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CAS No. : | 644-36-0 | MDL No. : | MFCD00004328 |
Formula : | C9H10O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RZWGTXHSYZGXKF-UHFFFAOYSA-N |
M.W : | 150.17 | Pubchem ID : | 69519 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 42.95 |
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) : | -5.85 cm/s |
Log Po/w (iLOGP) : | 1.43 |
Log Po/w (XLOGP3) : | 1.93 |
Log Po/w (WLOGP) : | 1.62 |
Log Po/w (MLOGP) : | 1.98 |
Log Po/w (SILICOS-IT) : | 2.01 |
Consensus Log Po/w : | 1.79 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.26 |
Solubility : | 0.828 mg/ml ; 0.00551 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.34 |
Solubility : | 0.691 mg/ml ; 0.0046 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.54 |
Solubility : | 0.429 mg/ml ; 0.00286 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.23 |
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 |
---|---|---|
42% | With sulfuric acid; nitric acid In dichloromethane at -20 - 20℃; | Intermediate 80A: Preparation of 2-(2-methyl-5-nitrophenyl)acetic acid [00224] A solution of 2-o-tolylacetic acid (3.54 g, 23.6 mmol) in DCM (12 mL) was added to a pre-cooled mixture of concentrated sulfuric acid (10 mL, 188 mmol) and 90percent nitric acid (1 mL, 22.4 mmol) at - 20 0C. The reaction mixture was stirred at - 20 0C for 30 minutes, then slowly warmed to room temperature and stirred overnight. The reaction mixture was poured into ice-water. The white solid was collected by filtration, rinsed with water, and concentrated. The solid was triturated with ether and filtered to obtain Intermediate 8OA (2.4 g, 42percent) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.62 (1 H, br. s.), 8.13 (1 H, d, J = 2.51 Hz), 8.04 (1 H, dd, J = 8.28, 2.51 Hz), 7.47 (1 H, d, J = 8.53 Hz), 3.80 (2 H, s), 2.34 (3 H, s). |
34.6% | Stage #1: With sulfuric acid In dichloromethane at 0℃; for 0.5 h; Stage #2: With nitric acid In dichloromethane at -2 - 3℃; for 16 h; |
The starting material 2-methyl-phenylacetic acid (200.0 g, 1.33 mol)Was dissolved in dichloromethane (700 mL)0 ° C below slowly addedConcentrated sulfuric acid (584 mL),After the addition reaction was continued for 0.5 hours,Then concentrated nitric acid (30 mL)Maintain the temperature at -2 ~ 3 reaction 16 hours;After the reaction,Poured into 500 mL of water,Extracted with dichloromethane, dried,Concentrated to give Compound 1-2 (90.0 g) in a yield of 34.6percent. |
32% | With sulfuric acid; nitric acid In dichloromethane at -10℃; for 1 h; | Step 1: a 500 mL round bottom flask was charged with conc. sulfuric acid (130 mL) and cooled to -10°C. A solution of o-tolyacetic acid (10 g, 66.58 mmol) in CH2CI2 (35 mL) was added dropwise. After that, a solution of conc. sulfuric acid(27 mL) and nitric acid (2.7 mL) was slowly added dropwise. The reaction mixture was stirred at -10°C for 1 h and then poured onto ice. The aqueous phase was extracted with EtOAc. The organic layer was washed with water and brine, dried, filtered and the solution was concentrated under reduced pressure. The resulting solid was triturated in Et20 and filtered off to afford 2-(2-methyl-5-nitrophenyl)acetic acid as white solid (4.21 g, 32percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With lithium aluminium tetrahydride; In diethyl ether; for 3h;Reflux; | Preparation of 2-(o-tolyl)ethanol (S1) A solution of o-tolylacetic acid 23 (330 mg, 2.20 mmol) in dry ether (5 mL) was slowly added to a stirred mixture of LiAlH4 (180 mg, 4.7 mmol) in dry ether (5 mL) in a 100 mL round-bottom flask. Once gas evolution had subsided, the mixture was refluxed for 3 h. The mixture was quenched by careful addition of 0.2 mL of water, 0.2 mL of 15% NaOH aqueous solution, and 1.2 mL of water. The insoluble salts were removed by filtration, and the organic layer was washed with brine and dried over anhydrous MgSO4. The ether was removed on a rotary evaporator with an ambient temperature bath to leave 2-(o-tolyl) ethanol (S1) (Sakai, N., et al., Eur. J. Org. Chem. 2011, 3178-3183) as a light yellow liquid (219 mg, 1.61 mmol, 75%). 1H NMR (500 MHz, CDCl3) delta 7.22-7.10 (m, 4H), 3.85 (t, J=6.9 Hz, 2H, CH2OH), 2.90 (t, J=6.8 Hz, 2H, CH2Ar), 2.34 (s, 3H, CH3), and 1.42 (br s, 1H, OH). |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 4.5h;Reflux; | General procedure: To a mixture of LiAlH4 (15 mmol) in anhydrous THF (25 mL) in an ice-bath was added dropwise a solution of phenylacetic acids (15 mmol) in THF (8 mL). This mixture was stirred at room temperature for 30 min, and then heated to reflux for 4 h. After it was cooled to room temperature, water (0.5 mL) was added, and then NaOH (15%, 0.5 mL) and water (1.5 mL) were added in sequence. After stirring for another 30 min, the mixture was filtered, dried over anhydrous Na2SO4 and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 50-85% yield by column chromatography. Alternative method: To a solution of phenylacetic acids (15 mmol) in MeOH (30 mL) was added SOCl2 (30 mmol). This mixture was heated to reflux for 3 h before evaporation. The residue was dissolved in DCM (30 mL), washed with aqueous NaHCO3, water and brine, dried over anhydrous Na2SO4, and concentrated to give 100% yield of crude methyl phenylacetates which were used to next step without further purification. To a solution of the methyl phenylacetates in THF (30 mL) was added NaBH4 (60 mmol). When the mixture was heated to gently reflux, MeOH (1.0 mL) was added dropwise from a syringe over 5 min. After refluxing for another 6 h, the mixture was cooled to room temperature and poured into 30 mL ice water, and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 70-85% yield by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichlorosulfoxide | ||
With dichlorosulfoxide | ||
With phosphorus(V) chloride In benzene |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 0.416667h; | ||
With phosphorus trichloride at 70 - 80℃; for 2h; | ||
With oxalyl dichloride In benzene for 5h; | ||
With dichlorosulfoxide In benzene for 1h; Heating; | ||
With oxalyl dichloride In dichloromethane at 20℃; for 0.333333h; | ||
In dichlorosulfoxide | R.10 2-Methylphenylacetyl chloride Reference Example 10 2-Methylphenylacetyl chloride A solution of 2.0 g of o-tolylacetic acid in 27 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.1 g of the desired product as a light brown oil. | |
In dichlorosulfoxide | R.10 2-Methylphenylacetyl chloride REFERENCE EXAMPLE 10 2-Methylphenylacetyl chloride A solution of 2.0 g of o-tolylacetic acid in 27 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.1 g of the desired product as a light brown oil. | |
With oxalyl dichloride In tetrahydrofuran at 20℃; for 1h; | 89 To a solution of 2-methylphenylacetic acid ( 8 . 9 g) inTHF (200 mil) was added DMF (5 drops) and then oxalyl chloride (8.0 mL) was added at room temperature, and the mixture was stirred for 1 hr. The mixture was concentrated in vacuo to give 2-methylphenylacetyl chloride. Aluminum chloride (16.0 g) was added to a suspension of 2H-1, 4-benzoxazin-3 (4H) -one (8.0 g) in nitrobenzene (80 mL) under ice-cooling and then 2- methylphenylacetyl chloride obtained above was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 hr. The mixture was poured into ice-cooled water (200 mL) . The mixture was extracted with ethyl acetate, The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and water, dried over Na2SC>4 and concentrated in vacuo. The residue was crystallized from toluene to give the title compound as crystals (3.8 g) .1H-NMR (300 MHz, DMSO-d6) δ: 2.15 (s, 3H), 4.33 (s, 2H), 4.69 (s, 2H), 7.04 - 7.21 (m, 5H), 7.53 (d, J = 2.2 Hz, IH), 7.75 (dd, J = 8.5, 2.2 Hz, IH), 10.88 (s, IH). | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3h; | To a solution of o-tolylacetic acid (18. 02 g, 120 MMOL) in CH2CI2 (200 ML) was added oxalyl chloride (32 ML, 360 MMOL) followed by DMF (3 drops). The reaction was stirred at room temperature for 3h then concentrated in vacuo. The residue was dissolved in THF (50 ml) then added to a suspension of compound (C) in THF (150 mi) and pyridine (9.7 MI, 120 MMOL). The mixture was heated at 50°C for 30 mins. After this time the reaction was concentrated in vacuo and a mixture of ethyl acetate (250 mi) and a saturated solution of NAHCO3 (250 mi) was added. This resulted in the formation of a solid, which was collected by filtration to give the desired compound as a brown solid (16.4 G, 79%). OH (250 MHz, DMSO) 2.3 (s, 3H), 3.86 (s, 2H), 7.12-7. 16 (m, 3H), 7.27-7. 30 (m, 1H), 7.87 (s, 1H), 8.76 (d, J 1.2, 1H), 8.87 (d, J 1.2 1H) ; M/Z (APCI) 345 (M+); HPLC 100%. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; | ||
With dichlorosulfoxide In benzene for 1h; Reflux; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; Inert atmosphere; | ||
With dichlorosulfoxide In toluene at 60℃; | ||
With dichlorosulfoxide; N,N-dimethyl-formamide In toluene at 40℃; for 0.5h; Inert atmosphere; | ||
With dichlorosulfoxide at 80℃; for 3h; | ||
With dichlorosulfoxide; N,N-dimethyl-formamide In dichloromethane at 20℃; for 4h; | General procedure: To a solution of substituted phenyl acetic acid or naphthylacetic acid (200 mg, 1.1 mmol) in dry DCM (10 ml) was added SOCl2 (128 mg, 1.1 mmol) and DMF (1 drop). The mixture was stirred at room temperature for 4 hours, following which the solvent was removed in vacuo. Dry DCM (10 ml) was added to re-dissolve the residue. After that, the solution was dropwise added into the mixture of 4-methoxybenzyl hydroxylamine (3) (165 mg, 1.1 mmol) and Et3N (223 mg, 2.2 mmol) in DCM (10 ml) and stirred at room temperature for 1h. The reaction mixture was quenched with water (20 ml) and then extracted with DCM (3 x 20ml). The combined organic layers was washed with brine and dried with anhydrous Na2SO4. The solvent was removed in vacuo. The crude product was purified with column chromatography (33% EA/Petroleum ether) to obtain a white solid in yields range from 68 to 88% yield. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; | General procedure: To an over-dried 100 mL three-necked flask, the carboxylic acid (10 mmol), DMF (5 drops) and DCM (30 mL) were added under a N2 atmosphere. Oxalyl chloride (1.0 mL, 12 mmol) was added dropwise at 0 °C resulting in vigorous bubbling. The mixture was stirred for 3 h at room temperature, and the solvent was then removed in vacuo. The resulting acid chloride was used immediately without further purification. To a solution of the acid chloride in DCM (30 mL) ,a solution of 1,1,1,3,3,3-hexamethyldisilazane (30 mmol) in DCM (10 mL) was added dropwise at 0 °C, and the solution was then allowed to warm to room temperature. After stirring overnight, the reaction system was quenched with 1 M HCl aq. and saturated aqueous NH4Cl (excess amount) and the organic layer was separated. The aqueous layer was extracted with DCM (2x15 mL). The combined organic layers were washed with saturated aqueous NH4Cl (30 mL) and brine (30 mL), dried over MgSO4, filtered and evaporated in vacuo. The resulting crude material was purified by recrystallization from EtOAc and hexane. The resulting product (5 mmol), 8-bromomethylquinoline (6 mmol), Al2O3 (50 mmol), KOH (25 mmol) and dioxane (30 mL) were added to an over-dried 100 mL three-necked flask. The mixture was stirred for 8 h at 60 °C and then was filtered through a celite pad. The filtrate was washed with H2O (30 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2x15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtrated and evaporated in vacuo. The resulting crude amide was purified by column chromatography on silica gel (eluent: hexane/EtOAc = 1/1). | |
With oxalyl dichloride In dichloromethane at 0 - 20℃; for 3h; | ||
With 1,1-dichloromethyl methyl ether In dichloromethane for 0.5h; Reflux; | ||
With dichlorosulfoxide In dichloromethane at 55℃; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; | Synthesis of different aromatic chain substitutedchloride 6 General procedure: A five or six membered aromatic carboxylic acid 5 wasdissolved in CH2Cl2 with dropping three drop DMF. 1.5times the amount of oxalylchloride was cautiously addedinto the reaction solution at 0 °C. After stirring at ambienttemperature for 3 h, the reaction mixture was concentratedunder reduced pressure to give the corresponding acidchloride intermediate 6. The remaining acid chloride weresynthesized according to the method described above with ayield of 83-92%. | |
With oxalyl dichloride; N,N-dimethyl-formamide In toluene at 20℃; for 2h; Inert atmosphere; | ||
With dichlorosulfoxide at 65 - 70℃; for 12h; | 2.3. General synthetic procedures for intermediates 4 General procedure: The substituted phenylacetic acid (3 mmol) and thionyl chloride (10 ml) were placed in a dry round-bottomed flask, and the mixture was heated to reflux at 65-70 °C for 12 h, which was detected by TLC. After the completion of reaction, the solvent was removed in vacuo and the residue was washed with CH2Cl2. The above procedure was repeated twice to obtain the crude intermediates 4, which were used for the next reaction without further purification. | |
In dichlorosulfoxide | 92 2-Methylphenylacetyl chloride EXAMPLE 92 2-Methylphenylacetyl chloride A solution of 2.0 g of o-tolylacetic acid in 27 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.1 g of the desired product as a light brown oil. | |
In dichlorosulfoxide; toluene | b b) b) o-Tolylacetyl chloride 4.8 g of o-tolylacetic acid are dissolved in 36 ml of SOCl2 and refluxed for 12 h. The volatile constituents are then removed in vacuo and the residue is taken up 3 times in each case in 50 ml of toluene and the volatile constituents are removed in vacuo. 6.6 g of a pale yellow liquid are obtained, which is employed further without purification. | |
With oxalyl dichloride In dichloromethane at 20℃; for 4h; | 5 To a solution of o-tolylacetic acid (1.00 g, 6.66 mmol) in dichloromethane (CH2Cl2 , 20 mL) was added dropwise oxalyl chloride ((COCl)2 , 0.717 mL, 7.99 mmol) at room temperature, followed by addition of N,N-dimethylformamide (DMF, one drop) and the mixture was stirred at such temperature for 4 hours. Then thereto was added 28% aqueous ammonia (5 mL) under ice-cooling, and the mixture was warmed to room temperature and stirred for 3 hours. The reaction was quenched with 10% hydrochloric acid, and the mixture was extracted with ethyl acetate, and the organic layer was washed once with water. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The resulting residue was crystallized from a mixture of diethylether-hexane to give the title compound 701 mg as white crystals. 1H-NMR δ (DMSO-d6); 2.25 (3H, s), 3.40 (2H, s), 6.87 (1H, br), 7.08-7.19 (4H, m), 7.36 (1H, br). | |
With dichlorosulfoxide at 80℃; for 3h; | 237.a 2-(o-Tolyl)acetic acid (2.0 g, 13 mmol) was dissolved in thionyl chloride (10 mL) and heated at 80 °C for 3 h. The remaining thionyl chloride was evaporated in vacuo. | |
With dichlorosulfoxide In 1,2-dichloro-ethane at 20℃; Reflux; | 2 Preparation of o-methylphenylacetyl chloride o-methylphenylacetic acid (3.02 g, 20.11 mmol) and 1,2-dichloroethane (40 ml) were placed in a 250 mL single-necked flask equipped with a magnetic stirring, a condensing tube and a drying tube.Stir at room temperature for 10 min, add thionyl chloride (4.79 g, 40.26 mmol) dropwise, and reflux for 3-4 h.Cooled, desolvated, and the residue obtained was used directly in the next step. | |
With dichlorosulfoxide at 90℃; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 2h; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 23℃; for 1h; Inert atmosphere; | General procedure A: synthesis of N-acyl 5,5-dimethyl oxazolidinones via acyl chloride General procedure: Oxalyl chloride (1.65 equiv) was added to a solution of arylacetic acid (1.5 equiv), dimethylformamide (10 ml), anddichloromethane (2.0 M) at 0 °C. After 10 min, the solution was warmed to 23 °C and stirred for 1 h (bubbling stops). Thesolution was concentrated in vacuo. In a separate flask, n-butyllithium (1.1 equiv, 2.42 M in hexanes) was added to asolution of (S)-4-benzyl-5,5-dimethyloxazolidin-2-one (1.0 equiv) in THF (0.3 M) at -78 °C under argon. The solution wasstirred for 30 min at -78 °C. A solution of the crude acyl chloride in THF was added dropwise at -78 °C. After stirring at -78 °C for 2 h, the reaction mixture was quenched with saturated ammonium chloride. The aqueous layer was extractedwith ethyl acetate (3 x 20 ml). The combined organic layers were washed with brine, dried with sodium sulfate andconcentrated in vacuo. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; | ||
With dichlorosulfoxide; sodium hydroxide In lithium hydroxide monohydrate at 23 - 70℃; for 1h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 1h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 6h; | ||
With dichlorosulfoxide | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h; | ||
With dichlorosulfoxide In dichloromethane Reflux; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With dichlorosulfoxide In dichloromethane at 20℃; for 3h; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1-butyl-3-methylimidazolium hydrogen sulfate; water at 60 - 65℃; for 1.25h; Green chemistry; | General procedure for the synthesis of carboxylic acids from nitriles General procedure: Aromatic or aliphatic nitriles (2 mmol) were dissolved in 5 ml of [bmim]HSO4 and the reaction mixture was heated at 60-65 °C for 1-3 h. The progress of reaction was monitored by TLC. After completion of reaction, as checked by TLC, the reaction mixture was poured into water containing crushed ice. The product was precipitated out, filtered and dried. The yield of the final product was high (>90%) in all cases. All final products obtained were found sufficiently pure so it didn’t need further purification.The filtrate was concentrated under vacuum, washed with diethylether twice and concentrated under high vacuum. After proper drying under reduced pressure, approximately 95% ionic liquid was recovered from the reaction and compared with the original ionic liquid to check its authenticity. The efficiency of recovered ionic liquid in conversion of nitriles to acids was found unchanged in comparison to the original one and we reused it up to 5-6 cycles without any significant loss of its activity. |
With sulfuric acid; acetic acid | ||
With potassium hydroxide; dihydrogen peroxide Behandlung mit Salzsaeure; |
With sulfuric acid | ||
With sulfuric acid | ||
In ethanol (alkaline hydrolysis); | ||
Multi-step reaction with 2 steps 1: sodium hydroxide / 6 h / 95 °C 2: hydrogenchloride; water / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sulfuric acid at 0℃; for 8h; Reflux; Inert atmosphere; | |
99% | With sulfuric acid for 6.5h; Inert atmosphere; Reflux; | |
98% | With sulfuric acid at 28℃; for 12h; | Synthesis of methyl 2-tolylacetate, 2. o-Tolylacetic acid 1 (1 g, 6.6 mmol) was dissolved in methanol. Catalytic amount of sulfuric acid was (0.2 mL) added to this solution. The mixture was stirred at RT for 12 h. Reaction completion was checked by TLC. Excess methanol was evaporated and 25 mL water was added. Product was extracted into 2×150mL ethyl acetate. Ethyl acetate layer was washed sequentially with 2×25 mL NaHCO3 solution, 25 mL water and 25 mL brine solution. The organic layerwas dried over anhyd. Na2SO4 and concentrated underreduced pressure to yield 1.09 g (98%) of methyl 2-tolylacetate 2 in the form of colorless oil. 1H NMR(CDCl3, 200 MHz): d 7.29 (m, 4H), 3.81 (s, 2H), 3.63(s, 3H), 2.28 (s, 3H); 13C (CDCl3, 50MHz): d 171.92,162.98, 131.13, 130.12, 129.84, 128.02, 127.58, 125.71,51.67, 38.79, 19.87; MS: m/z 187 [M+Na]+; IR (CHCl3):1724, 1369, 1174, 1024 cm-1. Anal. Calcd for C11H12O3:C, 73.15; H, 7.37. Found: C, 73.10; H, 7.37%. |
92% | With sulfuric acid Reflux; | 1.2 Preparation of Intermediate (2): methyl 2-o-tolylacetate Preparation of Intermediate (2): methyl 2-o-tolylacetate To a flask (1000 mL), 120 g of 2-methylphenylacetic acid and 400 mL of anhydrous methanol were added, and then 24 mL of concentrated sulfuric acid was further added with stiffing. The mixture was heated with an oil bath and refluxed. The reaction was monitored with thin layer chromatography (TLC) until the reactants were basically consumed. Subsequently, the solvent was removed by vacuum distillation. The residue was dumped into 400 mL of water and extracted with 400 mL of ethyl acetate. The organic layer was washed with water (2*200 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A light yellow oily product was obtained. The light yellow oily product was further distilled under vacuum condition to yield 117.3 g of a colorless oily product (135-140° C., 16 mmHg) with a yield of 92%. |
92% | With sulfuric acid Reflux; | 1 To a flask (1000 mL), 120 g of 2-methylphenylacetic acid and 400 mL of anhydrous methanol were added, and then 24 mL of concentrated sulfuric acid was further added with stirring. The mixture was heated with an oil bath and refluxed. The reaction was monitored with thin layer chromatography (TLC) until the reactants were basically consumed. Subsequently, the solvent was removed by vacuum distillation. The residue was dumped into 400 mL of water and extracted with 400 mL of ethyl acetate. The organic layer was washed with water (2*200 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A light yellow oily product was obtained. The light yellow oily product was further distilled under vacuum condition to yield 117.3 g of a colorless oily product (135-140°C, 16 mmHg) with a yield of 92%. |
90% | With sulfuric acid for 3h; Reflux; | |
87% | With sulfuric acid Reflux; | 1.1. General procedure of synthesis of esters 3e, 7e-15e General procedure: To an appropriately substituted phenylacetic acid (10 mmol) dissolved in dried methanol (50 mL), concentrated sulfuric acid (0.5 mL) was added dropwise.The mixture was refluxed from 7 to 9 h. Next, the solvent was evaporated, and residue was dissolved in 40 mL of ethyl acetate, washed with 0.5% NaOH andbrine. Organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was evaporated to give the products as colorless oils. |
85% | With acetyl chloride at 0 - 20℃; for 5h; Inert atmosphere; | |
With sulfuric acid Heating; Yield given; | ||
With sulfuric acid Heating; | ||
With dichlorosulfoxide at 20℃; for 30h; | ||
With sulfuric acid Reflux; | ||
With sulfuric acid | ||
With sulfuric acid for 3h; Reflux; | ||
With dichlorosulfoxide | ||
With sulfuric acid Reflux; | ||
With sulfuric acid Reflux; | Representative procedure for preparation of methyl 2-(4-bromophenyl)-2-diazoacetate (1d) General procedure: (Step 1) A mixture of 4-bromophenylacetic acid (1.08 g, 5.0 mmol) and 95 wt.% sulfonic acid (0.28 mL) inmethanol (5.0 mL) was refluxed for 5 h. The resulting mixture was cooled to room temperature and diluted withsaturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the combinedextracts were washed with brine, dried over sodium sulfate, and concentrated to obtain methyl (4-bromophenyl)acetate (18) (1.13 g, 99% yield) as a colorless oil. The crude product was used without purification.(Step 2)8 A solution of 18 (1.12 g, 4.89 mmol) and p-toluenesulfonyl azide9 (1.16 g, 5.88 mmol) in acetonitrile(9.8 mL) was treated with DBU (1.10 mL, 7.36 mmol) at 0 °C and the mixture was stirred for overnight at roomtemperature. The resulting mixture was quenched with saturated aqueous ammonium chloride and extracted withethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. Theresidue was purified by chromatography on silica gel (hexane/ethyl acetate = 10/1 as the eluent) to afford 1d | |
With sulfuric acid for 2h; Reflux; | ||
With sulfuric acid for 6h; Reflux; | ||
With sulfuric acid for 5h; Reflux; | ||
With sulfuric acid at 90℃; for 24h; | ||
With sulfuric acid for 8h; Reflux; | 4.2.2. General Procedure for Synthesis of the Key Lactone Intermediate II (6a-6k) General procedure: General synthetic procedure for the key lactone intermediates II (6a-6k), for example 6a.2-(O-tolyl) acetic acid (0.15 g, 1 mmol) was dissolved in 15 mL of methanol, slowly add 2-3 drops ofconcentrated sulfuric acid, then refluxing for 8 h and monitored by TLC, after the reaction is completed,the solvent methanol was removed by rotary evaporation, 30 mL of water was added to the residueand stirred, extracted three times with ethyl acetate, washed with water, dried and concentrated to givecompound 5a. The obtained compound 5a was placed in a round bottom flask, and 1.2 eq of methylglycolate, 20 mL of tetrahydrofuran, and 2.2 eq of potassium t-butoxide were added, refluxing andstirring the reaction and monitored by TLC, after the reaction is completed, 50 mL of water was addedto the residue and stirred, adjust the pH of the solution to 5-6, then extracted three times with ethylacetate, washed with water, dried and concentrated to obtain key lactone intermediates II (6a) | |
With sulfuric acid for 6h; Reflux; | ||
With sulfuric acid In methanol for 5h; Reflux; | ||
With dichlorosulfoxide at 0 - 60℃; for 3.5h; Inert atmosphere; | ||
With sulfuric acid for 6h; Reflux; Inert atmosphere; | ||
With sulfuric acid for 16h; Reflux; | ||
With sulfuric acid for 6h; Reflux; | ||
With 4-dimethylaminopyridine; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.6% | With bromine In tetrachloromethane for 2.25h; Heating; Irradiation; | |
32.9% | With bromine In tetrachloromethane; ethyl acetate n-hexane | 92.a a a 2-(Bromomethyl)benzeneacetic acid A solution of 10 g (66.6 mmoles) of commercial 2-methylbenzeneacetic acid in 100 ml of carbon tetrachloride is refluxed, under a UV lamp. A solution made of 13.8 g (86.6 mmoles) of bromine and 33 ml of carbon tetrachloride is poured dropwise during 2 hours. The reflux condition is maintained 1 hour after the end of the addition and the mixture is concentrated to dryness. The residue recrystallizes in carbon tetrachloride then, in a hexane-ethyl acetate mixture, gives 5 g (yield=32.9%) of a white solid. M.P.=129°-32° C. (Lit.: 129°-32° C.; Leroy Chauffe L. J. A. and Keefer R. M., J. Org. Chem. (1966) 31, 3758-68). I.R. (KBr): ν (C=O)=1675 cm-1. N.M.R. (CDCl3 +DMSO d6): δ=3.7 (2H,s); 4.55 (2H,s); 7.2 (4H,s); 10.75 (1H,s wide, exchangeable with CF3 COOD). |
With N-Bromosuccinimide; dibenzoyl peroxide |
With N-Bromosuccinimide In tetrachloromethane for 2h; Heating; | ||
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 77℃; for 4h; | ||
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane | 23.a a) a) Preparation of o-(bromomethyl)phenylacetic acid o-Tolylacetic acid (40 g, 266 mmol), N-bromosuccinimide (52.147 g, 293 mmol) and benzoyl peroxide (0.174 g, catalytic) are dissolved in 300 ml of CCl4. The suspension is brought to and maintained at reflux for 12 hours. After cooling, the solid particles are separated out by filtration. and the CCl4 is evaporated off under vacuum, which allows a white solid to appear. This is sufficiently pure without recrystallization. 1H-NMR (CDCl3, ppm): 7.25 (4H, m, ArH); 4.3 (2H, s, CH2COOH); 3.7 (2H, S, CH2Br). | |
With N-Bromosuccinimide In chloroform for 8h; Reflux; | ||
With N-Bromosuccinimide In chloroform for 8h; Reflux; | 1 Intermediate 1 : Methvl r2-(bromomethvl)DhenvllacetateA solution of (2-methylphenyl)acetic acid (2 g, 13.32 mmol) in chloroform (20 ml) containing N-bromosuccinimide (2.370 g, 13.32 mmol) was heated under reflux for 8 hours, cooled, filtered and evaporated to give a crude containing 2-(bromomethyl)phenyl acetic acid. This material was dissolved in dichloromethane (40 ml) and methanol (10 ml) and the mixture was cooled at O0C. A 2M solution of trimethylsilyl diazomethane in Et2O (9.99 ml, 19.98 mmol) was added dropwise and the temperature was allowed to rise to ROOM TEMPERATURE and the mixture was stirred for 2 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (Biotage 40 M column) eluting with ethyl acetate / cyclohexane (1/9) to afford the title compound (1.9 g, 7.82 mmol) as a pale yellow oil; UPLC/MS Rt=0.73 min; m/z (ES): 243/245 [M+H]+ and 163 [M-Br] +; 1H NMR (CDCI3): δ 3.73 (s, 3H), 3.84 (s, 2H), 4.61 (s, 2H), 5.42-5.55 (m, 2H), 7.16-7.24 (m, 1 H), 7.26-7.35 (m, 2H), 7.37-7.42 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfur tetrafluoride; water at 120℃; for 4.5h; Yield given. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: carbon monoxide With C28H22CoN4O6 In butan-1-ol at 60℃; for 2h; Glovebox; High pressure; Green chemistry; Stage #2: 1-chloromethyl-2-methylbenzene With tetra-(n-butyl)ammonium iodide; sodium hydroxide In butan-1-ol at 60℃; for 22h; Glovebox; High pressure; Green chemistry; regioselective reaction; | 4.4 Synthesis of 2a-u General procedure: A 100 mL reactor equipped with Teflon-coated magnetic stir bars was charged with n-Butyl alcohol (20 mL) and the catalyst (0.5 mmol). The reactor was then taken out of the glove box and pressured with carbon monoxide (1 atm). The mixture was stirred 2 h at 60 °C, cooled to ambient temperature and slowly vented. After benzyl chloride (10 mmol), NaOH (15 mL, 15%), and TBAI (0.25 mmol) were added, the reactor was sealed and the reaction mixtures were stirred for 22 h at 60 °C under carbon monoxide (1 atm). After the reaction, the water phase was detached and washing the organic phase three times with H2O (3×5 mL), the combined water layer was washed with Et2O, then the resulting solution was cooled to 0 °C and adjusted to pH=1-2 with HCl (6 mol/L). The product was filtered, dried in RT, and then recrystallized. |
83% | With bis-triphenylphosphine-palladium(II) chloride; tetraethylammonium chloride; sodium hydroxide In 5,5-dimethyl-1,3-cyclohexadiene at 80℃; for 20h; Autoclave; regioselective reaction; | Catalytic experiments General procedure: The carbonylation reaction was performed in a 150 mL polytetrafluoroethylene(PTFE)-lined autoclave equipped witha magnetic stir bar. In a typical experiment, the substituted benzyl chloride (0.01 mol), Pd(PPh3)2Cl2 (0.13 mmol),TEAC (0.18 mmol), NaOH (4 M, 8 mL) and DMB (10 mL)were placed in the autoclave. The autoclave was purged three times with N2 and three times with CO, and then heated to 80 °C. During the reaction, the CO pressure was maintained at 1.5 MPa. When the reaction was complete,the autoclave was cooled to room temperature in ice water,and the CO was discharged to atmospheric pressure. The mixture was then adjusted to pH 2 with HCl (12 M), and the solid was collected via filtration and air-dried. The crude product was recrystallised in MeOH/H2O (1:1, v/v) to obtain 2,4-DCPA. The remaining commercially available catalysts were evaluated under the same conditions. The percent conversion and yield were quantified by the method reported by Lei et al. |
55% | With sodium hydroxide In toluene at 85 - 95℃; for 7.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 9 % Spectr. 2: 56% | With tetrakis(triphenylphosphine) palladium(0); hydrogen iodide In acetone at 90℃; for 42h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sulfuric acid; nitric acid; In dichloromethane; at -20 - 20℃; | Intermediate 80A: Preparation of 2-(2-methyl-5-nitrophenyl)acetic acid [00224] A solution of 2-o-tolylacetic acid (3.54 g, 23.6 mmol) in DCM (12 mL) was added to a pre-cooled mixture of concentrated sulfuric acid (10 mL, 188 mmol) and 90% nitric acid (1 mL, 22.4 mmol) at - 20 0C. The reaction mixture was stirred at - 20 0C for 30 minutes, then slowly warmed to room temperature and stirred overnight. The reaction mixture was poured into ice-water. The white solid was collected by filtration, rinsed with water, and concentrated. The solid was triturated with ether and filtered to obtain Intermediate 8OA (2.4 g, 42%) as a white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 12.62 (1 H, br. s.), 8.13 (1 H, d, J = 2.51 Hz), 8.04 (1 H, dd, J = 8.28, 2.51 Hz), 7.47 (1 H, d, J = 8.53 Hz), 3.80 (2 H, s), 2.34 (3 H, s). |
34.6% | The starting material 2-methyl-phenylacetic acid (200.0 g, 1.33 mol)Was dissolved in dichloromethane (700 mL)0 C below slowly addedConcentrated sulfuric acid (584 mL),After the addition reaction was continued for 0.5 hours,Then concentrated nitric acid (30 mL)Maintain the temperature at -2 ~ 3 reaction 16 hours;After the reaction,Poured into 500 mL of water,Extracted with dichloromethane, dried,Concentrated to give Compound 1-2 (90.0 g) in a yield of 34.6%. | |
32% | With sulfuric acid; nitric acid; In dichloromethane; at -10℃; for 1h; | Step 1: a 500 mL round bottom flask was charged with conc. sulfuric acid (130 mL) and cooled to -10C. A solution of o-tolyacetic acid (10 g, 66.58 mmol) in CH2CI2 (35 mL) was added dropwise. After that, a solution of conc. sulfuric acid(27 mL) and nitric acid (2.7 mL) was slowly added dropwise. The reaction mixture was stirred at -10C for 1 h and then poured onto ice. The aqueous phase was extracted with EtOAc. The organic layer was washed with water and brine, dried, filtered and the solution was concentrated under reduced pressure. The resulting solid was triturated in Et20 and filtered off to afford 2-(2-methyl-5-nitrophenyl)acetic acid as white solid (4.21 g, 32%). |
With sulfuric acid; nitric acid; In dichloromethane; | A. Acylating Reagent (2-Methyl-5-nitrophenyl)acetic acid A 1 L round bottom flask was charged with conc. sulfuric acid (500 mL) and cooled to -12 C. (ethyleneglycol-dry ice). (2-Methylphenyl)acetic acid (35.4 g, 0.24 mol) dissolved in dichloromethane (120 mL) was added during 10 minutes and the mixture was then treated dropwise during two hours with a pre-cooled (ethylene glycol-dry ice) solution of conc. sulfuric acid (100 mL) and 100% nitric acid (10 mL). The reaction mixture was stirred for one hour at -12 C. and then poured on ice. The aqueous phase was extracted with ethyl acetate (3*1 L). The combined organic phases were washed with brine (2*1L) and water (2*1 L), dried (Na2SO4) and concentrated in vacuo to give the 38.1 g crude mixture (38 g). 1H NMR showed a 70:30 mixture of the title compound and (2-methyl-3-nitrophenyl)acetic acid, and the title compound was purified by trituration with diethyl ether. | |
With sulfuric acid; nitric acid; In dichloromethane; at -20 - 20℃; for 0.75h; | - Step 1: a solution of o-tolyacetic acid (5.0 g, 33.29 mmol), in CH2CI2 (15 mL) was added dropwise to a pre-cooled mixture of conc. sulfuric acid (26 mL, 266.3 mmol) and 99.5% nitric acid (1.35 mL, 31.63 mmol) at -20C. The reaction mixture was stirred at that temperature for 30 mm, then slowly warmed to rt and stirred for 1 5h. The reaction mixture was poured into ice-water. The white solid was collected by filtration and washed with water. The solid was triturated with Et20 and filtered to obtain the mono and di-nitration products in a 1:1 ratio (4.78 g), that will be separated after the next esterification step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With dihydrogen peroxide In water monomer; acetonitrile at 25℃; for 10h; UV-irradiation; | |
92% | With K5CoW12O40 In water monomer; acetonitrile for 0.166667h; Microwave irradiation; | |
87% | With oxygen; Mn(dtbpy)<SUB>2</SUB>(OTf)<SUB>2</SUB> In acetonitrile at 45℃; for 12h; Irradiation; Schlenk technique; |
85% | With mercury(II) fluoride; oxygen In acetonitrile at 25℃; for 24h; Irradiation; | |
77% | With potassium peroxodisulfate In water monomer at 90℃; for 12h; Green chemistry; | General Procedure for the preparation of Aldehydes and Ketones from Aryl acetic acids General procedure: In an oven dried tube containing a mixture of 4-methyl phenyl acetic acid 1a (200 mg, 1.33mmol) and potassium persulfate (360 mg, 2.66 mmol), water (2 mL) was added and heated at 90 °C for 12 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature (24°C) and it was extracted with ethyl acetate (3 x 5 mL). The crude product was purified by column chromatography to furnish compound 2a as colorless liquid (136 mg, 85% yield). |
72% | With oxygen; mercuric (II) oxide In methanol; acetonitrile at 25℃; UV-irradiation; | |
64% | With ferric(III) chloride; oxygen In N,N-dimethyl-formamide at 110℃; | |
With oxygen In N,N-dimethyl-formamide at 120℃; for 4h; | 2.2 Catalytic studies General procedure: In a typical experiment, a solution of phenylacetic acid (0.3mmol, 40.8mg) in DMF (0.5mL) was added to a 10mL vial with the VNU-21 catalyst (5.5mg, 5mol%). The mixture was stirred at 120°C for 4h under an oxygen atmosphere. After that, the catalyst was removed by filtration. A solution of 2-aminobenzamide (0.2mmol, 27.2mg) in DMSO (0.5mL) was then added to the reactor. The mixture was additionally stirred at 120°C for 5h under oxygen. The GC yield of benzaldehyde and 2-phenylquinazolin-2(3H)-one were monitored by withdrawing samples from the reaction mixture, quenching with brine (1mL), extracting with ethyl acetate (3×1mL), drying over anhydrous Na2SO4, and analyzing by GC regarding diphenyl ether as internal standard. After the completion of the second step, the reaction mixture was cooled to room temperature. Resulting solution was quenched with brine (5mL), extracted by ethyl acetate (3×5mL), dried over anhydrous Na2SO4 prior to the removal of solvent under vacuum. The crude product was purified by silica gel column chromatography using hexane and ethyl acetate (1:1, v/v) as eluent. The structure of 2-phenylquinazolin-4(3H)-one was verified by GC-MS, 1H NMR and 13C NMR. For the leaching test, after the first 4h reaction time, the catalyst was removed by filtration. The solution phase was transferred to a new and clean reactor. New phenylacetic acid was added, and the resulting mixture was subsequently stirred for additional 4h at 120°C under an oxygen atmosphere. The yield of benzaldehyde was monitored by GC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium In tetrahydrofuran at -70 - -20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
B.28 Synthesis of 2-[(2-methylphenyl)acetamido]butyric Acid Iso-butyl Ester Example B28 Synthesis of 2-[(2-methylphenyl)acetamido]butyric Acid Iso-butyl Ester Following General Procedure BI above and using 2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.18 (m, 4H), 5.79 (m,1H), 4.54 (m, 1H), 3.85 (m, 2H), 3.59 (s, 2H), 3.29 (s, 3H), 1.81 (m, 2H), 1.59 (m, 1H) 0.87 (d, 6H), 0.77 (t, 3H). | ||
B.28 Synthesis of 2-[(2-Methylphenyl)acetamido]butyric Acid iso-Butyl Ester Example B28 Synthesis of 2-[(2-Methylphenyl)acetamido]butyric Acid iso-Butyl Ester Following General Procedure BI above and using 2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.18 (m, 4H), 5.79 (m, 1H), 4.54 (m, 1H), 3.85 (m, 2H), 3.59 (s, 2H), 3.29 (s, 3H), 1.81 (m, 2H), 1.59 (m, 1H) 0.87 (d, 6H), 0.77 (t, 3H). C17H25NO3 (MW=291.39 Mass Spectroscopy (M+291)). | ||
28 Synthesis of 2-[(2-methylphenyl)acetamido]butyric acid iso-butyl ester Example 28 Synthesis of 2-[(2-methylphenyl)acetamido]butyric acid iso-butyl ester Following General Procedure I above and using 2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1 H-nmr (CDCl3): δ=7.18 (m, 4H), 5.79 (m, 1H), 4.54 (m, 1H), 3.85 (m, 2H), 3.59 (s, 2H), 3.29 (s, 3H), 1.81 (m, 2H), 1.59 (m, 1H) 0.87 (d, 6H), 0.77 (t, 3H). |
A.28 Synthesis of 2-[(2-methylphenyl)acetamido]butyric acid iso-butyl ester EXAMPLE A28 Synthesis of 2-[(2-methylphenyl)acetamido]butyric acid iso-butyl ester Following General Procedure I' above and using 2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.18 (m, 4H), 5.79 (m, 1H), 4.54 (m, 1H), 3.85 (m, 2H), 3.59 (s, 2H), 3.29 (s, 3H), 1.81 (m, 2H), 1.59 (m, 1H) 0.87 (d, 6H), 0.77 (t, 3H). | ||
A.28 Synthesis of 2-[(2-methylphenyl)acetamido]butyric Acid Iso-butyl Ester EXAMPLE A28 Synthesis of 2-[(2-methylphenyl)acetamido]butyric Acid Iso-butyl Ester Following General Procedure I' above and using 2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.18 (m, 4H), 5.79 (m, 1H), 4.54 (m, 1H), 3.85 (m, 2H), 3.59 (s, 2H), 3.29 (s, 3H), 1.81 (m, 2H), 1.59 (m, 1H) 0.87 (d, 6H), 0.77 (t, 3H). | ||
With 1-(3-(1-pyrrolidinyl)-propyl)-3-ethylcarbodiimide In chloroform at 23℃; for 96h; | 28 Synthesis of 2-[(2-methylphenyl)acetamido]butyric acid iso-butyl ester Example 28 Synthesis of 2-[(2-methylphenyl)acetamido]butyric acid iso-butyl ester Following General Procedure I above and using 2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ = 7.18 (m, 4H), 5.79 (m, 1H), 4.54 (m, 1H), 3.85 (m, 2H), 3.59 (s, 2H), 3.29 (s, 3H), 1.81 (m, 2H), 1.59 (m, 1H) 0.87 (d, 6H), 0.77 (t, 3H). C17H25NO3 (MW = 291.39 Mass Spectroscopy (M+ 291)). GENERAL PROCEDURE IP-EPC coupling P-EPC coupling employs an amino acid ester and a substituted acetic acid compound. The acetic acid derivative is well known in the art and is typically commercially available. The amino acid ester is prepared by conventional methods from the known and typically commercially available N-BOC amino acid as described in GENERAL PROCEDURE J below.Specifically, the appropriate amino ester free base (0.0346 mmols) and substituted phenylacetic acid (0.069 mmols) were dissolved in 2.0 mL CHCl3 (EtOH free), treated with 150 mg of P-EPC (0.87 meq./g) and the reaction was mixed for 4 days at 23°C. The reaction was filtered through a plug of cotton, rinsed with 2.0 mL of CHCl3 and the filtrate evaporated under a stream of nitrogen. The purity of each sample was determined by 1H NMR and ranged from 50% to >95%. Between 8.0 and 15.0 mg of final product was obtained from each reaction and was tested without additional purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | EXAMPLE 1 o-Tolylacetic acid (346. 5g, 2.307moles) was charged to a glass reactor fitted with stirrer, thermometer condenser and vented to a caustic scrubber. Fluorobenzene (476.2g, 4.96moles) was added and the contents heated to 75-80C with stirring. To the mixture was added 2,2'-azobis (2-methylbutyronitrile) (8.9g, 0.046moles) in fluorobenzene (79.7g, 0.83moles). Sulphuryl chloride (311.4g, 2.307moles) was added over 3 hours while maintaining the temperature at 75-80C. After the addition was complete, the mixture was held for lhour at 75-80C. The temperature was adjusted to 60C and 50% potassium hydroxide (180. 9g, 1.615moles) added, followed by potassium iodide (1.53g, 0. 009moles). The pH was then adjusted to 6.3 using 20% potassium bicarbonate. After settling, the aqueous phase was separated from the organic phase. The aqueous phase was held for extraction and re-cycle of the o-tolylacetic acid. The organic phase was distilled to remove the fluorobenzene and leave the crude 3-isochromanone 286.6g at 81% strength w/w (equivalent to 232g (Z100% wt, 1.568moles) representing a yield of 68% from o-tolylacetic acid. The aqueous phase (1042g) was charged to a reaction vessel containing fluoro- benzene (524g, 5.458moles) and 36% hydrochloric acid (55g, 0.542moles) was added to reduce the pH to 1.0. The organic and aqueous phases were stirred, allowed to settle and separated. Analysis of the upper fluorobenzene layer (642.2g) showed it contained 3. 1% o- tolylacetic acid (19.9g, 0.13moles) equivalent to 6% of the original charge. This layer was recycled for use in a subsequent preparation. | |
61.5% | EXAMPLE 12 This Example illustrates a distillative work-up of 3-isochromanone Chlorobenzene (481 g, 4.27 moles) and o-Tolylacetic acid (350g, 2.33moles) were charged to a glass reactor fitted with stirrer, thermometer condenser and vented to a caustic scrubber. Additional chlorobenzene (102.4g, 0.91 moles) was added and the contents azeotropically dried under vacuum at 75-80C with stirring (100.4 g removed). To the mixture was added 2,2'-azobis (2-methylbutyronitrile) (8.95g, 0.046moles) in chlorobenzene (80g, 0.71 moles). Sulphuryl chloride (389.2g, 2.80moles) was added over 3 hours while maintaining the temperature at 75-80C. After the addition was complete, the mixture was held for 1 hour at 75-80C. The temperature was adjusted to 60C and water (121g) charged. A 50% potassium hydroxide solution (182g, 1.625moles) added, followed by potassium iodide solution (1.5g, 0. 009moles in water (3.5g)). The pH was adjusted to pH 6.5 using 20% potassium bicarbonate (768g of 20% solution). Additional water (81g) was added and, after settling, the aqueous phase was separated from the organic phase. The chlorobenzene was removed in vacuo and the remaining melt (310g at 81% strength, 72.5% yield) distilled at 145-155C and 9 mbar to give the final product (222g at 95.5% strength, 1.43 moles, 61.5% yield). | |
48% | With ammonium iodide; Oxone; potassium bromide; In 2,2,2-trifluoroethanol; acetonitrile; at 20℃; for 12h;Green chemistry; | General procedure: To a mixture of MeCN and CF3CH2OH (6:4) (5.0 mL), carboxylic acid 1 (0.5 mmol), NH4I (0.25mmol), KBr (0.4 mmol) and Oxone? (0.75 mmol) were added. The resulting solution was stirred at room temperature for 12 h and then solvents were removed under reduced pressure. Water (10mL), sat. aq Na2S2O3 (4 mL) and sat. aq Na2CO3 (4 mL) were added to the residue and the mixture was stirred for another 5 min. The mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gelusing (hexane-AcOEt 3:1) as eluant to give the pure product of aryl lactone 2. |
41 - 57.3% | EXAMPLE 2 o-Tolylacetic acid (3.96kg, 26.36moles) was charged to a 20 litre glass reactor fitted with stirrer, thermometer and condenser and vented to a caustic scrubber. Chlorobenzene (6kg, 53.3moles) was added and the contents heated to 78-79C with stirring. To the mixture was added 2,2'-azobis (2-methylbutyronitrile) (0. 103kg, 0.54moles) in chlorobenzene (0.93kg, 8.3moles). Sulphuryl chloride (2.86kg, 21.34moles) was added over 3 hours while maintaining the temperature at 75-80C. After the addition was complete, the mixture was held for lhour at 78-80C. The temperature was adjusted to 60C and 50% potassium hydroxide (1. 4kg, 12. 5moles) was added, followed by 30% potassium iodide (0. 05kg, 0.09moles). The pH was then adjusted to 6.8 using 20% potassium bicarbonate (11. 2kg, 22. 4moles). After settling, the aqueous layer was separated from the organic phase. The organic phase was given a further aqueous potassium bicarbonate wash at pH 6.8 (4.8kg containing 0.06kg, 0.6moles potassium bicarbonate). The two aqueous washes were combined for recycling. The organic phase was distilled to remove some of the chlorobenzene and water. Methylcyclohexane was added (6kg, 61.2moles). The solution of 3-isochromanone was cooled to-5C and the 3-isochromanone isolated by filtration followed by washing with methylcyclohexane. The isolated 3-isochromanone weighed 1.8 kg (12.2 moles), at 98% strength w/w and contained less than 1% o-tolylacetic acid. The isolated yield was 45% from the o-tolylacetic acid charged (60% from the o-tolylacetic acid consumed taking into account the o-tolylacetic acid recovered). The combined aqueous washes saved for recycling (ca. 15.9kg) were charged to a reaction vessel containing chlorobenzene (4kg, 35.6moles). Hydrochloric acid 32% strength (l. lkg, 9.6moles) was added to reduce the pH to 3.5. The phases were then settled and separated. Analysis of the upper chlorobenzene layer showed it contained o-tolylacetic acid (0.96kg, 6.4moles) equivalent to 24.2% of the original charge. This layer was re-cycled in a subsequent preparation as part of the batch charge. EXAMPLE 3 o-Tolylacetic acid (3.04kg, 20.3moles) was charged to a 20 litre glass reactor fitted with stirrer, thermometer and condenser and vented to a caustic scrubber. Chlorobenzene containing re-cycled o-tolylacetic acid (5.23kg at 18.3% equivalent to 0.96kg 100%, 6.4moles) recovered from Example 2 was added followed by a make up charge of chlorobenzene (1. 5kg/13. 3moles) to give a total chlorobenzene charge of 6kg (53.3moles). The contents were heated to 78-79C with stirring. To the mixture was added 2, 2'-azobis (2- methylbutyronitrile) (0.103kg, 0.54moles) in chlorobenzene (0.93kg, 8.3moles). Sulphuryl chloride (3.28kg, 24.2moles) was added over 3 hours maintaining the temperature at 75-80 C. After the addition was complete, the mixture was held for 1 hour at 78-80C. The temperature was adjusted to 60C and 2kg of water were added followed by 50% potassium hydroxide (2kg, 17.8moles). Potassium iodide 30% (0. 05kg, 0.09moles) was added and the pH was then adjusted to 6.8 using 20% potassium bicarbonate (10.7kg, 21. 5moles). After settling, the aqueous phase was separated from the organic phase for extraction and recycling of the o-tolylacetic acid : The organic phase was distilled to remove some of the chlorobenzene and water. Methylcyclohexane was added (6kg, 61.2moles). The solution of 3-isochromanone was cooled to-5C, the 3-isochromanone isolated by filtration and washed with methylcyclohexane. The isolated 3-isochromanone weighed 1.65 kg (98% strength w/w, 11.15 moles). The isolated yield was 41% from o-tolylacetic acid charged (58% from o- tolylacetic acid consumed taking into account the o-tolylacetic acid recovered). The aqueous phase saved for recycling (ca. 17. 1kg) was charged to a reaction vessel containing chlorobenzene (4kg, 35.6moles). Hydrochloric acid 32% strength (1.36kg, 11. 9moles) was added to reduce the pH to 3.5. The phases were then settled and separated. Analysis of the upper chlorobenzene layer showed it to contain o-tolylacetic acid (1.19kg, 7.9moles) equivalent to 29.6% of the original charge. This layer was held for re-cycling in a subsequent preparation as part of the batch charge. EXAMPLE 4 o-Tolylacetic acid (3.96 kg, 26.4moles) was charged to a 20 litre glass reactor fitted with stirrer, thermometer, condenser and scrubber. Chlorobenzene (6 kg) was charged to the reaction vessel and the contents heated to 78-79C. A solution of 2, 2'-azobis (2- methylbutyronitrile) (103g) in chlorobenzene (930g) was added to the vessel. This was followed by sulphuryl chloride (2.86 kg, 22.19 moles) added at a steady rate over 3 hours. After complete addition, the reaction mixture was held for an hour. Potassium hydroxide (50% w/w solution, 1.4kg) was dosed to the reactor to control an exotherm. Potassium iodide (30% aqueous solution, 50g) was then added. The pH was finally adjusted to 6.8 with 20% potassium bicarbonate... | |
41.8 - 42.7% | EXAMPLE 10 o-Tolylacetic acid (199.5 g, 1.33moles) was charged to a 1 litre glass reactor fitted with stirrer, thermometer and condenser and vented to a caustic scrubber. Chlorobenzene was added (275 g, 2.44moles). The contents were heated to 78-79C with stirring. To the mixture was added 2,2'-azobis (2-methylbutyronitrile) (5.15g, 0.027moles) in chlorobenzene (46. 5g, 0.41moles). Chlorine (75. 5g, 1.06moles) was added over 3 hours while maintaining the temperature at 75-80C. After the addition was complete, the mixture was held for lhour at 78-80C. The temperature was adjusted to 60C and water (67 g) was added followed by 50% potassium hydroxide (77.2g, 0.69moles) Potassium iodide 30% (2. 5g, 0.0045moles) was added and the pH was adjusted to 6.4 using 20% potassium bicarbonate (448.8g, 0.897moles). After settling, the aqueous phase was separated from the organic phase for extraction and re-cycling of the o-tolylacetic acid. The organic phase was distilled to remove some of the chlorobenzene/water. Methylcyclo- hexane was added (300g, 3.06moles), the chlorobenzene/methylcyclohexane ratio being 50/50% w/w. The solution was cooled to-5C and the 3-isochromanone isolated by filtration followed by methylcyclohexane washing. The isolated 3-isochromanone (85g at 99.0% strength w/w, 0.57 mol) contained less than 0. 1% o-tolylacetic acid. The isolated yield was 42.7% from the o-tolylacetic acid charged, or 58.3% from the o-tolylacetic acid consumed taking into account the o-tolylacetic acid recovered, (63.8% including recovered 3- isochromanone). The aqueous phase (ca. 686g) was charged to a reaction vessel containing chlorobenzene (275g, 2.44moles). Hydrochloric acid 32% strength (59. 5g, 0.52moles) was added to reduce the pH to 3.5. The phases were then settled and separated. The organic layer contained o- tolylacetic acid (55.3g, 0.37moles), and 3-isochromanone (10.8g, 0.07moles). This layer was held for re-cycling in Example 11 as part of the batch charge. EXAMPLE 11 o-Tolylacetic acid (145.2, 0.967moles) was charged to a 20 litre glass reactor fitted with stirrer, thermometer and condenser and vented to a caustic scrubber. Chlorobenzene containing the re-cycled o-tolylacetic acid from Example 10 (345g at 15.8% o-tolylacetic acid; 54. 5g, 0.37 moles) was added. The contents were heated to 78-79C with stirring. To the mixture was added 2, 2'-azobis (2-methylbutyronitrile) (5. 15g, 0.027moles) in chlorobenzene (46. 5g, 0.41moles). Chlorine (75. 5g, 1.063moles) was added over 3 hours while maintaining the temperature at 75-80C. After the addition was complete, the mixture was held for 1 hour at 78-80C. The temperature was adjusted to 60C and water (67g) was added followed by 50% potassium hydroxide (100g, 0.89moles). Potassium iodide 30% (2. 5g, 0.0045moles) was added and the pH was adjusted to 6.4 using 20% potassium bicarbonate (442g, 0.88moles). After settling, the aqueous phase was separated from the organic phase for extraction and re-cycling of the o-tolylacetic acid. The organic phase was distilled to remove some of the chlorobenzene/water. Methylcyclo- hexane was added (250g, 2. 55moles), the chlorobenzene/methylcyclohexane ratio being 51/49% w/w. The solution was cooled to-5C, the 3-isochromanone isolated by filtration and washed with methylcyclohexane. The isolated 3-isochromanone (61. Og at 98.3% strength w/w) contained less than 0. 1% o-tolylacetic acid. The isolated yield was 41.8% from the o- tolylacetic acid charged, or 69.9% from the o-tolylacetic acid consumed taking into account the o-tolylacetic acid recovered. The aqueous phase (ca. 739g) was charged to a reaction vessel containing chlorobenzene (275g, 2.44moles). Hydrochloric acid 32% strength (84.2g, 0.74moles) was added to reduce the pH to 3.5. The phases were settled and separated. The organic layer contained o- tolylacetic acid (55.3g, 0.373moles) equivalent to 28. 1% of the original charge. | |
With trichlorophosphate; In benzene; at 55℃; | At 500 ml round bottom flask was added 100g o-tolylacetic acid (1), 150g benzene, heating to 55 C. Under stirring, slowly drop phosphorus oxychloride (122.4 g). Reaction to disappearance of the raw material. Stop the reaction. Cool to room temperature, the organic uses 30% NaOH is washed to neutral, take off the dry solvent to obtain product 103.0 g, yield 99.1%, purity 93.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In benzene at 50℃; for 20h; | 29.1 o-Tolylacetic acid (2.0 g, 13.3 mmol) was combined with p-nitrobenzyl bromide (5.8 g, 26.8 mmoles) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.4 mL, 16.0 mmol) in 65 mL of benzene, and was stirred at 50° C. for 20 hours. After this period the heterogeneous mixture was gravity filtered and the filtrate was evaporated in vacuo. The residue was combined with CH2Cl2 and was washed with 1N HCl (2×25 mL) and sat'd NaHCO3 (2×25 mL), and the resulting CH2Cl2 solution was dried over anhydrous Na2SO4. The crude solid was purified using flash silica chromatography (0-10% EtOAc/Hexane) to yield 3.61 g (95%) of the intermediate as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, 2H), 7.39 (d, 2H), 7.22-7.16 (m, 4H), 5.21 (s, 2H), 3.72 (s, 2H), 2.30 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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59% | With 4-methyl-morpholine; hydrogenchloride; In hexane; dichloromethane; | Reference Example 22 Synthesis of N-alpha-[2-(2-tolyl)acetyl]-N-epsilon-t-butoxycarbonyl-L-lysine] N-epsilon-t-butoxycarbonyl-L-lysine (1.35 g) was suspended in dichloromethane (8 ml), and then N,O-bis(trimethylsilyl) acetamide (2.8 ml) was added while stirring at room temperature to prepare a solution (hereinafter referred to as Solution A). Next, 2-(2-tolyl)acetic acid (0.75 g) and N-methylmorpholine (605 mul) were dissolved in dichloromethane (15 ml), isobutyloxycarbonyl chloride (722 mul) was added while stirring at -10 C., and stirring was continued for 20 minutes. Solution A was then added dropwise, and the mixture was stirred at a temperature of between -10 C. and 0 C. for 3 hours. Dichloromethane and 1 N hydrochloric acid were added to the reaction mixture which was then vigorously shaken, and the organic layer was separated off. The aqueous layer was washed with dichloromethane. After combining the organic layer and washing with saturated saline, drying was performed over magnesium sulfate. The organic layer was filtered and the filtrate was concentrated under reduced pressure. The residue was washed with n-hexane and dissolved in dichloromethane (10 ml), and then n-hexane (100 ml) was added. The produced precipitate was isolated and dried under reduced pressure to obtain 1.12 g of the title compound as a colorless powder (59% yield). The NMR data and mass spectrometry (MS) data for the obtained compound were as follows. NMR: (270 MHz, CDCl3) delta: 1.14-1.93 (15H,m), 2.28 (3H,s), 2.93-3.11 (2H,m), 3.61 (2H,s), 4.43-4.60 (1H,m), 7.11-7.24 (4H,m) MS: m/z 401 (M++23). |
Yield | Reaction Conditions | Operation in experiment |
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98% | With sulfuric acid In methanol | 1.1 Step 1 Step 1 Preparation of Methyl o-tolylacetate 30.0 g of o-tolylacetic acid (0.2 mol) was dissolved in 100 ml of methanol, 5 ml of concentrated sulfuric acid was added thereto and the resulting solution was stirred with heating for 6 to 12 hours. The resulting solution was cooled and the solvent was removed under a reduced pressure to obtain a residue. The residue was washed twice with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was removed under a reduced pressure. The residue thus obtained was subjected to column chromatography using a mixture of n-hexane and ethyl acetate (4:1) as an eluent to obtain 32.15 g (yield 98%) of the title compound as a colorless liquid. 1H-NMR (CDCl3, TMS) δ: 7.21-7.01(m, 4H), 3.61(s, 3H), 3.60(s, 2H), 2.35(s, 3H); MS (m/e): 164(M+, 42), 133(100), 31(82). |
98% | With sulfuric acid In methanol | 1.1 Step 1 Step 1 Preparation of Methyl o-Tolylacetate 30.0 g (0.2 mol) of o-tolyl acetic acid was dissolved in 100 ml of methanol, 5 ml of concentrated sulfuric acid was added thereto and the resulting solution was stirred with heating for 6 to 12 hours. The resulting solution was cooled and the solvent was removed under a reduced pressure to obtain a residue. The residue was washed twice with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was removed under a reduced pressure. The residue thus obtained was subjected to column chromatography using a mixture of n-hexane and ethyl acetate (4:1) as an eluent to obtain 32.15 g (yield 98%) of the title compound as a colorless liquid. 1H-NMR (CDCl3, TMS) δ (ppm) 7.21-7.01 (m, 4H), 3.61 (s, 3H), 3.60 (s, 2H), 2.35 (s, 3H); MS (m/e): 164 (M+, 42), 133 (100), 31 (82). |
With sulfuric acid In formic acid for 6h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuryl dichloride; azobisisobutyronitrile In fluorobenzene | 4 EXAMPLE 4 EXAMPLE 4 This Example illustrates the preparation of 3-isochromanone from recrystallized 2-chloromethylphenylacetic acid using different work-up procedures. o-Tolylacetic acid (100 g) was slurried in fluorobenzene (153.4 g) under a nitrogen blanket, and heated to reflux. An additional amount of fluorobenzene (100 ml) was then added to the reaction mixture and the solution dried by azeotropic distillation under atmospheric pressure at 85-90° C. The reaction mixture was then cooled to 80° C. and AIBN (2.14 g) was charged to the vessel in one portion. Sulphuryl chloride (105.55 g) was then added to the refluxing reaction mixture (temperature maintained at 80-85° C.) over a period of 3 hours, closely monitoring the progress of the reaction by means of 1 H NMR. Analysis showed ~80% conversion to 2-chloromethylphenylacetic acid at this point. After the addition was complete, the reaction mixture was allowed to cool slowly to ambient temperature, cooling finally to 0-5° C. The precipitate was filtered by suction, washed with n-hexane (70 g) and pulled dry on the filter, to give a fine off-white powder (75.73 g); 1 H NMR (CDCl3)δ 3.8(s,2H); 4.6(s,2H); 7.2-7.5(m,4H) ppm; mp 114.5-117.1° C.; quantitative yield 62.15%; % strength 95.7% by 1 H NMR. A sample of the 2-chloromethylphenylacetic acid was recrystallized from toluene which, following a hot filtration, gave a white solid of strength 97.75%. | |
With sulfuryl dichloride at 120℃; | 1-5 Example 5: 50 grams of o-methylphenylacetic acid and50 grams of sulfonyl chloride are configured separately250 ml of tetrachloroethylene solution,Set the microchannel reactor temperature to 120 ° C to 5 mL / minThe flow rate of the two raw materials of tetrachloroethylene into the microchannel reactor for reaction;After collecting the reaction solution, wash it once in cold water.Adjust the pH to 7.2 with a saturated aqueous solution of potassium hydrogencarbonate, and keep the reaction at 50 ° C.The reaction system was detected by HPLC without change, washed with 100 ml of water and dried with an organic phase.The solvent was removed by concentration, and the residue was recrystallized from methanol.Drying gave 39 g of 3-isochromanone in a yield of 79% and a purity of 99.5%. | |
870 g | With 2,2'-azobis(isobutyronitrile); chlorine In dichloromethane at 75℃; | 1.5; 2.5; 3.5 The specific process of step (5) is to add 800 g of o-toluene acetic acid and 440 g of dichloroethane in a 2000 liter reaction flask, increase the temperature to 75°C, then add 88 g of azobisisobutyronitrile, and then start the introduction of chlorine gas 488.89 g. When the content of the raw material is between 1% and 5%, the reaction is stopped, and 870 g of 2-chloromethylphenylacetic acid solid is obtained by cooling and centrifuging. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dmap; diisopropyl-carbodiimide In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: o-methylphenylacetic acid; O,N-dimethyl-hydroxylamine hydrochloride In chloroform for 0.166667h; Cooling with ice; Stage #2: With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In chloroform for 0.166667h; Stage #3: With triethylamine In chloroform for 3.16667h; | 36.a Example 36 Production of N-benzyl-2-[3-isobutyl-5-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine a) Production of 2-(2-toluyl)-N-methoxy-N-methylacetamide; [Show Image] A solution of 2.60 g of 2-methylphenyl acetic acid and 2.53 g of N,O-dimethylhydroxylamine monohydrochloride in 50 mL of chloroform was stirred under ice-cooling for 10 minutes, and 4.98 g of WSC monohydrochloride was added thereto, followed by stirring for 10 minutes. 5.25 g of triethylamine was further added thereto, followed by stirring for 10 minutes, and then reacting at room temperature for 3 hours. After completion of the reaction, the reaction liquid was diluted by addition of 1 N hydrochloric acid under ice-cooling, followed by extraction with chloroform. The chloroform layer was washed with a saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 3.20 g (yield 96%) of a title compound as a colorless oily substance. 1H-NMR (CDCl3) δ: 2.31 (3H, s), 3.21 (3H, s), 3.61 (3H, s), 3.77 (2H, s), 7.12-7. 21 (4H, m). |
96% | With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In dichloromethane at 22℃; for 18h; Inert atmosphere; | |
94% | With 4‐dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; Inert atmosphere; |
94% | Stage #1: o-methylphenylacetic acid With 1,1′-carbonyldiimidazole In dichloromethane at 0℃; for 0.5h; Stage #2: O,N-dimethyl-hydroxylamine hydrochloride With triethylamine In dichloromethane at 0 - 20℃; | |
80% | Stage #1: o-methylphenylacetic acid With NBS; triphenylphosphine In dichloromethane at 0℃; for 0.25h; Stage #2: O,N-dimethyl-hydroxylamine hydrochloride With triethylamine In dichloromethane at 20℃; for 1h; chemoselective reaction; | General procedure for the synthesis of Weinreb amides General procedure: A. To a mixture of benzoic acid (50 mg, 0.41 mmol, 1 equiv), PPh3 (160 mg, 0.61 mmol, 1.5 equiv) and NBS (108.5 mg, 0.61 mmol, 1.5 equiv), CH2Cl2 (2 ml) was added and the reaction was stirred at 0 °C for 15 min. The reaction was brought to room temperature and N,O-dimethylhydroxylamine hydrochloride (59.5 mg, 0.61 mmol, 1.5 equiv) and Et3N (45.5 mg, 63 µl, 0.45 mmol, 1.1 equiv) were added and reaction was stirred for 1 h at room temperature. The reaction mixture was quenched with aqueous sodium bicarbonate solution and diluted with CH2Cl2. The bicarbonate washings were again extracted with CH2Cl2 and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Column chromatography was performed using EtOAc/Petroleum ether (1:5). |
78% | With triethylamine; 1,1′-carbonyldiimidazole In tetrahydrofuran; lithium hydroxide monohydrate at 0 - 10℃; for 5h; | 4 N-Methoxy-N-methyl-2-(o-tolyl)acetamide (34) To a solution of NHMe(OMe)HCl (203 g, 2.1 mol) in THF (1 L), H2O (400 mL) and TEA (263 g, 2.2 mol) was added 33 (200 g, 1.3 mol) and CDI (243 g,1.5 mol) at 0-10 °C. The reaction mixture was stirred at 0-10 °C for 5 h. After HPLC showed that the reaction was complete, the mixture was filtered through celite and the filtrate was partitioned with water and EtOAc. The organic solution was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (5-10% EtOAc/PE) to give 34 (200 g, 78% yield). ‘H NMR (CDC13, 400 MHz): ö 7.17-7.13 (m, 4 H), 3.75 (m, 2 H), 3.66 (d, 3 H), 3.11 (s, 3H), 2.20 (s, 3 H), 1.63-1.55 (m, 1 H); MS (ESI) mle [M+H]: 194.1. |
78% | With triethylamine; 1,1′-carbonyldiimidazole In tetrahydrofuran; lithium hydroxide monohydrate at 0 - 10℃; for 5h; | 4 N-Methoxy-N-methyl-2-(o-tolyl)acetamide (34) To a solution of NHMe(OMe).HCl (203 g, 2.1 mol) in THF (1 L), H2O (400 mL) and TEA (263 g, 2.2 mol) was added 33 (200 g, 1.3 mol) and CDI (243 g, 1.5 mol) at 0-10° C. The reaction mixture was stirred at 0-10° C. for 5 h. After HPLC showed that the reaction was complete, the mixture was filtered through celite and the filtrate was partitioned with water and EtOAc. The organic solution was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (5-10% EtOAc/PE) to give 34 (200 g, 78% yield). 1H NMR (CDCl3, 400 MHz): δ 7.17-7.13 (m, 4H), 3.75 (m, 2H), 3.66 (d, 3H), 3.11 (s, 3H), 2.20 (s, 3H), 1.63-1.55 (m, 1H); MS (ESI) m/e [M+H]+: 194.1. |
With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 1h; Inert atmosphere; | ||
With 4‐dimethylaminopyridine; triethylamine In dichloromethane; 1,2-dichloro-ethane at 20℃; for 2h; Inert atmosphere; | ||
With 4‐dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With hexachloroethane; triethylamine; triphenylphosphine In dichloromethane; acetonitrile at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With [bis(acetoxy)iodo]benzene; iodine; palladium diacetate In N,N-dimethyl-formamide at 60℃; for 12h; Darkness; | |
With [bis(acetoxy)iodo]benzene; iodine; palladium diacetate In N,N-dimethyl-formamide at 60℃; for 15h; Darkness; | ||
With [bis(acetoxy)iodo]benzene; iodine; palladium diacetate In N,N-dimethyl-formamide at 60℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: o-methylphenylacetic acid With 1,2-diphenyl-1,2-disodiumethane In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; Stage #2: 2-iodo-propane In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Stage #3: With hydrogenchloride In water regioselective reaction; | 4.4. Metalation of arylacetic acids 2, and reaction with electrophiles. General procedure General procedure: To 5 mL of a 0.24 M solution of diorganometal 1b or 1c (1.2 mmol), chilled at 0 °C, was added a solution of the appropriate arylacetic acid 2 (1.1 mmol) dissolved in 5 mL of dry THF, and the resulting mixture was vigorously stirred for 2 h at 0 °C. To the resulting dark brown mixture, chilled at the same temperature, were added 1.7 mmol of the appropriate electrophile. The resulting mixture was vigorously stirred and allowed to reach rt overnight, after which time it was quenched by slow dropwise addition of H2O (15 mL). The organic solvent was evaporated in vacuo and the resulting mixture was extracted with CH2Cl2 (3×10 mL). The aqueous phase was acidified with 1 N HCl, extracted with CH2Cl2 (3×10 mL), and the organic phases were collected, washed with H2O (1×10 mL), brine (10 mL), dried (Na2SO4), and the solvent was evaporated. Crude reaction products were purified and characterized as reported below. The reaction mixture containing crude β-hydroxyacid 2df was quenched by adding it to 15 mL of 10% HCl containing about 15 g of crushed ice,14 and worked up as described above. After evaporation of the solvent, the resulting crude material was purified and characterized as reported below. Quenching with D2O was realized as described in the above paragraph. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | Stage #1: o-methylphenylacetic acid With oxalyl dichloride In dichloromethane at 0℃; for 0.5h; Stage #2: 1-bromo-4-methoxy-benzene In dichloromethane at 0℃; | 11 Intermediate 11 1-(5-bromo-2-hydroxyphenyl)-2-o-tolylethanone 2-Methylphenylacetic acid (9.60 g, 64.15 mmoles) was dissolved in 10 ml dichloromethane. To this mixture, oxalylchloride (7 ml, 80.19 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 100 ml dichloromethane. To this mixture, 4-bromoanisole (10 g, 53.47 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (10.6 g, 80.19 mmoles) was added and the reaction mixture was warmed to RT and stirred for 24 h. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as white solid (5.5 g, 33% yield. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 11.52 (s, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.65 (dd, J=8.8, 2.5 Hz, 1H), 7.16 (m, 4H), 6.97 (d, J=8.9 Hz, 1H), 4.47 (s, 2H), 2.14 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 28℃; | A155 Example A155. N-(6-methyl-3-(3-sulfamoylphenyl)- l-(tetrahvdro-2H-pyran-2-yl)-lH-indazol-5-yl)-2-o-tolylacetamideTo a solution of 3-(5-amino-6-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3- yl)benzenesulfonamide (50 mg, 0.13mmol) and 2-(2-methylphenyl)acetic acid (29 mg, 0.20mmol) in DMF (5 mL) was added HATU (73 mg, 0.26mmol) and DIEA(34 mg,0.26mmol). The mixture was stirred at 28°C overnight, poured into water, and extracted with CH2CI2. The organic layer was washed with brine twice, dried over Na2S04> concentrated. The residue was purified by preparation TLC (Si02, CH2Cl2/MeOH 20: 1) to give the title compound-201- 820v.1 N-(6-methyl-3-(3-sulfamoylphenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-5-yl)-2-o- tolylacetamide as yellow solid (27 mg, 37%). The material was taken in 3 M HCl/dioxane and stirred overnight. After concentratinon under reduced pressure, the residue was treated with Na2C03 in MeOH, filtered and the filtrate purified by preparative TLC (Si02, CH2Cl2/MeOH 20: 1) to give the title compound as yellow solid (17 mg, 75%). NMR (300MHz/ CD3OD): NMR (300 MHz, METHANOL-^) δ ppm 8.45 (s, 1 H), 8.14 (d, 7=7.80 Hz, 1 H), 8.01 (s, 1 H), 7.92 (d, 7=7.80 Hz, 1 H), 7.67 (t, 7=7.80 Hz, 1 H), 7.44 (s, 1 H), 7.31 - 7.36 (m, 1 H), 7.15 - 7.23 (m, 3 H), 3.83 (s, 2 H), 2.42 (s, 3 H), 2.30 - 2.35 (s, 3 H). MS ESI 435.1 [M + H]+, calcd for [C23H22N403S+H]+ 435.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With trimethylsilyl bromide; 1,1,3,3-Tetramethyldisiloxane; indium tribromide In chloroform at 60℃; for 1h; Sealed tube; Inert atmosphere; | |
With indium(III) bromide; 1,1,3,3-Tetramethyldisiloxane; trimethylsilyl cyanide In chloroform at 60℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With water; sodium hydroxide In 1,4-dioxane at 60℃; for 2h; | 8 Preparation of o-Methylphenylacetic Acid from o-Xylene and Ethanol o-Xylene (1.59 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 81 mg ethyl o-methylphenylacetate was obtained by column chromatography, in a yield of 91%. 1HNMR (400 MHz, CDCl3) δ 1.23 (t, J=7.2 Hz, 3H), 2.32 (s, 3H), 3.63 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 7.15-7.21 (m, 4H); 13CNMR (100 MHz, CDCl3) δ 14.2, 19.6, 39.3, 60.8, 126.1, 127.3, 130.1, 130.3, 132.9, 136.8, 171.5; HRMS (ESI) calcd. for C11H14NaO2 [M+Na]: 201.0886. found: 201.0882. The ethyl o-methylphenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 66 mg product o-methylphenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 97%. |
0.33 g | With potassium hydroxide In ethanol at 20℃; for 15h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: o-methylphenylacetic acid With 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1h; Stage #2: 5-amino-3-(4-fluoro-3-methyl)-4-(4-pyrimidinyl)isoxazole With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 11h; | 1 Typical procedure for the preparation of 3-aryl-4-(4-pyrimidinyl)-5-substituted phenylacetylaminoisoxazole 26. General procedure: To a solution of 20-fluorophenylaceticacid (0.12 g, 0.78 mmol) in THF (5 mL) was added1,10-carbonyldiimidazole (CDI) (0.126 g, 0.78 mmol) and the mixturewas stirred at room temperature for 1 h. Then a solution ofDBU (0.237 g, 1.56 mmol) and 5-amino-3-(4-fluorophenyl)-4-(4-pyrimidinyl)isoxazole (25a) (0.100 g, 0.39 mmol) in THF (5 mL)was added to the mixture and stirred at room temperature for11 h. After the reaction solvent was evaporated in vacuo, waterwas added to the residue and extracted with ethyl acetate. Theorganic extracts was dried over MgSO4 and evaporated. The resultingresidue was purified by column chromatography (eluent: chloroform/methanol = 100:1) and washed with n-hexane/diethylether to afford the title compound 26b (0.090 g, 59%). Mp:160.0-163.0 C; 1H NMR (CDCl3) d: 11.57 (s, 1H), 8.62 (s, 1H), 8.39 (d,J = 5.7 Hz, 1H), 7.50-7.40 (m, 4H), 7.30-7.17 (m, 4H), 6.76 (dd,J = 1.6, 5.7 Hz, 1H), 3.97 (s, 2H); MS (EI): m/z 392 (M+); HRMS(ESI) calcd for C21H15F2N4O2 [M+H]+ 393.1163, found 393.1172. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; | 4.2.1.1 Method A (amide coupling) General procedure: A DMF solution of 3-(5-amino-1H-indazol-3-yl)benzenesulfonamide 2,2,2-trifluoroacetate (1.0equiv), DIPEA (N,N-diisopropylethylamine, 3equiv) and RCO2H (1.05equiv) at 0°C was treated with TBTU (O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate) (1.05equiv) added in one portion. The reaction was stirred allowing slowly to warm to rt. After several hours or overnight stirring the crude reaction was purified directly by preparative HPLC. Alternatively, a DMF solution of 3-(3-sulfamoylphenyl)-1H-indazole-5-carboxylic acid (1.0equiv), DIPEA (3equiv) and RR′NH (1.05equiv) at 0°C or rt was treated with TBTU (1.05equiv) added in one portion. The reaction was stirred allowing slowly to warm to rt. After several hours or overnight stirring the crude reaction was purified directly by prepHPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: o-methylphenylacetic acid With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.5h; Stage #2: 1,2-benzisothiazolin-3-one With 4-methyl-morpholine In dichloromethane at 0 - 20℃; | 2 4.2. General procedure for the preparation of N-acyl substituted 1,2-benzisothiazol-3-one derivatives 5-40 General procedure: The acid 4 (5 mmol), EDC (1.2 g, 6.26 mmol), HOBt (0.9 g,5.88 mmol), NMM (1.2 mL, 10.74 mmol), and dichloromethane (10 mL) were mixed at ice-bath and stirred at 0 °C for half an hour. 1,2-Benzisothiazol-3-one 1 (800 mg, 5.3 mmol) was added to NMM (1.6 mL, 14.32 mmol) in 10 mL of dichloromethane at 0 °Ct hen the above mixture was added and stirred at room temperature overnight. After stirring overnight, the mixture was diluted with CH2Cl2, and then successively through washed with water, 5% KHSO4 solution, saturated NaHCO3 solution, and brine, the extract was dried with anhydrous Na2SO4 and evaporated under vacuum. The product was isolated by column chromatography (petroleum ether/CH2Cl2, 10:1) to yield the final compound. 4.2.2 2-(2-(o-Tolyl)acetyl)benzo[d]isothiazol-3(2H)-one (6) Compound 6 was prepared through o-tolyacetic acid, obtained a white solid in 83% yield. Mp 150.5-152.0 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 8.0 Hz, 2H), 7.81 (t, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.22-7.13 (m, 4H), 4.49 (s, 2H), 2.22 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 171.3, 163.7, 141.4, 137.5, 135.1, 133.2, 130.7, 130.4, 127.6, 127.5, 126.7, 126.3, 125.7, 122.6, 41.5, 19.6. IR (KBr, cm-1): 1701. HRMS-ESI (m/z) calcd for C16H13NO2S [M+H+] 284.0745, found 284.0746. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: o-methylphenylacetic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 3h; Stage #2: 6-bromo-imidazo[1,2-a]pyrazin-3-ylamine In tetrahydrofuran; pyridine at 50℃; for 0.5h; | 17-5 Example 17-5 Synthesis of intermediate (15*) by amide coupling with carboxyl chloride(14*): typical example;N-(6-bromo-imidazo[1,2-a]pyrazin-3-yl)-2-methyl-benzamide. [0186] To a solution of o-tolylacetic acid (18.02 g, 120 mmol) in CH2Cl2 (200 ml) was added oxalyl chloride (32 ml,360 mmol) followed by DMF (3 drops). The reaction was stirred at room temperature for 3 hours then concentrated invacuo. The residue was dissolved in THF (50 ml) then added to a suspension of 6-bromo-imidazo[1,2-a]pyrazin-3-ylmine13* in THF (150 ml) and pyridine (9.7 ml, 120 mmol). The mixture was heated at 50 °C for 30 minutes. After this timethe reaction was concentrated in vacuo and a mixture of ethyl acetate (250 ml) and a saturated solution of NaHCO3(250 ml) was added. The resultant brown solid was collected by filtration to give the desired compound 15*a (16.4 g,79%). 1H-NMR (250 MHz, DMSO): δ = 2.3 (3H, s), 3.86 (2H, s), 7.12-7.16 (3H, m), 7.27-7.30 (1 H, m), 7.87 (1 H, s),8.76 (1 H, d, J 1.2 Hz), 8.87 (1 H, d, J 1.2 Hz); m/z (APCI) 345 (M+); HPLC 100%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With palladium diacetate; silver trifluoroacetate In water at 80℃; for 4h; Microwave irradiation; Micellar solution; Green chemistry; | 2.2. Generalprocedure for the C-H activations of acids and 1-chloro-4-iodobenzene General procedure: Toa 5 mL microwave reactor were added 2-naphthoic acid (100 mg), substitutediodobenzene (2 equiv.), silver trifluoroacetate (1.3 equiv.), diacetoxypalladium (0.05equiv.),and tween 20/H2O (3 mL, 2% w/w) sequentially and the reactor was sealedwith a septum. The resulting mixture was stirred at 80 °C for 4 h or 24 hdepending on substrates. Then it was cooled to room temperature and ethanol (10mL) was added. The resulting mixture was filtrated through a pad of silica gel.The filtrate was concentrated and the residue was purified by flash columnchromatography to afford the desired product . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With copper(I) oxide; 1,10-Phenanthroline; di-tert-butyl peroxide; Trimethylacetic acid at 130℃; for 24h; Schlenk technique; | Typical Procedure for the Synthesis of N,N-Dimethyl-Substituted α-Ketoamides (3a) and N,N-Diethyl-Substituted α-Ketoamide (5a) General procedure: Cu2O (0.05mmol), PivOH (1.0mmol), 1,10-phenanthroling (0.1mmol), DTBP (1.5 mmol), phenylacetic acid (0.5mmol), and DMF (1mL) or DME (1mL) were added into a Schlenk tube (25mL) equipped with a magnetic stirrer bar. The Schlenk tube was then closed, and the resulting mixture was stirred at 130°C for 24 h. After cooling down to room temperature, the mixture was filtered with celite, and the filtrate was washed with water and dried over Na2SO4. The residue was directly purified by silica-gel column chromatography with petroleum ether/EtOAc (10:1 to 4:1) to give α-ketoamides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With ammonium acetate; oxygen; copper diacetate In 1-methyl-pyrrolidin-2-one at 120℃; for 20h; | 10 Example 10 Adding reaction bottle 1a (2mmol, 394 mg), 2j (4mmol, 600 mg), ammonium acetate (4mmol, 308 mg), copper acetate (20mol %, 80 mg) and NMP (10 ml). Oxygen is then used to replace the three times in the oxygen atmosphere of the reaction system, the 120 °C heating reaction 20 hours. After the reaction is finished first quenching with saturated sodium carbonate solution, then using ethyl acetate extraction, anhydrous sodium sulfate for drying, after decompression turns on lathe does solvent, petroleum ether and ethyl acetate mixed solvent for carrying out simple column chromatography to get product 3aj, the yield is 84%.White solid |
74% | With ammonium acetate; oxygen; copper diacetate In 1-methyl-pyrrolidin-2-one at 120℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 87% 2: 9% | With indium(III) bromide; Hexamethyldisiloxane; copper dichloride In 1,2-dichloro-ethane at 60℃; Sealed tube; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; trichlorophosphate In diethyl ether at 0 - 20℃; for 6.16667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Inert atmosphere; | General procedure: An oven-dried 50 mL round-bottom flask containing a magnetic stirrer bar was sealed with a septum, charged with Ar and tared on a balance. KH (~0.5 g, 30% mineral oil dispersion) was then added to the flask and the mineral oil removed by trituration under Ar with pet. spirit (2 x 30 mL) using a syringe. The flask containing dry KH was purged with Ar and reweighed to obtain an accurate mass of KH. Dry THF (10 mL) was added to the flask containing KH (0.15 g, 3.7 mmol, under Ar) and the mixture cooled to 0 oC. 3,5-Dimethyl-1H-pyrrole-2-carbaldehyde 5 (0.23 g, 1.9 mmol) was dissolved in dry THF (5 mL) under Ar and added dropwise to the stirring KH solution (Caution - flask requires outlet needle to release evolving H2 gas). After complete addition the mixture was stirred for a further 5 minutes at 0 oC. The phenylacetic acid derivative (1.9 mmoles) was added to a separate dry 50 mL round-bottom flask under Ar along with HBTU (0.71 g, 1.9 mmoles) and dry CH2Cl2 (10 mL). DIPEA (0.65 mL, 3.7 mmoles) was added dropwise to the stirring solution and upon complete addition the mixture was stirred for a further 5 minutes or until the HBTU was completely dissolved. The HBTU solution was then cooled to 0 oC and added in a single portion to the K+ pyrrolate salt solution at 0 oC and the combined mixture allowed to warm slowly to room temperature. A dark red colour observed in each reaction indicated formation of the desired 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one. The reaction was quenched after ~ 2 h with ice-cold water (100 mL) and extracted with Et2O (2 x 50 mL). The combined organic phase was washed with 1 M HCl (2 x 50 mL), saturated NaHCO3 (2 x 50 mL) and brine (2 x 50 mL), dried over anhydrous MgSO4 and concentrated. The crude residue was purified by silica gel column chromatography using a gradient from 100% pet. spirit to 1:9 acetone:pet. spirit to afford the 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one as a deep red solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 16 (2-Methylphenyl)acetic acid (53.1 mg, 354 μιτιοΙ) was provided in DMF (1.5 mL). N,N- diisopropylethylamine (250 μ, 1.4 mmol), the compound of intermediate 4 (100 mg, 424 μιτιοΙ) and propane phosphonic acid anhydride (T3P, 250 μ, 50% in DMF, 420 μιτιοΙ) were added, and the mixture was stirred at room temperature for 2 h. After filtration, purification by HPLC (method 1) yielded 70.0 mg (58% of theory) of the title compound. (0525) LC-MS (method 2): Rt = 1.03 min; MS (ESIpos): m/z = 332 [M+H]+ (0526) XH-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.083 (8.03), 2.302 (16.00), 2.523 (0.80), 3.386 (0.73), 3.696 (8.20), 7.145 (1.78), 7.151 (1.50), 7.156 (1.93), 7.162 (2.77), 7.168 (6.56), 7.176 (4.54), 7.179 (4.00), 7.183 (3.68), 7.191 (3.70), 7.201 (0.90), 7.240 (1.42), 7.251 (1.47), 7.256 (0.63), 7.262 (0.97), 7.943 (5.19), 8.646 (5.00), 10.523 (3.19), 13.046 (0.78). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With pyridine; 1,3,5-trichloro-2,4,6-triazine In acetonitrile at 140℃; for 0.0833333h; Microwave irradiation; | General Experimental Procedure for Microwave-Assisted TCT-Acylation General procedure: To a stirred mixture of a corresponding acid (0.819 mmol, 1equiv), cyanuric chloride (90.5 mg, 0.491 mmol, 0.6 equiv), dry pyridine (99.1 mg, 1.23 mmol, 1.5 equiv), and dry MeCN (4.5mL) in a 5 mL Pyrex microwave vial, equipped with a magnetic stir bar, the corresponding amine (0.983 mmol, 1.2 equiv) was added after initial stirring at r.t. for 5 min. The reaction mixture was then crimped with a Teflon septum, stirred for 10 s, and subjected to microwave heating for 5 min (fixed hold time) at 140 °C and subsequently cooled down to 40 °C. The resulting reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (with CHCl3or a gradient of 0-10% MeOH in CHCl3) to afford amides 1a-g. For pharmacological experiments, analytical-grade samples of compounds 1a-g were additionally purified by the means of a semipreparative HPLC (see the provided Supporting Information). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With palladium 10% on activated carbon; W(OTf)6; hydrogen; acetic acid; at 50℃; under 760.051 Torr; for 12h; | General procedure: Specific methods are as follows: propiolactone was added (0.36g, 5mmol), palladium on carbon (10%, 26.5mg, 0.025mmol, 0.5mol%) in the reactor and W (OTf)6(107.8mg, 0.1mmol, 2mol%). A hydrogen balloon connected to the top of the reactor, and the reactor was purged with hydrogen gas atmosphere. Hydrogen atmosphere at normal pressure, the reaction was stirred at 135 deg.] C after 12h, detected by gas, gamma- valerolactone complete conversion of starting material, and only n-valeric acid. The method carried out as follows completion of the hydrogenation reaction of the ring-opening reaction system separation, to obtain the desired product n-valeric acid: The reaction was completed reaction mixture was dissolved with methylene chloride, filtered to remove the palladium on carbon catalyst and W (OTf)699% yield measured propionic acid, purity of the product was 99%. NMR data for the product using the embodiment of the present invention is the NMR identified the product as follows:The specific reaction procedure and operation method were the same as in Example 27 except that the substrate used was 2 mmol and lmL of acetic acid was added as a solvent at a reaction temperature of 50 C, a yield of 98% and a purity of 99%. The product was subjected to nuclear magnetic identification using the manner described in the present invention, and the NMR data of the product were as follows |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: o-methylphenylacetic acid With potassium carbonate In acetone Stage #2: 2-(3-bromopropyl)isoindole-1,3-dione In acetone at 20℃; for 3h; UV-irradiation; Inert atmosphere; Schlenk technique; | Photodecarboxylative addition General procedure: A mixture of 15 mmoles of phenylacetic acid derivative, 7.5 mmoles of K2CO3 in 5 mL of acetone and 15 mL of buffer (pH 7) was added to 5 mmoles of N-(bromoalkyl)phthalimide in 10 mL of acetone in a Pyrex Schlenk flask, followed by 70 mL of a 1:1 mixture of acetone:pH 7 buffer. The mixture was sonicated for 10 min and irradiated in a Rayonet chamber reactor while a continuous slow stream of N2 is passed through the reaction mixture. The progress of the reaction was monitored by TLC or by passing the leaving gas stream through a saturated Ba(OH)2 solution. When all phthalimide was consumed or when precipitation of BaCO2 had ceased, the reaction was stopped. In cases where the product had precipitated during irradiation, the product was isolated by filtration, washed with water and n-hexane and dried. In all other case, most of the acetone was removed via rotary evaporation at low temperatures (water bath <35 °C). In cases where the product precipitated on standing it was isolated by filtration and treated as described above. In all other cases, the reaction mixture was extracted with CH2Cl2 (3 × 40 mL) and washed with saturated NaHCO3 (2 × 40 mL) and brine (1 × 40 mL). After drying over MgSO4, the reaction mixture was evaporated to dryness on a rotary evaporator at low temperatures (<35 °C). When necessary, the crude products were purified by column chromatography using mixtures of ethyl acetate and cyclohexane or ethyl acetate and n-hexane, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: o-methylphenylacetic acid With potassium carbonate In acetone Stage #2: 2-(2-bromoethyl)isoindoline-1,3-dione In acetone at 20℃; for 3h; UV-irradiation; Inert atmosphere; Schlenk technique; | Photodecarboxylative addition General procedure: A mixture of 15 mmoles of phenylacetic acid derivative, 7.5 mmoles of K2CO3 in 5 mL of acetone and 15 mL of buffer (pH 7) was added to 5 mmoles of N-(bromoalkyl)phthalimide in 10 mL of acetone in a Pyrex Schlenk flask, followed by 70 mL of a 1:1 mixture of acetone:pH 7 buffer. The mixture was sonicated for 10 min and irradiated in a Rayonet chamber reactor while a continuous slow stream of N2 is passed through the reaction mixture. The progress of the reaction was monitored by TLC or by passing the leaving gas stream through a saturated Ba(OH)2 solution. When all phthalimide was consumed or when precipitation of BaCO2 had ceased, the reaction was stopped. In cases where the product had precipitated during irradiation, the product was isolated by filtration, washed with water and n-hexane and dried. In all other case, most of the acetone was removed via rotary evaporation at low temperatures (water bath <35 °C). In cases where the product precipitated on standing it was isolated by filtration and treated as described above. In all other cases, the reaction mixture was extracted with CH2Cl2 (3 × 40 mL) and washed with saturated NaHCO3 (2 × 40 mL) and brine (1 × 40 mL). After drying over MgSO4, the reaction mixture was evaporated to dryness on a rotary evaporator at low temperatures (<35 °C). When necessary, the crude products were purified by column chromatography using mixtures of ethyl acetate and cyclohexane or ethyl acetate and n-hexane, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With copper(II) acetate monohydrate; sulfur; sodium hydroxide In dimethyl sulfoxide at 130℃; for 24h; Sealed tube; Inert atmosphere; | 2. General procedure for the synthesis of 2-substituted benzothiazoles General procedure: A mixture of o-iodoaniline (0.5 mmol, 1 equiv), arylacetic acid (0.6 mmol), elemental sulfur (1.5mmol), Cu(OAc)2·H2O (20 mmol%), and NaOH (1.0 mmol) in DMSO (3 mL) was put into a sealed pressure vessel (25 mL) containing a magnetic stirring bar. The tube was purged with nitrogen three times, and then capped and stirred in a preheated oil bath at 130 °C for 24 h. The reaction mixture then cooled to room temperature and extracted with ethyl acetate (3x10 mL), the organic layer was washed with saturated NaCl (2x10 mL), dried over anhydrous Na2SO4, evaporated under vacumm and then purified by silica gel column chromatography by using petroleum ether and ethyl acetate (PE:EA=200:1) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sulfur trioxide pyridine complex at 160℃; Schlenk technique; Inert atmosphere; | General procedure for SO3-medaiated amidation reaction and characterizationdata of the amides General procedure: A typical procedure for the reaction of 4-trifluoromethylbenzoic acid 1a is described.A magnetic stirrer bar was placed in a Schlenk tube. This tube was then dried with aheat gun under reduced pressure and the test-tube was filled with nitrogen. 1a (19.0 mg,0.100 mmol) and SO3. py (63.7 mg, 0.400 mmol) were added to the test tubesuccessively under nitrogen atmosphere at room temperature. DMF (0.5 mL) orDMF(0.2 mL) - 1,2-dichlorobenzene(0.3 mL), were added to the tube. After beingstirred for 2 h at 160 °C, the mixture was filtered through a short silica gel pad (ca. 3.5cm × 0.5 cm, eluent AcOEt (60 mL)). The filtrate was concentrated under reducedpressure, and the residue was further dried in vacuo (ca. 7-8 mmHg at 70-80 °C) toremove DMF (and 1,2-dichlorobenzene). The residue was purified by preparative thinlayer chromatography on silica gel (AcOEt / hexane = 1 / 2) to give 20.8 mg (0.0959mmol, 96%) of 2a as colorless oil) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With selenium tetrachloride at 35℃; for 3h; Reflux; | 3 Example 3 In a reaction vessel with agitation and reflux,Add 5mol mass fraction of 85% 2-methyl-phenylacetic acid solution,6.5 mol of selenium chloride, after the addition, reacted at a temperature of 35 ° C for 110 min. Reflux for 70 min, 70 kPa vacuum distillation, The fraction at 45 ° C was collected, washed with a mass fraction of 75% dimethylamine solution, washed with a mass fraction of 95% dichloromethane solution, and dehydrated with anhydrous sodium sulfate dehydrating agent to obtain 362.7 g of finished acetyl chloride, yield 93% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With selenium; potassium hydroxide; copper(I) bromide In dimethyl sulfoxide at 120℃; for 18h; Inert atmosphere; Schlenk technique; | General procedure for the synthesis of benzoselenazoles: General procedure: A 25mL oven-dried Schlenk tube were added 2-iodoaniline 1a (110mg, 0.5mmol), phenylacetic acid 2a (81.7mg, 0.6mmol) or benzyl chloride 4a (75.9mg, 0.6mmol), selenium powder (118mg, 1.5mmol), CuBr (7.17mg, 10mmol%), KOH (56.1mg, 1.0mmol) or Cs2CO3 (326mg, 1.0mmol), DMSO (1.5mL). The tube was purged with nitrogen three times. Then the reaction mixture was stirred in a preheated oil bath at 120°C for 18h. After the reaction was completed, the mixture was diluted with a saturated solution of Na2CO3 (15mL) and extracted with ethyl acetate (3×10mL). The organic layer was dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1) to give pure product 3aa. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With cobalt(II) pyridine-2-carboxylate; palladium diacetate; sodium hydroxide In methanol at 150℃; for 6h; Autoclave; | 30 312 ml of methanol, 0.55 g of cobalt pyridine-2-carboxylate,1.37 g of palladium acetate was added to the autoclave reactor.Stir the catalyst for 5 minutes, and replace the air in the kettle 3 times with CO.Warm up to 150 ° C, flush into CO until the pressure rises to 1.5 MPa. Within 1 hour,At the same time, 74.0 g (0.4 mol) of o-methylbenzyl bromide and 30% NaOH 160 g (1.2 mol) were added dropwise to the reaction vessel.After reacting for 5 hours, the temperature was lowered to room temperature, methanol was removed by distillation under reduced pressure, and the catalyst was filtered off.Add 30% hydrochloric acid to adjust the pH to 1, filter,Dry to obtain o-methylphenylacetic acid, the purity is:99.12%, the yield was 89%. |
65% | With palladium hydroxide, 20 wt% on carbon; tetrabutylammomium bromide; water In tetrahydrofuran at 110℃; for 4h; Sealed tube; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h; | 1-9 Example 1 Take a 100 mL round bottom flask, DCC (1.0320 g, 5 mmol), DMAP (0.1527 g, 1.25 mmol) and4-Methylphenylacetic acid (0.3754 g, 2.5 mmol) was added to 10 mL of dry dichloromethane and stirred at 20 ° C until all dissolved.2-Methylphenylacetic acid (0.3754 g, 2.5 mmol) was dissolved in 20 mL of dry dichloromethane, and then slowly added dropwise to the above solution using a constant pressure dropping funnel.After stirring for 24 h, it was spin-dried and then separated by column chromatography. The eluent was petroleum ether to give the title compound. Characterized as follows:1,3-bis(2,4-methylphenyl)acetone: yield: 65%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: o-Tolylacetic acid (0.59 g; 1.0 equiv; 3.77 mmol) and47.0 mg 4-DMAP (10 mol %; 0.38 mmol) were added to a100-mL round flask containing 1 g compound c (3.77 mmol) and stirred in an ice bath for 5 min after the addition of 20 mL methylene chloride. Afterward, 0.80 g DCC (1.0 equiv; 3.77 mmol) was added into the mixture and allowed to react for 3 h at room temperature, until the starting materials (TLC analysis) began to disappear. The resulting DHU was filtered under reduced pressure. The filtrate was extracted using 0.5 M HCl and a saturated solution of NaHCO3 in order. The solvent was removed under reduced pressure after dehydration using anhydrousMgSO4. The purified solid was obtained by recrystallization from ethanol as a light yellow solid. Synthesis of compounds 39-57 is shown in Scheme 1. 4-((2,4-Dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenyl2-(o-tolyl)acetate (39)Compound 39 was obtained by recrystallization fromethanol as a light yellow solid. 1H NMR (DMSO-d6,300 MHz) delta 12.63 (s, 1H), d 7.78 (s, 1H), d 7.33 (m, 2H), d7.24 (s, 1H), d 7.22 (m, 4H), d 4.08 (q, J = 6.96 Hz, 2H), d3.97 (s, 2H), d 2.33 (s, 3H), d 1.27 (t, J = 6.96 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With trans-bis(acetonitrile)palladium(II) chloride; silver(I) acetate In 1,2-dichloro-ethane at 40℃; for 8h; | 16 Example 16 A method for preparing an aromatic vinyl silane compound includes the following steps: To a 25 mL reaction tube were added 0.0751 g of 2-methylphenylacetic acid, 0.22 mL of trimethylvinylsilane, 0.0130 g of bis(acetonitrile)palladium dichloride, and 0.2504 g of silver acetate, and then 5 mL of dichloroethane. The reaction tube was moved to an oil bath at 40 °C for 8 h. After flash column chromatography, the product was concentrated under reduced pressure with a yield of 51%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | 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 3h; | 2 Synthesis of N-(2-oxo-3-(phenyl((4-(piperidin-1-ylmethyl)phenyl)amino)methylene)indolin-5-yl)-2-methylphenylacetamide Add N,N-dimethylformamide (2mL) to the reaction flask,1-Acetyl-5-amino-3-(phenyl((4-(piperidin-1-ylmethyl)phenyl)amino)methylene)indolin-2-one(47mg, 0.10mmol), 2-methylphenylacetic acid(15mg, 0.10mmol)And N,N-diisopropylethylamine(40mg, 0.30mmol),HATU (57mg, 0.15mmol). Stir at room temperature for 3 hours,Concentrate under reduced pressure to obtain a solid, which is purified by column chromatography to obtainN-(2-oxo-3-(phenyl((4-(piperidin-1-ylmethyl)phenyl)amino)methylene)indoline-5-yl)-2-methyl Phenylacetamide(26.8 mg, yield 48%), as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.3% | Stage #1: o-methylphenylacetic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.5h; Stage #2: 2-ethyl-8-(hydroxymethyl)-7-methoxy-4H-chromen-4-one In dichloromethane at 20℃; | 4.9. General procedure for the synthesis of compounds 6a-w, 7a-fand 8a-e General procedure: The corresponding aromatic acids (1.2 eq) and EDCI (1.2 eq)were dissolved and stirred in CH2Cl2 (10 mL) in an ice bath for30 min, and then the corresponding alcohol 5a-c (1.0 eq)was addedto the reaction solution. The reaction mixturewas removed to roomtemperature and monitored by TLC. After reaction completion,15 mL of water were added to the mixture solution. The organiclayers were washed with saturated sodium chloride solution(2 15 mL) and dried over anhydrous sodium sulfate. Then, thesolvent was removed under reduced pressure, and the residue waspurified by column chromatography to yield 6a-w, 7a-f and 8a-e. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1,4-diaza-bicyclo[2.2.2]octane; sulfur; urea In dimethyl sulfoxide at 140℃; for 2h; | 2.1. General procedure General procedure: To a 4-mL screw-cap vial was added 2-nitrobenzyl alcohol (15.3 mg, 0.1 mmol), phenylacetic acid (34.0 mg, 0.25 mmol), base, elemental sulfur, urea, and DMSO (0.3 mL).The reaction tube was tightly capped and the resulting mixture was then stirred at a given temperature. After completion of the reaction, the mixture was cooled to room temperature and diphenyl ether (17.2 mg, 0.1 mmol) as an internal standard was added. The organic components were then extracted into ethyl acetate (3×2 mL), washed with NaHCO3 solution (10% in water, 3×1 mL), dried over anhydrous Na2SO4, filtered, and analyzed by GC with reference to diphenyl ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85 %Chromat. | With 1,10-Phenanthroline; oxygen; copper(II) oxide; potassium ferrocyanide In dimethyl sulfoxide at 120℃; for 40h; Autoclave; | 2.2. General procedure for the conversion of arylacetic acids to aromatic nitriles General procedure: The reaction was carried out in a 40 mL stainless steel autoclave lined with Teflon. Typically, 0.5 mmol substrate, 0.6 mmol K4Fe(CN)6, 0.1mmol CuO, 0.5 mmol 1,10-phenanthroline and 2 mL DMSO were added into the reactor and 1.5MPa of oxygen was filled. Then the reaction system was heated under magnetic stirring at 120°C for 40h. Once the reaction time was reached, the mixture was cooled to room temperature. GC analysis of the reaction mixture provided the GC yields of the products. In addition, the crude product from another parallel experiment was purified by column chromatography, and identified by 1H NMR and 13C NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; | 4.1.1 General procedure for the synthesis of 10-65 (Method A) General procedure: The mixture of 4-substituted o-aminophenol (1 equiv) and m-aminobenzoic acid (1 equiv) was stirred in polyphosphoric acid at 185°C for 6h. The mixture was neutralized with 6N NaOH solution until the pH was 10-13, and then the mixture was filtered, the upper solid was retained and dried in an oven. Then it was dissolved in ethyl acetate, the insolubles was filtered off, and the filtrate was evaporated under reduced pressure. The intermediate compounds 9a-9c were obtained by silica gel column chromatography (petroleum ether/ethyl acetate=4:1). Then react it with substituted acetic acid at a ratio of 1:1, EDCI/HOBt/DIPEA=1.5:1.5:3, to obtain the final compounds 10-65 [52-55]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; | 4.1.1 General procedure for the synthesis of 10-65 (Method A) General procedure: The mixture of 4-substituted o-aminophenol (1 equiv) and m-aminobenzoic acid (1 equiv) was stirred in polyphosphoric acid at 185°C for 6h. The mixture was neutralized with 6N NaOH solution until the pH was 10-13, and then the mixture was filtered, the upper solid was retained and dried in an oven. Then it was dissolved in ethyl acetate, the insolubles was filtered off, and the filtrate was evaporated under reduced pressure. The intermediate compounds 9a-9c were obtained by silica gel column chromatography (petroleum ether/ethyl acetate=4:1). Then react it with substituted acetic acid at a ratio of 1:1, EDCI/HOBt/DIPEA=1.5:1.5:3, to obtain the final compounds 10-65 [52-55]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; | 4.1.1 General procedure for the synthesis of 10-65 (Method A) General procedure: The mixture of 4-substituted o-aminophenol (1 equiv) and m-aminobenzoic acid (1 equiv) was stirred in polyphosphoric acid at 185°C for 6h. The mixture was neutralized with 6N NaOH solution until the pH was 10-13, and then the mixture was filtered, the upper solid was retained and dried in an oven. Then it was dissolved in ethyl acetate, the insolubles was filtered off, and the filtrate was evaporated under reduced pressure. The intermediate compounds 9a-9c were obtained by silica gel column chromatography (petroleum ether/ethyl acetate=4:1). Then react it with substituted acetic acid at a ratio of 1:1, EDCI/HOBt/DIPEA=1.5:1.5:3, to obtain the final compounds 10-65 [52-55]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With ammonium hydroxide; oxygen In neat (no solvent) at 120℃; for 6h; Sealed tube; | General Procedure for preparation of amides catalyzed by Fe3O4*SiO2-SMTU-Cu General procedure: A sealed pressure vessel was charged with phenylacetic acids (68.0 mg, 0.5 mmol), Fe3O4*SiO2-SMTU-Cu catalyst (20 mg), and aqueous ammonia solution (28 wt% in H2O; 1.5 mL). The resulting solution was stirred at 120 °C under O2 (monitored by TLC and GC) for 6 hours. Upon completion of the reaction, the catalyst was separated using magnetic stirring bar and ethyl acetate (20 mL) was added, the organic layer was washed with saturate NaHCO3 (20 mL) solution twice, brine (20 mL) once, the combined aqueous layers was extracted with EtOAc (20 mL) twice. The combine organic layers were dried over anhydrous Na2SO4. The solvents were removed via rotary evaporator and the residue was purified with flash chromatography (silica gel, ethyl acetate: petroleum ether=2:1) to give amide products. |
Tags: 644-36-0 synthesis path| 644-36-0 SDS| 644-36-0 COA| 644-36-0 purity| 644-36-0 application| 644-36-0 NMR| 644-36-0 COA| 644-36-0 structure
[ 7500-53-0 ]
2,2'-(1,2-Phenylene)diacetic acid
Similarity: 0.97
[ 30981-98-7 ]
2,3-Dimethylbenzeneacetic acid
Similarity: 0.97
[ 13612-34-5 ]
2-(2,5-Dimethylphenyl)acetic acid
Similarity: 0.97
[ 7500-53-0 ]
2,2'-(1,2-Phenylene)diacetic acid
Similarity: 0.97
[ 30981-98-7 ]
2,3-Dimethylbenzeneacetic acid
Similarity: 0.97
[ 13612-34-5 ]
2-(2,5-Dimethylphenyl)acetic acid
Similarity: 0.97
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