01 mmol, 5 mol%) dissolved in MeCN (5 ml);At room temperature,Add tert-butyl nitrite (62 μL, 0.5 mmol, 2.5 equiv)Stir with 2,2-difluoroethylamine (38 μL, 0.5 mmol, 2.5 equiv)The temperature was raised to 80 ° C and the reaction was continued for 12 hours. After the reaction was completed, it was dried under reduced pressure and separated by flash column chromatography on silica gel.Thus, the title compound 1 (44 mg, 0.164 mmol) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; | |
90% | Stage #1: N-hydroxyphthalimide; 2-methyl-2-phenylpropionic acid With dmap In dichloromethane for 0.0833333h; Inert atmosphere; Stage #2: With diisopropyl-carbodiimide In dichloromethane at 20℃; Inert atmosphere; | |
87% | With dmap; diisopropyl-carbodiimide In tetrahydrofuran at 20℃; Inert atmosphere; |
With dmap; diisopropyl-carbodiimide In dichloromethane | ||
With diisopropyl-carbodiimide In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | [362] To a solution of <strong>[1128-56-9]1-phenyl-1H-pyrazol-3-amine</strong> (60 mg, 0.38 mmol, 1.0 eq) and 2-methyl-2- phenylpropanoic acid (62 mg, 0.38 mmol, 1.0 eq) in DMF (2.0 mL) was added HBTU (143 mg, 0.38 mmol, 1.0 eq) and iPr2NEt (66 muL, 0.38 mmol, 1.0 eq). The resultant reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was concentrated. The crude residue thus obtained was purified by C18 preparatory HPLC (acetonitrile/water with TFA modifier) to provide 2-methyl-2- phenyl-N-(1-phenyl-1H-pyrazol-3-yl)propanamide (66 mg, 56% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; | 43 To a solution of 4-(quinolin-4-yl)cyclohexan-1 -amine DMF (3ml_), was added 2-methyl-2-phenylpropanoic acid (105 mg, 0.64 mmol), DIPEA (0.28 ml_, 1 .59 mmol) and HATU (303 mg, 0.80 mmol) successively. After stirred at r.t. overnight, the reaction was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give the crude product which was purified by Prep. HPLC to afford the title compound (34 mg, 17% yield). 1 H NMR (400 MHz, DMSO) d 8.82 (d, J = 4.5 Hz, 1 H), 8.17 (d, J = 8.4 Hz, 1 H), 8.02 (d, J = 8.3 Hz, 1 H), 7.77 - 7.71 (m, 1 H), 7.65 - 7.59 (m, 1 H), 7.44 (d, J = 4.5 Hz, 1 H), 7.37 - 7.31 (m, 4H), 7.26 - 7.19 (m, 1 H), 7.14 (d, J = 7.9 Hz, 1 H), 3.82 - 3.69 (m, 1 H), 3.32 - 3.28 (m, 1 H), 1 .94 - 1 .83 (m, 4H), 1 .71 - 1 .61 (m, 2H), 1 .57 - 1 .49 (m, 2H), 1 .46 (s, 6H). LCMS (ESI) m/z calcd for C25H28N20: 372.22. Found: 373.23 (M+1 )+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; ethylene dibromide; potassium iodide at 60℃; for 10h; Sealed tube; | General procedure for the synthesis of α-acyloxycarbonyl compounds 3a-3p and4a-4l General procedure: 1,2-dibromoethane (258 uL, 3.0 mmol), KI (66 mg, 0.4 mmol) and K2CO3 (414 mg, 3.0 mmol) were added to a 15 mL sealed tube, followed by the addition of carboxylic acid (2.0 mmol). Then 8.0 mL acetone 2a was added to the reaction system. The mixed solution was stirred at 60 °C under air conditions. Completion of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was diluted with 100 mL water and extracted with 50 mL ethyl acetate. The organic layer was dried over anhydrous Na2SO4, evaporated under reduced pressure and separated by column chromatography on silica gel (200-300) with petroleum ether/ethyl acetate mixtures to obtain the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 2,4,6-trimethyl-pyridine; silver(I) hexafluorophosphate; tert-butylammonium hexafluorophosphate(V) In dichloromethane at 20℃; for 3h; Electrolysis; Molecular sieve; | General procedure for decarboxylative etherification. General procedure: With no precautions to exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2,4,6-collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 Å molecular sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn vial cap equipped with anode (graphite) and cathode (graphite) were inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with Et2O (2 ml), which was combined with the crude mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative thin-layer chromatography to furnish the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 2,4,6-trimethyl-pyridine; tetrabutylammonium perchlorate; silver perchlorate In dichloromethane at 20℃; for 3h; Electrolysis; Molecular sieve; | General procedure for decarboxylative etherification. General procedure: With no precautions to exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2,4,6-collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 Å molecular sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn vial cap equipped with anode (graphite) and cathode (graphite) were inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with Et2O (2 ml), which was combined with the crude mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative thin-layer chromatography to furnish the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With 2,4,6-trimethyl-pyridine; tetrabutylammonium perchlorate; silver perchlorate In dichloromethane at 20℃; for 3h; Electrolysis; Molecular sieve; | General procedure for decarboxylative etherification. General procedure: With no precautions to exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2,4,6-collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 Å molecular sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn vial cap equipped with anode (graphite) and cathode (graphite) were inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with Et2O (2 ml), which was combined with the crude mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative thin-layer chromatography to furnish the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With 2,4,6-trimethyl-pyridine; tetrabutylammonium perchlorate; silver perchlorate; In dichloromethane; at 20℃; for 3h;Electrolysis; Molecular sieve; | General procedure: With no precautions to exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2,4,6-collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 A molecular sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn vial cap equipped with anode (graphite) and cathode (graphite) were inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with Et2O (2 ml), which was combined with the crude mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative thin-layer chromatography to furnish the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With 2,4,6-trimethyl-pyridine; tetrabutylammonium perchlorate; silver perchlorate; In dichloromethane; at 20℃; for 3h;Electrolysis; Molecular sieve; | General procedure: With no precautions to exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2,4,6-collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 A molecular sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn vial cap equipped with anode (graphite) and cathode (graphite) were inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with Et2O (2 ml), which was combined with the crude mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative thin-layer chromatography to furnish the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With 2,4,6-trimethyl-pyridine; tetrabutylammonium perchlorate; silver perchlorate In dichloromethane at 20℃; for 3h; Electrolysis; Molecular sieve; | General procedure for decarboxylative etherification. General procedure: With no precautions to exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2,4,6-collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 Å molecular sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn vial cap equipped with anode (graphite) and cathode (graphite) were inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with Et2O (2 ml), which was combined with the crude mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative thin-layer chromatography to furnish the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 2,4,6-trimethyl-pyridine; silver(I) hexafluorophosphate; tert-butylammonium hexafluorophosphate(V) In dichloromethane at 20℃; for 3h; Electrolysis; Molecular sieve; | General procedure for decarboxylative etherification. General procedure: With no precautions to exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2,4,6-collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 Å molecular sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn vial cap equipped with anode (graphite) and cathode (graphite) were inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with Et2O (2 ml), which was combined with the crude mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative thin-layer chromatography to furnish the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With 2,4,6-trimethyl-pyridine; tetrabutylammonium perchlorate; silver perchlorate In dichloromethane at 20℃; for 3h; Electrolysis; Molecular sieve; | General procedure for decarboxylative etherification. General procedure: With no precautions to exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2,4,6-collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 Å molecular sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn vial cap equipped with anode (graphite) and cathode (graphite) were inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with Et2O (2 ml), which was combined with the crude mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative thin-layer chromatography to furnish the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With 2,4,6-trimethyl-pyridine; tetrabutylammonium perchlorate; silver perchlorate; In dichloromethane; at 20℃; for 3.0h;Electrolysis; Molecular sieve; | General procedure: With no precautions to exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2,4,6-collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 A molecular sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn vial cap equipped with anode (graphite) and cathode (graphite) were inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with Et2O (2 ml), which was combined with the crude mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative thin-layer chromatography to furnish the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With 2,4,6-trimethyl-pyridine; tetrabutylammonium perchlorate; silver perchlorate In dichloromethane at 20℃; for 3h; Electrolysis; Molecular sieve; | General procedure for decarboxylative etherification. General procedure: With no precautions to exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2,4,6-collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 Å molecular sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn vial cap equipped with anode (graphite) and cathode (graphite) were inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with Et2O (2 ml), which was combined with the crude mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative thin-layer chromatography to furnish the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With dipotassium peroxodisulfate; (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; caesium carbonate In dimethyl sulfoxide Irradiation; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 2h; | 3 The synthesis of 2-methyl-2-phenyl-N-propylpropanamide (SU20666-0042). To a solution of compound 0042-1 (200 mg, 1.2 mmol) in DCM (10 mL) was added propan- 1 -amine (86 mg, 1.5 mmol), DIEA (472 mg, 3.7 mmol) and HATU (695 mg, 1.8 mmol). The resulting reaction mixture was stirred for 2 h at rt, then added water, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated, the crude was purified by prep-HPLC to give the desired product SU20666-0042 (70 mg, yield: 28%) as colorless oil.[0901] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5 pm); Column Temperature: 40 °C; Flow Rate: 2.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under this condition for 1.4 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 0.7 min), Purity: 100%, Rt = 1.754 min; MS Calcd.: 205.2; MS Found: 206.3 [M+H]+.[0902] HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm*4.6 mm*3.5 pm); Column Temperature: 40 °C; Flow Rate: 1.0 mL/min; Mobile Phase: from 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100%[CH3CN] in 10 min, then under this condition for 5 min, finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min and under this condition for 5 min), Purity: 100%, Rt = 9.027 min. [0903] NMR (400 MHz, DMSO-^e) d 0.74 (3H, t, J =1.6 Hz), 1.33-1.38 (2H, m), 1.43 (6H, s), 2.98 (2H, q, J= 6.8 Hz), 7.18-7.22 (1H, m), 7.28-7.32 (5H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | General procedure for the removing of Boc protecting group and coupling reaction. General procedure: The freshly prepared primary free amine (1.00 equiv., 1.00 mmol) was added to a solution of the carboxylic acid (1.30 equiv, 1.30 mmol), HATU (0.49 g, 1.30 mmol) and DIPEA (0.45 mL, 2.60 mmol) in dry DMF (5 mL), under argon atmosphere. The resulting solution was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with a saturated NaHCO3 solution (3 x 20 mL) and brine (3 x 20 mL). The organic phase was dried over Na2SO4 and evaporated to give a crude residue that was purified by flash silica column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With Cu(2+)*2C2F3O4S(1-) In acetonitrile at 20℃; for 0.25h; Inert atmosphere; | III. General procedures for the preparation of acyl fluoridesfrom carboxylic acids with Cu(O2CCF2SO2F)2 General procedure: Carboxylic acid (0.4 mmol, 1.0 equiv) was dissolved in dry MeCN (4 mL) in Schleck tube under Ar atmosphere, and Cu(O2CCF2SO2F)2 (334.2 mg, 0.8 mmol, 2equiv.) was added. Then the reaction mixture was stirred at room temperature for 15 minutes. Benzotrifluoride was added into the reaction mixture as an internal standard and the yield of the desired product was measured by 19F NMR before working up. After removal of the solvent under reduced pressure with a rotary evaporator, the crude product was purified by flash column chromatography on a pad of silica gel to give the desired product. |
Multi-step reaction with 3 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 3 h / 20 °C 2: triethylamine / acetonitrile / 0 - 20 °C 3: pyridinium polyhydrogenfluoride; bis(tertbutylcarbonyloxy)iodobenzene / acetonitrile / 0.5 h / 0 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 3 h / 80 °C / Inert atmosphere 2: Selectfluor; copper(ll) bromide / acetonitrile / 1 h / 80 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With dichloro(dimethylglyoxime)(dimethylglyoximato)cobalt(III); [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; triphenylphosphine In dichloromethane at 20℃; for 12h; Inert atmosphere; Sealed tube; Irradiation; | 20 Example 20 First weigh (32.8mg, 0.2mmol), [Ir(dF(CF3)ppy)2(dtbbpy)]PF6(2.3mg, 0.002mmol), PPh3(52.5mg, 0.2mmol) and Co(dmgH)(dmgH2) Cl2 (3.6mg, 0.01mmol) was added to the reaction tube, sealed with a stopper, and vented through the vacuum line three times. Under a nitrogen atmosphere, dichloromethane (6.0mL) was added, and then slowly added (26.1μL, 0.3mmol) , And then placed under blue LEDs, reacted at room temperature for 12h, stirring speed is 1200r/min. After the reaction was monitored by TLC, the solvent was removed by rotary evaporation, and the product was separated by column chromatography (300-400 mesh chromatography silica gel, eluent: petroleum ether-ethyl acetate) to obtain 36.7 mg of the product, with a yield of 79%. |
79% | With dichloro(dimethylglyoxime)(dimethylglyoximato)cobalt(III); [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; triphenylphosphine In dichloromethane at 20℃; Inert atmosphere; Sealed tube; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 2-methyl-2-phenylpropionic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: N-(2-methoxy-4-aminophenyl)-3-chlorobenzamide In N,N-dimethyl-formamide at 20℃; for 10h; | 46 Example 46: Synthesis of N-(2-methoxy-4-(2-methyl-2-phenylpropionamido)phenyl)-3-chlorobenzamide (46) Dissolve HATU (0.38g, 1.28mmol), 2-methyl-2-phenylpropionic acid (0.11g, 0.67mmol) and N,N,-diisopropylethylamine (0.17g, 1.34mmol) In water DMF (7mL), react at room temperature for 30min, add 5B (0.20g, 0.70mmol), react at room temperature for 10h, add 30mL water, extract with ethyl acetate (15mL×5), combine the organic phases, wash with saturated brine, anhydrous It was dried over sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain 0.39 g of a white solid with a yield of 75.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With oxalyl dichloride; triethylamine; Triphenylphosphine oxide In 1,2-dichloro-ethane at 20℃; for 0.166667h; Inert atmosphere; | |
86% | With oxalyl dichloride; triethylamine; Triphenylphosphine oxide In 1,2-dichloro-ethane at 50℃; for 0.166667h; Inert atmosphere; | 6 In a 25mL round-bottom flask, dissolve triphenylphosphine oxide (0.056g, 0.2mmol) in 3.0mL tetrahydrofuran, under argon protection, add oxalyl chloride (0.127mL, 1.5mmol), 2-phenyl Isobutyric acid (0.164g, 1.0mmol), 4-aminophthalonitrile (0.215g, 1.5mmol) and triethylamine (0.277mL, 2.0mmol) were stirred and reacted for 10 min at 50°C.After completion of the reaction, 50mL of ethyl acetate was added to the reaction solution, a saturated Na2CO3 solution was washed three times with 30mL and 20mL saturated brine three times, the organic phase was dried with anhydrous Na2SO. 4dried, filtered, and the solvent was evaporated under reduced pressure A crude product is obtained.The crude product was purified by column chromatography, using a mixture of ethyl acetate (EA) and petroleum ether (PE) with a volume ratio of 20:80 as the eluent for elution. The eluent was collected and distilled under reduced pressure again to obtain a white solid 0.194g, which is the amide product of the above formula, with a yield of 86%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate In dichloromethane at 20℃; for 24h; Inert atmosphere; | 6 Example 6 First weigh compound M06 (39.4mg, 0.24mmol), K2CO3 (27.6mg, 0.20mmol) and compound A01 (82.4mg, 0.20mmol) into the reaction tube,Air was evacuated through a vacuum line three times, DCM (2.0 mL) was added under a nitrogen atmosphere, and the reaction was carried out at room temperature for 24 h.After the reaction was completed, the solvent was removed by rotary evaporation, the sample was loaded dry, and column chromatography (300-400 mesh chromatography silica gel) (petroleum ether-ethyl acetate = 19:1) to obtain the product P06 was 48.5 mg, and the yield was 89%. |
89% | With potassium carbonate In dichloromethane at 20℃; for 24h; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With pyridine; copper(II) bis(trifluoromethanesulfonate); acetonitrile In toluene at 20℃; Irradiation; Inert atmosphere; | General procedure for etherification General procedure: To an oven-dried Schlenk tube (diameter of 1.5 cm), carboxylic acid (0.3 mmol), alcohol (0.3-1.5 mmol, 1-5 equiv.) and Cu(OTf)2 (0.75 mmol, 271.3 mg) were added, followed by toluene (2.85 ml), freshly distilled pyridine (0.9 mmol, 73 μl) and acetonitrile (0.15 ml). The reaction mixture was degassed by a freeze-pump-thaw cycle for four 4-min cycles and refilled with nitrogen. It was then irradiated for variable periods of time in front of a 40-W blue LED lamp. The reaction mixture was diluted with ethyl acetate or diethyl ether (2 ml) and then washed with deionized water (2 × 5 ml). The aqueous layer was extracted with ethyl acetate or diethyl ether (5 ml). The combined organic layers were dried over Na2SO4 and concentrated and purified by flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With Isobutyronitrile; copper(II) bis(trifluoromethanesulfonate); sodium phosphate In dichloromethane at 20℃; for 24h; Irradiation; Inert atmosphere; Sealed tube; | General procedure for sulfonamidation General procedure: An oven-dried 6-ml vial equipped witha stir bar was placed in a nitrogen-filled glovebox and charged with Cu(OTf)2 (180.8 mg, 2.5 equiv., 0.50 mmol), Na3PO4 (98.2 mg, 3.0 equiv., 0.60 mmol), the sulfonamide nucleophile (1.5-3.0 equiv.), carboxylic acid (1.0 equiv., 0.20 mmol), methylene chloride (2.0 ml, 0.10 M) and isobutyronitrile (100 μl, 5.5 equiv.,1.1 mmol). The vial was sealed with a screwcap bearing a Teflon septum, removed from the glovebox and placed on a stir plate. The vial was irradiated at 427 nm with two 40-W Kessil PR160 lamps at a distance of 10 cm with stirring at 800 r.p.m. A fan was used to maintain the vial at room temperature. After 24 h, the crude reaction mixture was diluted with 1.5 ml of EtOAc and adsorbed directly on diatomaceous earth (Celite). The product was purified by flash chromatography on silica gel, eluting with mixtures of ethyl acetate and hexanes. |
Tags: 826-55-1 synthesis path| 826-55-1 SDS| 826-55-1 COA| 826-55-1 purity| 826-55-1 application| 826-55-1 NMR| 826-55-1 COA| 826-55-1 structure
[ 37828-19-6 ]
1-Phenylcyclobutanecarboxylic acid
Similarity: 0.94
[ 37828-19-6 ]
1-Phenylcyclobutanecarboxylic acid
Similarity: 0.94
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
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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