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CAS No. : | 3006-96-0 | MDL No. : | MFCD00017598 |
Formula : | C8H8O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WWYFPDXEIFBNKE-UHFFFAOYSA-N |
M.W : | 152.15 | Pubchem ID : | 76360 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 39.53 |
TPSA : | 57.53 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.57 cm/s |
Log Po/w (iLOGP) : | 1.27 |
Log Po/w (XLOGP3) : | 0.93 |
Log Po/w (WLOGP) : | 0.73 |
Log Po/w (MLOGP) : | 1.05 |
Log Po/w (SILICOS-IT) : | 1.06 |
Consensus Log Po/w : | 1.01 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.64 |
Solubility : | 3.48 mg/ml ; 0.0229 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.72 |
Solubility : | 2.87 mg/ml ; 0.0189 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.58 |
Solubility : | 3.97 mg/ml ; 0.0261 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
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 |
---|---|---|
With air; cobalt-salts |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With C55H44O2P4Ru; hydrogen; at 80℃; under 38002.6 Torr; for 18h;Glovebox; Autoclave; | In an argon glove box,A 5 mL vial equipped with a magnetic stir bar was charged with the desired amount of catalyst 2 (0.02 mol%),3i (5 mmol) and toluene (1.5 mL), the mixture was transferred to a non-polluting autoclave,Then use the H2 (10atm) pressure / exhaust three cycles for ventilation.It was then pressurized with H2 (50 atm) and disconnected from the H2 source, the autoclave was placed in an oil bath preheated to 80 C,After the reaction was stirred for 18h, the autoclave was cooled in an ice bath and the hydrogen was slowly released.The yield of product 4i on a silica gel column was 99% |
92% | With [Ir(2,2':6',2'?-terpyridine)(1,10-phenanthroline)Cl](PF6)2; sodium formate; In ethanol; water; at 100℃; for 0.416667h;Microwave irradiation; | General procedure: An aldehyde (1 mmol),sodium formate (4.5 eq), and catalyst (0.2 mol%) were taken in70% ethanol in water (4 mL) in a microwave vial and vortexed togenerate a homogenous solution. The mixture was heated in MWat 100 C using 150W of irradiation. Reaction progress was monitored by TLC. If complete conversion took place, the reaction colorturns to emerald green (color disappears after sometime) from paleyellow, and byproduct Na2CO3 precipitates. The Na2CO3 solid wasremoved by decanting the supernatant. The solid was washed withethyl acetate (20 mL). The combined decanted solution waswashed with water (5.0 mL), followed by brine solution (5.0 mL),dried over Na2SO4, filtered, and evaporated to dryness to affordthe desired alcohol as a pale-yellow liquid or off-white solid. |
90% | With C43H42N2O4P2Ru; hydrogen; In isopropyl alcohol; at 100℃; under 22801.5 Torr; for 24h;Glovebox; Autoclave; | In a glove box, furfural (0.48 g, 5 mmol) was placed in a 5 mL glass vial and 0.33 mL of a solution of catalyst Ru(DPPP) (S-phgly) 2 in isopropanol (1 mg/mL, 0.01 mol %) was added,The stir bar was added, the reaction bottle was placed in an autoclave, hydrogen gas was charged (10 atm×3 times), and the corresponding pressure as shown in Table 1 was charged. The autoclave was placed in an oil bath preheated to 100 C. Inside, heat and stir for 24h,The reactor was cooled to room temperature in a cold water bath, and hydrogen gas was slowly released. The yield of the reaction solution was analyzed by gas chromatography. The gas phase conditions (SPBTM-5, FUSED SILICA Capillary Column, 30m×0.25mm×0.25mum, film thickness), and the injection temperature 250 C, detection temperature 260 C, program temperature 150 C (0min) -30C/min-200 C (5 min), yield 90%. |
75% | With sodium hydroxide; sodium borohydrid; In ethanol; water; | STAGE A: 4-(HYDROXYMETHYL)BENZOIC ACID A solution of 3.68 g (92.3 mmol) of sodium borohydride, dissolved in 30 ml of water to which 5 ml of 5N NaOH have been added, is added dropwise and with stirring to a solution of 13.86 g (92.3 mmol) of 4-formylbenzoic acid in 200 ml of absolute ethanol. The reaction medium is left thus for 5 hours with stirring at room temperature. The ethanol is then removed by evaporation under vacuum and the residue is taken up with water and then acidified with 5N hydrochloric acid: the precipitate obtained is separated by filtration on a sinter. On the one hand the filtrate is extracted with ethyl ether (3*150 ml), and on the other hand the precipitate is exhaustively extracted with ethyl ether in the heated state. Evaporation of the organic phases yields 10.5 g of the expected product. Overall yield: 75% Melting point: 178 C. |
With D-glucose; D-glucose dehydrogenase; a putative aldehyde reductase (OsAR) from Oceanospirillum sp.MED92; NADPH; In aq. phosphate buffer; at 25℃; for 18h;pH 6.5;Enzymatic reaction; | General procedure: The bioreduction of 4-acetylbenzaldehyde was carried out as follows: d-Glucose (280 mg), d-glucose dehydrogenase (11 U), NADPH (10 mg), QsAR (40 U) and 4-acetylbenzaldehyde (50 mg) were mixed in sodium phosphate buffer (25 ml, 100 mM, pH 6.5). The mixture was stirred at 25 C for 18 h. The mixture was extracted with methyl tert-butyl ether. The organic extract was dried over anhydrous sodium sulfate and removal of the solvent gave product, 4-acetylbenzyl alcohol (38.2 mg, 76.4% yield). 1H NMR (CDCl3), delta: 2.58 (d, 3H), 4.76 (s, 2H,), 7.44(d, 2H, 2JH-H = 7.2 Hz,), 7.93 (d, 2H, 2JH-H = 7.2 Hz)). The bioreductions of hexanal and 2-nonanone were as follows: d-Glucose (36 mg), d-glucose dehydrogenase (2 U), NADPH (1.0 mg), QsAR (4 U), hexanal (10 mM) and 2-nonanone (10 mM) were mixed in sodium phosphate buffer (2 ml, 100 mM, pH 6.5). The mixture was stirred at 25 C for 12 h. The mixture was extracted with methyl tert-butyl ether. The products were identified by comparison with authentic samples in an Agilent 7890 gas chromatography with Gamma DEXTM 225 capillary column (30 m × 0.25 mm × 0.25 mm, SUPELCO, Japan). The column temperature was controlled as follows: 50 C for 5 min; 30 C/min to 80 C; 80 C for 5 min; 20 C/min to 100 C; 100 C for 8 min. The retention times for hexanal and hexanol were 6.99 and 8.66 min; 16.08 and 16.44 min for 2-nonanone and 2-nonanol, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 1H-imidazole; In dichloromethane; at 40℃; for 8h; | To a solution of TBDMSCl (9.29 g, 61.7 mmol) in DCM (100 ml) was added imidazole (4.20 g, 61.7) followed by 4-(hydroxymethyl)benzoic acid (5.0 g, 32.9 mmol). The reaction was heated at 40 0C for 8 h then cooled to room temperature. Excess solvent was removed and EtOAc (100 ml) was added giving a white slurry. This was filtered and the solvent concentrated. The residue was dissolved in 1 :1 THF/water (200 ml), basified by addition of K2CO3 (4.5 g, 32.5 mmol) and heated at 50 0C for 2 h. The reaction was then cooled to room temperature and acidified to pH3 with 10% aqueous citric acid and extracted with DCM (3 x 100 ml). The organic layers were combined and washed with brine (100 ml) and water (100 ml), dried (MgSO4), filtered and concentrated at reduced pressure to give the title compound (12.9 g, 79%) as colourless oil. The product was used directly in the next step without further purification.LCMS data: Calculated MH+ (266); Found 94% (MH+) m/z 266, Rt 2.38 mins. NMR data: 1H NMR (400 MHz, MeOD) delta ppm 8.08 (2 H, d, J=8.3 Hz), 7.43 (2 H, d, J=8.6 Hz), 4.82 (2 H, s), 0.94 - 0.98 (9 H, m), 0.12 - 0.13 (6 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Yield given. Multistep reaction. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Yield given. Multistep reaction. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-hydroxyphthalimide; air at 150℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With LACTIC ACID; dihydrogen peroxide; at 30℃; for 7h; | General procedure: A mixture of alcohol (1 mmol) and lactic acid (1 mL) was charged in 25 mL round bottom flask subjected to constant magnetic stirring at room temperature (30C). The reaction mixture was further activated by addition of 30% H2O2 (1.07 equiv.). The reaction progress was monitored by GC. After completion of the reaction, Dichloromethane (2×6 mL) was added to the reaction mixture and then washed with distilled water (2×2mL). The organic layer was separated and dried over Na2SO4 and removed under reduced pressure. The crude product was obtained by evaporation method and again purified by column chromatography using ethyl acetate and n-hexane as eluting system. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With caesium carbonate; In methanol; water; N,N-dimethyl-formamide; at 20℃; for 2h; | Reference Example 6; 4-Hydroxymethylbenzoic acid benzyl ester (Reference Compound No.6-1); Benzyl bromide (7.8 mL, 66 mmol) was added to a suspension of <strong>[3006-96-0]4-hydroxymethylbenzoic acid</strong> (10 g, 66 mmol) and cesium carbonate (11 g, 33 mmol) in a mixed solvent (DMF (100 mL)-methanol (30 mL)-water (30 mL)), and then the mixture was stirred at room temperature for 2 hours. Water (500 mL) was added thereto, the whole was extracted with ethyl acetate (500 mL), and then the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (300 mL) twice and water (300 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration with hexane, and dried at 35C under reduced pressure to give 13 g of the title reference compound as a white solid. (Yield 81%) [Show Image] 1H-NMR (400 MHz, DMSO-d6) delta 4.58 (d, J = 5.8 Hz, 2H), 5.35 (s, 2H), 5.38 (t, J = 5.8 Hz, 1H), 7.33-7.44 (m, 4H), 7.46 (m, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 8.2 Hz, 2H) |
81% | With caesium carbonate; In methanol; water; N,N-dimethyl-formamide; at 20℃; for 2h; | Reference Example 7 4-Hydroxymethylbenzoic acid benzyl ester (Reference Compound No.7-1); Benzy bromide (7.8 mL, 66 mmol) was added to a suspension of <strong>[3006-96-0]4-hydroxymethylbenzoic acid</strong> (10 g, 66 mmol) and cesium carbonate (11 g, 34 mmol) in mixed solvent (DMF 0.10 L - methanol 30 mL - water 30mL), and then the reaction mixture was stirred at room temperature for 2 hours. Water (0.50 L) and ethyl acetate (0.50 L) were added to the reaction solution, and the mixture was partitioned. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (0.30 L) and water (0.30 L) twice, respectively. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained solid was filtered and dried at 35C under reduced pressure to give 13 g of the title reference compound as a white solid. (Yield 81%) |
81% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | General procedure: A mixture of 20a (4.00 g, 26.3 mmol), K2CO3 (4.00 g, 28.9 mmol), and BnBr (3.1 mL, 26 mmol) in DMF (30 mL) was stirred at room temperature overnight. After dilution with water, the resulting mixture was extracted with EtOAc. The extract was washed with water and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc = 4:1-7:3-3:2) to give 3b (5.18 g, 81%) as a colorless oil.1H NMR (CDCl3) delta: 1.79 (1H, t, J = 5.9 Hz), 4.77 (2H, d, J = 5.9 Hz), 5.37 (2H, s), 7.31-7.48 (7H, m), 8.07 (2H, d, J = 8.0 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 25℃; for 12h; | 9B: 4-(Hydroxymethyl)-N'-(4-isobutylbenzoyl)benzohydrazide 4-Isobutylbenzohydrazide (2.10 g, 10.9 mmol) was added to a stirred solution of <strong>[3006-96-0]4-hydroxymethylbenzoic acid</strong> (1.66 g, 11.2 mmol), HBTU (4.25 g, 11.2 mmol), diisopropylethylamine (1.45 g, 11.2 mmol) and DMF (50 mL) and stirred at room temperature for 12 hours. The reaction was diluted with ethyl acetate (200 mL), washed with 5% NaHCO3 (aq.) and brine, dried (MgSO4), filtered and concentrated in vacuo to give a white solid. The solid was triturated with ethyl acetate and filtered to give the title compound (2.01 g, 56% yield). 1H NMR (400 MHz, CDCl3) 0.78 (d, 6H), 1.77 (m, 1H), 2.42 (d, 2H), 4.58 (s, 2H), 7.13 (d, 2H), 7.33 (d, 2H), 7.70 (d, 2H), 7.76 (d, 2H); ESI-MS: 327 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 60 percent / H2SO4 / 8 h / Heating 2: 77 percent / InCl3; benzil; HSiMe2Cl / CH2Cl2 / 1.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | A solution of commercial 4-(hydroxymethyl)benzoic acid (1.52 g, 10.0 mmol) in pyridine (50 mL) is treated with 4,4'-dimethoxytrityl chloride (3.73 g, 11.0 mmol) overnight at room temperature and concentrated to an oil in vacuo. The residue is dissolved in a mixture of MeOH and CH2Cl2 (95:5, v/v; 200 mL) and washed with 2 M aqueous triethylammonium acetate (5×20 mL). The organic solution is evaporated, re-dissolved in CH2Cl2, dried over Na2SO4, and evaporated to give crude triethylammonium 4-[[(4,4'-dimethoxytrityl)oxy]methyl]benzoate in quantitative yield (1016 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With NaH; In N,N-dimethyl-formamide; | (169-1) Under nitrogen atmosphere, a solution of 4-(hydroxymethyl)-benzoic acid (5.00 g) in DMF (200 mL) was cooled to 0 C., and thereto was added NaH (2.76 g, 60%). The mixture was stirred at the same temperature for 10 minutes, and stirred at room temperature for 20 minutes. The mixture was cooled to 0 C., and thereto were added DMF (100 mL) and iodomethane (18.7 g), and the mixuture was stirred at room temperature for 48 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=15/1) to give methyl 4-(methoxymethyl)benzoate (4.27 g, 72%). 1H NMR (CDCl3, 400 MHz) delta 8.02 (d, 2H, J=8.3 Hz), 7.40 (d, 2H, J=8.3 Hz), 4.51 (s, 2H), 3.91 (s, 3H), 3.42 (s, 3H). |
72% | With NaH; In N,N-dimethyl-formamide; | (169-1) Under nitrogen atmosphere, a solution of 4-(hydroxymethyl)benzoic acid (5.00 g) in DMF (200 mL) was cooled to 0C, and thereto was added NaH (2.76 g, 60 %). The mixture was stirred at the same temperature for 10 minutes, and stirred at room temperature for 20 minutes. The mixture was cooled to 0C, and thereto were added DMF (100 mL) and iodomethane (18.7 g), and the mixuture was stirred at room temperature for 48 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate = 15/1) to give methyl 4-(methoxymethyl)benzoate (4.27 g, 72 %). 1H NMR (CDCl3, 400MHz) delta 8.02 (d, 2H, J=8.3Hz), 7.40 (d, 2H, J=8.3Hz), 4.51 (s, 2H), 3.91 (s, 3H), 3.42 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitric acid; In acetic anhydride; | Step 1 Synthesis of 4-(nitrooxymethyl)benzoic Acid Nitric acid (760 ml) was cooled to -30 C. and acetic anhydride (1520 ml) was added portionwise with stirring. This mixture was stirred at -30 C. for 15 minutes. 4-(Hydroxymethyl)benzoic acid (400 g, 2.63 moles) slurried in acetic anhydride (1520 ml) was added and the beaker was rinsed with the remaining acetic anhydride (800 ml). After 2 hours at ~-10 C., the reaction was complete as evidenced by high performance liquid chromatography (HPLC) analysis. The reaction mixture was poured into water (10 L) and stirred for 30 minutes. The resulting white solid was filtered and washed with water (3*1.5 L) and dried overnight. | |
With silver nitrate; In acetonitrile; at 20℃; | The commercially available 4-(hydroxymethyl)benzoic acid (10 g) was reacted with 3 equivalents of silver nitrate in acetonitrile as solvent. The reaction was allowed to proceed at room temperature for several hours and the resulting 4-(nitromethyl)benzoic acid precipitated from the reaction mixture upon addition of water. The product (8 g) obtained as a white powder, after drying, was utilized in the reaction below, without further purification. | |
With silver nitrate; In acetonitrile; at 20℃; | The commercially available 4-(hydroxymethyl) benzoic acid (10 g) was reacted with 3 equivalents of silver nitrate in acetonitrile as solvent. The reaction was allowed to proceed at room temperature for several hours and the resulting 4-(nitromethyl) benzoic acid precipitated from the reaction mixture upon addition of water. The product (8 g) obtained as a white powder, after drying, was utilized in the reaction below, without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With formic acid; acetic anhydride; In water; | (a) 4-Formyloxymethylbenzoic Acid Formic acid (1.24 ml) and acetic anhydride (0.62 ml) were mixed and stirred at 50 C. for 30 minutes. This solution was cooled to 0 C., added with <strong>[3006-96-0]4-hydroxymethylbenzoic acid</strong> (500 mg) and stirred at room temperature for 4.5 hours. The reaction mixture was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 536 mg of the title compound. Yield: 91%. 1H-NMR (DMSO-d6) delta (ppm); 5.24 (2H, s), 7.49 (2H, d, J=8 Hz), 7.94 (2H, d, J=8 Hz), 8.40 (1H, s), 13.01 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8%; 80% | Complex 2 (8.3 mg, 10 mmol), CsOHH2O (0.84 g, 5 mmol),alcohol (5 mmol) was added to a 25 mL schlenk tube and the solutionwas heated at 150 C (oil bath) for 24 h in an open systemunder argon. After cooling to room temperature, the degassedwater (5 mL)was added and the mixturewas extracted with diethylether (3 10 mL). A sample of ether phasewas subjected to the GCMSanalysis and the residual solution was evaporated, then subjected to the NMR analysis. The aqueous phase was acidifiedwith 6 M HCl and extracted with ethyl acetate (5 20 mL). Thecombined organic phasewaswashed with brine (25 mL), dried overanhydrous Na2SO4, and evaporated under reduced pressure, thepure carboxylic acid was collected and weighed for calculating theyield, which was further characterized by its 1H NMR which isconsist with the standard sample. | |
56%; 30% | Complex 2 (8.3 mg, 10 mmol), CsOHH2O (0.84 g, 5 mmol),alcohol (5 mmol) was added to a 25 mL schlenk tube and the solutionwas heated at 150 C (oil bath) for 24 h in an open systemunder argon. After cooling to room temperature, the degassedwater (5 mL)was added and the mixturewas extracted with diethylether (3 10 mL). A sample of ether phasewas subjected to the GCMSanalysis and the residual solution was evaporated, then subjected to the NMR analysis. The aqueous phase was acidifiedwith 6 M HCl and extracted with ethyl acetate (5 20 mL). Thecombined organic phasewaswashed with brine (25 mL), dried overanhydrous Na2SO4, and evaporated under reduced pressure, thepure carboxylic acid was collected and weighed for calculating theyield, which was further characterized by its 1H NMR which isconsist with the standard sample. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Example No.11: Preparation of (4-(3-(3-chloro-4-isopropoxyphenyl)-l,2,4-oxadiazoI-5- yl)phenyl)methanol; <n="101"/>To a slurry of 4-(hydroxymethyl)benzoic acid (0.220 g, 1.443 mmol) in DMF (1.640 ml) was added EDC (0.277 g, 1.443 mmol) followed by HOBT hydrate (0.195 g, 1.443 mmol). After about 45 min. a solution of (Z)-3-chloro-N'-hydroxy-4-isopropoxybenzimidamide (0.300 g, 1.31 mmol) in DMF (1.640 ml) was added and the reaction mixture was heated to about 140 0C for about 2h. After cooling to room temperature the reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide (4- (3-(3-chloro-4-isopropoxyphenyl)-l,2,4-oxadiazol-5-yl)phenyl)methanol (0.336g, 71%) as an off-white solid. LCMS (Table 1, Method c) R, = 2.80 min, mJz 345 (M+H)+. | |
71% | Preparation No.6: Preparation of (4-(3-(3-chloro-4-isopropoxyphenyl)-l,2,4-oxadiazol-5- yl)phenyl)methanol; To a slurry of 4-(hydroxymethyl)benzoic acid (0.220 g, 1.443 mmol) in DMF (1.640 mL) was added EDC (0.277 g, 1.443 mmol) followed by HOBT hydrate (0.195 g, 1.443 mmol). After about 45 min. a solution of (Z)-3-chloro-A^-hydroxy-4-isopropoxybenzimidamide (0.300 g, 1.31 mmol) in DMF (1.640 mL) was added and the reaction mixture was heated to about 140 C for about 2 h. After cooling to RT the reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (eluting with EtO Ac/Hep) to provide (4-(3-(3- chloro-4-isopropoxyphenyl)-l,2,4-oxadiazol-5-yl)phenyl)methanol (0.336g, 71%) as an off- white solid. LC/MS (Table 1, Method c) Rt = 2.80 min, m/z 345 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; | Under ice-cooling, 6.94 g (36 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 5 g (33 mmol) of 4-(hydroxymethyl)benzoic acid, 7.7 g (33 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 5.29 g (35 mmol) of 1-hydroxybenzotriazole in methylene chloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, and it was dried with anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography to obtain 6.83 g (56%) of the title compound.1H-NMR (CDCl3, delta): 1.23-1.79 (6H, m), 1.82-2.23 (4H, m), 4.73 (2H, m), 5.16 (2H, s), 6.25 (1H, s), 7.20-7.32 (5H, m), 7.32-7.43 (2H, m), 7.62-7.79 (2H, m) |
56% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; | REFERENCE EXAMPLE 2011-[[[4-(Hydroxymethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester Under ice-cooling, 6.94 g (36 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 5 g (33 mmol) of 4-(hydroxymethyl)benzoic acid, 7.7 g (33 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 5.29 g (35 mmol) of 1-hydroxybenzotriazole in methylene chloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, and it was dried with anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography to obtain 6.83 g (56%) of the title compound.1H-NMR (CDCl3, delta): 1.23-1.79 (6H, m), 1.82-2.23 (4H, m) 4.73 (2H, m), 5.16 (2H, s), 6.25 (1H, s), 7.20-7.32 (5H, m), 7.32-7.43 (2H, m), 7.62-7.79 (2H, m) |
56% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; | Reference Example 155 1-[[[4-(Hydroxymethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester Under ice-cooling, 6.94 g (36 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 5 g (33 mmol) of 4-(hydroxymethyl)benzoic acid, 7.7 g (33 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 5.29 g (35 mmol) of 1-hydroxybenzotriazole in methylene chloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, it was dried with anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography to obtain 6.83 g (56%) of the title compound. 1H-NMR (CDCl3, delta): 1.23-1.79 (6H, m), 1.82-2.23 (4H, m), 4.73 (2H, m), 5.16 (2H, s), 6.25 (1H, s), 7.20-7.32 (5H, m), 7.32-7.43 (2H, m), 7.62-7.79 (2H, m) |
56% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; | Reference example 192; 1-[[[4-(Hydroxymethyl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester [Show Image] Under ice-cooling, 6.94 g (36 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 5 g (33 mmol) of 4-(hydroxymethyl)benzoic acid, 7.7 g (33 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 5.29 g (35 mmol) of 1-hydroxybenzotriazole in methylene chloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution, and then saturated brine, followed by drying with anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography to give 6.83 g (56%) of the title compound. 1H-NMR (CDCl3, delta): 1.23-1.79 (6H, m), 1.82-2.23 (4H, m), 4.73 (2H, m), 5.16 (2H, s), 6.25 (1H, s), 7.20-7.32 (5H, m), 7.32-7.43 (2H, m), 7.62-7.79 (2H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide; acetonitrile at 20℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
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67% | With triphenylphosphonium triflate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triphenylphosphonium triflate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With pyridine; In chloroform; for 2h;Reflux; | At room temperature, to 3000 ml three-neck bottle adding hydroxyl methyl benzoic acid 91.5 g (0.601 muM), and adding chloroform 600 ml, acetic anhydride 300 ml and pyridine 10 ml. Heating to reflux until the system dissolves clear, and at this temperature to continue stirring 2 h. After the reaction evaporate solvent, adding shui Yue 2000 ml and is warmed up to reflux 2 h. TLC detection after the reaction, lowering the temperature to 0 C and continue to stir 2 h. Filtering, cake 600 ml water washing after the 60 C drying 8 h the obtained white solid 103.9 g, yield 89%. |
With pyridine; In chloroform; at 80℃; for 3h; | Reference Example 8-1 Production of 4-[(acetyloxy)methyl]benzoic acid Acetic anhydride (60.0 mL) and pyridine (2.00 mL) were added to a chloroform solution (300 mL) of 4-(hydroxymethyl)benzoic acid (18.3 g), and stirred at 80C for 3 hours. The reaction liquid was concentrated under reduced pressure, and water (600 mL) was added to the residue and stirred at 90C for 5 hours. The reaction liquid was cooled to 0C, and the formed white solid was collected through filtration. The obtained solid was washed with water, and dissolved in ethyl acetate. The organic layer was washed with saturated saline, and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain the entitled compound (21.0 g) as a white solid. ESI-MS Found: m/z 217[M+Na]+ | |
With pyridine; In chloroform; at 80℃; for 3h; | Referential Example 6-1 Synthesis of 4-[(acetyloxy)methyl]benzoic acid To a chloroform solution (300 ml) of 4-(hydroxymethyl)benzoic acid (18.3 g), acetic anhydride (60.0 ml) and pyridine (200 ml) were added and the resultant mixture was stirred at 80 C. for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, water (600 ml) was added to the residue followed by stirring at 90 C. for 5 hours. Then, the liquid reaction mixture was cooled to 0 C. and the white solid thus formed was collected by filtration. The obtained solid was washed with water and dissolved in ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. Then, the title compound (21.0 g) was obtained as a white solid. ESI-MS Found: m/z 217[M+Na]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h; | In addition, the title reference compound can be also synthesized by the following method. HATU (17 g, 45 mmol) was added to a solution of 2-aminophenylcarbamic acid t-butyl ester (Reference Compound No.1-1, 8.3 g, 40 mmol), <strong>[3006-96-0]4-hydroxymethylbenzoic acid</strong> (6.2 g, 41 mmol) and N,N-diisopropylethylamine (21 mL, 120 mmol) in anhydrous DMF (200 mL), and then the mixture was stirred at room temperature for 16 hours. Water (500 mL) was added thereto, the whole was extracted with ethyl acetate (500 mL) twice, and then the organic layer was washed with brine (500 mL) twice. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 1.7 g of the title reference compound as a pale yellow solid. (Yield 42%) [Show Image] 1H-NMR (400 MHz, DMSO-d6) delta 1.45 (s, 9H), 4.59 (d, J = 5.7 Hz, 2H), 5.35 (t, J = 5.7 Hz, 1H), 7.13-7.22 (m, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.52 (dd, J = 7.8, 1.7 Hz, 1H), 7.56 (dd, J = 7. 7, 1.8 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 8.69 (br s, 1H), 9.80 (br s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; chloroform; at 20℃; for 5h; | Stage 1: N-cyclobutyl-4-(hydroxymethyl)benzamide 1-hydroxybenzotriazole (HOBt) (888 mg, 1 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.26 g, 1 eq) in solution in chloroform (40 ml) then cyclobutylamine (470 mg) are successively added to 4-(hydroxymethyl)benzoic acid (1 g, 1 eq) in solution in anhydrous THF (30 ml). After stirring for 5 hours at a temperature of approximately 20 C., the reaction mixture is concentrated under reduced pressure at 40 C. The residue is taken up in dichloromethane (100 ml) and water (60 ml). After decantation and extractions, the combined organic phases are washed with water, then with salt water, dried over Na2SO4 and concentrated under reduced pressure at 40 C. Purification by flash chromatography on silica gel (eluent: heptane/ethyl acetate 40:60 to heptane/ethyl acetate 25:75) produces the expected compound in the form of a white powder (1.3 g; 67% yield). MS/LC: calculated MM=205.5; m/z=206.2 (MH+) NMR (1H, 400 MHz, DMSO-d6): delta 1.66 (m, 2H), 2.05 (m, 2H), 2.20 (m, 2H), 4.40 (m, 1H), 4.54 (d, 2H), 5.26 (t, 1H), 7.36 (AB, 2H), 2.01 (AB, 2H), 8.52 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h; | (i) Synthesis of 4-(hydroxymethyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamide; A mixture of 4-(Hydroxymethyl)benzoic acid (0.75 g, 5 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.59 g, 5 mmol), and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (1.15 g , 6 mmol) in dichloromethane (50 mL) was stirred at room temperature for 2h (monitored by TLC). The mixture was extracted with water and dried over magnesium sulfate. The residue was purified by chromatography (MeOH:DCM = 1:50) to give the title compound (0.88 g, 70%). NMR (400 MHz in DMSO, Bruker AVANCE-400): delta 1.52(m, 3H, OTHP), 1.72(m, 3H, OTHP), 3.51(m, 1H, OTHP), 4.04(m, 1H, OTHP), 4.53(s, 2H, CH2), 4.98(s, 1H, OTHP), 5.28(s, 1H, NH), 7.38(d, 2H, J= 10.0Hz, Ar-H), 7.72(d, 2H, J = 5.0Hz, Ar-H), 11.55(s, 1H, OH). |
70% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h; | (i) Synthesis of 4-(hydroxymethyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamideA mixture of 4-(Hydroxymethyl)benzoic acid (0.75 g, 5 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.59 g, 5 mmol), and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (1.15 g, 6 mmol) in dichloromethane (50 mL) was stirred at room temperature for 2 h (monitored by TLC). The mixture was extracted with water and dried over magnesium sulfate. The residue was purified by chromatography (MeOH:DCM=1:50) to give the title compound (0.88 g, 70%). NMR (400 MHz in DMSO, Bruker AVANCE-400): delta 1.52 (m, 3H, OTHP), 1.72 (m, 3H, OTHP), 3.51 (m, 1H, OTHP), 4.04 (m, 1H, OTHP), 4.53 (s, 2H, CH2), 4.98 (s, 1H, OTHP), 5.28 (s, 1H, NH), 7.38 (d, 2H, J=10.0 Hz, Ar-H), 7.72 (d, 2H, J=5.0 Hz, Ar-H), 11.55 (s, 1H, OH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With C29H55IrN3P2(1+)*Cl(1-); potassium <i>tert</i>-butylate In toluene at 120℃; for 15h; Schlenk technique; Inert atmosphere; Glovebox; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 4H3N*4H(1+)*CuMo6O18(OH)6(4-); water monomer; oxygen; anhydrous sodium carbonate at 50℃; for 12h; | |
95% | With NADH oxidase and 3-succinoylsemialdehyde-pyridine dehydrogenase co-expressed in Escherichia coli cells In aq. phosphate buffer at 30℃; for 3h; Microbiological reaction; | |
85% | With C20H25N2(1+)*Cl(1-); water monomer; oxygen; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 16h; Schlenk technique; chemoselective reaction; |
With water monomer; copper atom; potassium hydroxide at 40℃; Electrochemical reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | General procedure: TMSOTf (336 mg, 1.51 mmol) is added to a solution of the alcohol (0.755 mmol) in the respective nitrile (3 mL) and the mixture is stirred at rt for 65 h. H2O (25 mL) and brine (25 mL) are added, and the mixture is extracted with EtOAc (3 × 30 mL). The combined organic layers are dried (Na2SO4) and concentrated, and excess nitrile is distilled off at reduced pressure (90 C, 0.1 mbar). The crude product is purified by flash column chromatography (silica gel). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | General procedure: TMSOTf (336 mg, 1.51 mmol) is added to a solution of the alcohol (0.755 mmol) in the respective nitrile (3 mL) and the mixture is stirred at rt for 65 h. H2O (25 mL) and brine (25 mL) are added, and the mixture is extracted with EtOAc (3 × 30 mL). The combined organic layers are dried (Na2SO4) and concentrated. The crude product is purified by flash column chromatography (silica gel). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 96% | With dihydrogen peroxide; In acetonitrile; at 30℃; for 5h; | Pipette 1.0 mL of p-xylene (? 8 mmol) in a 100 mL round bottom flask, and sequentially add Cu-MOF (0.30 g),Acetonitrile (20 mL), hydrogen peroxide (30%, 2.0 mL, density 1.11 g/mL, 65 mmol), reacted at 30 C for 5 h,The reaction was stopped, cooled, filtered and separated by column to give 1.06 g (yield: about 96%)The main by-product is p-methylbenzoic acid) p-hydroxymethylbenzoic acid. |
60% | With C23H33N2O4V; dihydrogen peroxide; In acetonitrile; at 50℃; for 24h; | General procedure: A mixture of complex 1 (the catalyst) (0.012g, 0.02mmol) and a representative substrate, namely toluene (5mmol), was dissolved in 10mL MeCN solvent and the resulting solution was taken into a 50mL capacity two necked round bottom flask, one neck of which was closed with a rubber septum and the other was fitted with a condenser. To the above solution was then added 2mL (67mmol) of 30% H2O2 and the resulting solution immediately turned yellow. The solution was then heated up to 50C on an oil bath for 24h and 0.5mL (17mmol) of H2O2 was added intermittently at a time intervals of 60min. When required, an aliquot (0.1mL) of the reaction solution was withdrawn with the help of a long needle syringe and was subjected to multiple ether extraction, then 1muL of the concentrated ether extract was injected to the GC port with the help of a 10muL syringe. The retention times of the peaks were compared with those of commercial standards and the unknown peaks were characterized by ESI-MS+ analysis. The same experiment was carried out separately in the presence of traces of azoisobutyronitrile (AIBN) and benzoquinone to check the involvement of radicals in the reaction mechanism. The experiments were carried out in triplicate runs and errors were found to fall within ±5%. |
With dihydrogen peroxide; In acetonitrile; at 30℃; for 5h; | All oxidation reactions of PX were performed in YuHua Parallel reactor (PPS-2510, five parallel reactions) equipped with magneticstirrer, super constant temperature and thermometer. A typical reactionwas as follows: PX (1.0 mL, 8.1 mmol), Cu-MOF (30.0 mg), acetonitrile(10.0 mL), and 30% H2O2 (3.0 mL) was successively added into theflask. The mixture was stirred at 30 C for 5 h, cooled to room temperatureand filtered. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | [0218] To a solution of 4-(hydroxymethyl)benzoic acid (500 mg, 3.28 mmol) in DMF (5 mL) was added morpholine (326 mg, 3.94 mmol), followed by HOBt (678.9 mg, 4.92 mmol), EDACHCl (944 mg, 4.92 mmol) and DIEA (846.2 mg, 6.56 mmol). The mixture was stirred at RT for 16 hrs. The reaction was diluted with water (5 mL) and extracted with DCM. Workup and purification with EtOAc/petroleum ether from 30% to 90% provided (4-(hydroxymethyl)phenyl)(morpholino)methanone (520 mg, 72% yield) as a colorless oil. MS (ESI) m/z 221.1 [M+H]+. |
52% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h; | To a stirred solution of commercially available <strong>[3006-96-0]4-hydroxymethylbenzoic acid</strong> (0.200 g,1.32 mmol), EDC (0.278 g, 1.45 mmol), dry Et3N (0.403 mL, 2.89 mmol), HOBt (0.196 g, 1.45 mmol) and DMAP (0.002 g, 0.01 mmol) in dry CH2C12 (8.0 mL), morpholine (0.172 mL, 1.97 mmol) was added in one portion. The resulting solution was stirred at r.t. for 16 h, and then sequentially washed with sat. NH4C1 solution (2 x 5.0 mL) and sat. NaHCO3 solution (10.0 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness, giving a solidresidue (0.288 g). Purification by typical silica gel flash chromatography (CH2C12/MeOH from100:0 to 95:5) afforded the title compound (0.152 g, 52%), as a white solid. R= 1.07 mm. MS(ESI) m/z: 222 [M-H], 244 [M-Na], 260 [M-K]. ?H NMR (DMSO-d6): oe 7.40-7.34 (m, 4H),5.26 (t, 1H, J= 5.8 Hz), 4.53 (d, 2H, J= 5.8 Hz), 3.80-3.20 (m, 8H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h; | To a stirred solution of commercially available <strong>[3006-96-0]4-hydroxymethylbenzoic acid</strong> (0.200 g,1.32 mmol), EDC (0.278 g, 1.45 mmol), dry Et3N (0.403 mL, 2.89 mmol), HOBt (0.196 g, 1.45mmol), DMAP (0.002 g, 0.01 mmol) in dry CH2C12 (8.0 mL), cyclohexylamine (0.224 mL, 1.97mmol) was added in one portion. The resulting solution was stirred at r.t. for 16 h, and thensequentially washed with sat. NH4C1 solution (2 x 5.0 mL) and sat. NaHCO3 solution (10.0 mL). The organic layer was dried over Na2504, filtered and concentrated to dryness, giving a solid residue (0.263 g). Purification by typical silica gel flash chromatography (CH2C12/MeOH from 100:0 to 96:4) afforded the pure title compound (0.19 g, 83%), as a white solid. R= 1.77 mm.MS (ESI) m/z: 234 [M-H], 256 [M-Na], 272 [M-K]. ?H NMR (DMSO-d6): oe 8.11 (d, 1H, J=8.0 Hz), 7.80 (d, 2H, J= 8.3 Hz), 7.36 (d, 2H, J= 8.3 Hz), 5.26 (t, 1H, J= 5.7 Hz), 4.54 (d, 2H, J = 5.7 Hz), 3.81-3.69 (m, 1H), 1.86-1.56 (m, 5H), 1.37-1.22 (m, 4H), 1.20-1.05 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h; | To a stirred solution of commercially available <strong>[3006-96-0]4-hydroxymethylbenzoic acid</strong> (0.200 g, 1.32 mmol), EDC (0.278 g, 1.45 mmol), dry Et3N (0.403 mL, 2.89 mmol), HOBt (0.196 g, 1.45mmol), DMAP (0.002 g, 0.01 mmol) in dry CH2C12 (8.0 mL), piperidine (0.195 mL, 1.97 mmol) was added in one portion. The resulting solution was stirred at r.t. for 16 h, and then sequentially washed with sat. NH4C1 solution (2 x 5.0 mL) and sat. NaHCO3 solution (10.0 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness, giving a solid residue (0.242 g). Purification by typical silica gel flash chromatography (CH2C12/MeOH from 100:0 to 96:4) afforded the title compound (0.174 g, 60%), as a white solid. R= 1.54 mm. MS (ESI) m/z: 220[M-H], 242 [M-Na], 258 [M-K]. ?HNMR(DMSO-d6): oe 7.37 (d, 1H,J= 8.1 Hz), 7.31 (d,2H, J= 8.1 Hz), 5.24 (t, 1H, J= 5.7 Hz), 4.53 (d, 2H, J= 5.7 Hz), 3.7 1-3.11 (m, 4H), 1.66-1.36 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h; | To a stirred solution of commercially available <strong>[3006-96-0]4-hydroxymethylbenzoic acid</strong> (0.200 g, 1.32 mmol), EDC (0.278 g, 1.45 mmol), dry Et3N (0.403 mL, 2.89 mmol), HOBt (0.196 g, 1.45 mmol), DMAP (0.002 g, 0.01 mmol) in dry CH2C12 (8.0 mL), benzylamine (0.2 15 mL, 1.97 mmol) was added in one portion. The resulting solution was stirred at r.t. for 16 h, and thensequentially washed with sat. NH4C1 solution (2 x 5.0 mL) and sat. NaHCO3 solution (10.0 mL). The organic layer was dried over Na2504, filtered and concentrated to dryness, giving a solid residue (0.258 g). Purification by typical silica gel flash chromatography (CH2C12/MeOH from 100:0 to 96:4) afforded the title compound (0.142 g, 43%), as a white solid. ?H NMR (DMSOd 6): oe 8.98 (t, 1H, J= 6.0 Hz), 7.86 (d, 2H, J= 8.1 Hz), 7.40 (d, 2H, J= 8.1 Hz), 7.34-7.20 (m,5H), 5.29 (t, 1H, J= 5.7 Hz), 4.60-4.5 1 (m, 2H), 4.48 (d, 2H, J= 5.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With Sn-Beta molecular sieve; In 1,4-dioxane; at 190℃; under 52476.2 Torr; for 12h;High pressure; Autoclave; | A series of experiments were conducted to test the variables related to the conversion of 5-hydroxymethyl-2-furoic acid (HMFA) to 4-hydroxymethylbenzoic acid (HMBA). This transformation is a key intermediate step in the transformation of hydroxymethyl furfural (HMF) to (purified) terephthalic acid (PTA), according to: The results are shown in Tables 8 and FIG. 9. Reaction conditions for FIG. 9 were 1000 psig ethylene at 190° C., 10 g of a 100 mM dioxane solution of HFMA, with 100 mg Sn-Beta catalyst. [TABLE-US-00008] TABLE 8 All reactions were run at 850-1000 psig total pressure, 190° C., 10 g of a 100 mM HFMA solution, 100 mg catalyst. HMFA HMBA HMBA Entry Catalyst Solvent Time (hr) Converson (percent) Yield (percent) Selectivity (percent) 1 Sn-Beta dioxane 0.5 18 4 22 2 Sn-Beta dioxane 2 36 11 31 3 Sn-Beta dioxane 4 57 15 26 4 Sn-Beta dioxane 6 61 19 31 5 Sn-Beta dioxane 12 76 21 28 dioxane/water 6 Sn-Beta 1:1 v/v 0.5 94 0 0 7 Sn-Beta THF+ 0.5 35 2 6 8 Zr-Beta dioxane 6 87 9 10 9 None dioxane 2 5 0 0 10 None dioxane 6 21 0 0 11 Si-Beta dioxane 2 20 0 0 12 Si-Beta dioxane 6 56 13 Si-MFI dioxane 2 25 0 0 |
19% | In 1,4-dioxane; at 20 - 190℃; under 27752.8 - 52505.3 Torr; for 6h;Inert atmosphere; | General procedure: Experiments were carried out in a 50-mL high pressure stainless steel batch reactor (Parr Series 4590) equipped with a magnetic stirrer and heater. The reactor setup allowed for ethylene gas(Matheson, 99.995percent purity) or helium to be charged to the reactor. In a typical experiment, 100 mg of catalyst and 10 g of a 0.1 M diene solution in dioxane (Sigma-Aldrich, 99.8percent) was loaded into the reactor. The magnetic stirrer was operated at 200 rpm and the head space of the reactor was purged with helium gas with a fill/vent cycle (10×). Next, the reactor was pressurized to 37 bar (room temperature) with ethylene gas, the inlet valve was closed, and the reaction was performed in batch operation. The reactor was heated to 190 °C within 15 min while the pressure increased autogenously to 70 bar. At the end of the reaction time, the reactor was allowed to cool to room temperature and the reactor gases were vented. The product was then collected for analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With sodium hydride; In N,N-dimethyl acetamide; mineral oil; at 0℃; for 1.75h; | Reference Example 159 ethyl 5-[([4-(hydroxymethyl)phenyl]carbonyl}oxy)methyl]-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate (2014) (2015) A mixture of ethyl 5-(bromomethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate (1000 mg, 3.15 mmol) obtained in Example 216, Step 1, 4-(hydroxymethyl)benzoic acid (504 mg, 3.31 mmol) and DMA (20 mL) was added dropwise to a mixture of sodium hydride (60% oil dispersion, 363 mg, 9.46 mmol) and DMA (10 mL) at 0 C. The reaction mixture was stirred for 1 hr. 45 min. and added dropwise to a mixture of 2N hydrochloric acid (100 mL) and dry ice. After dropwise addition, the mixture was added to ethyl acetate, washed with 1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained concentrated residue was crystallized from ethyl acetate-diethyl ether to give the title compound as a pale-yellow powder (347 mg, 28%). (2016) melting point: 196 C. (2017) 1H NMR (300 MHz, DMSO-d6) delta 1.35 (3H, t, J=7.1 Hz), 4.38 (2H, g, J=7.1 Hz), 4.59 (2H, d, J=5.7 Hz), 5.38 (1H, t, J=5.7 Hz), 5.62 (2H, s), 7.47 (2H, d, J=8.3 Hz), 7.86 (1H, s), 7.99 (2H, d, J=8.3 Hz), 12.95 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pDRf1-(4-coumaroyl:CoA ligase 5 from Arabidopsis thaliana)-(hydroxycinnamoyl/benzoyl-CoA:anthranilate N-hydroxycinnamoyl/benzoyltransferase 1 from Dianthus caryophyllus) recombinant yeast In dimethyl sulfoxide at 30℃; for 24h; | Production of cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates General procedure: An overnight culture from a single colony of the pDRf1-4CL5-HCBT1 recombinant yeast grown on 2X YNB medium without amino acids, supplemented with 6% glucose and 2X CSM-Ura, was used to inoculated 4 mL of fresh minimal medium at an OD600 = 0.15 and shaken at 200 rpm at 30°C. All precursors were prepared in DMSO and added 5 hours post inoculation at the concentrations indicated in S1, S2 and S3 Tables. The anthranilate acceptors were added to the medium at a final concentration of 300 μM (for anthranilate, 3-hydroxyanthranilate, 3-methylanthranilate, and 5-nitroanthranilate) or 50 μM (for 3-chloroanthranilate, 5-methylanthranilate, 3-methoxyanthranilate, 5-fluoroanthranilate, 5-iodoanthranilate, and 5-chloroanthranilate). These concentrations were selected to limit toxicity and growth inhibition due to either the supplied precursors or the metabolites produced. The cultures were shaken at 200 rpm at 30°C for 24 h in the presence of the precursors for the production of cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates. Yeast colonies harboring the pDRf1-HCBT1 or pDRf1-4CL5 control vectors were grown under similar conditions. For the detection of metabolites, an aliquot of the culture medium was collected and cleared by centrifugation (21,000xg for 5 min at 4°C), mixed with an equal volume of cold methanol:water (1:1, v/v), and filtered using Amicon Ultra centrifugal filters (3,000 Da MW cutoff regenerated cellulose membrane; Millipore, Billerica, MA) prior to LC-TOF MS analysis. The separation and identification of the metabolites were performed using high-performance liquid chromatography (HPLC), electrospray ionization (ESI), and time-of-flight (TOF) mass spectrometry (MS) as previously described [35]. For each compound, the measured masses agreed with the expected theoretical masses within less than 5 ppm mass error. Standard solutions of DHavnD and dianthramide B were prepared in methanol:water (1:1, v/v). Values obtained for the production of DHavnD and dianthramide B are the average of four replicates (n = 4). ESI-MS spectra of other cinnamoyl, dihydrocinnamoyl, and benzoyl anthranilates were obtained from single feeding experiments for each combination of precursors. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | To a mixture of (2S, 4R) -1- (5- ( (S) -1- ( (tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carbonyl) -4- ( (methoxycarbonyl) amino) pyrrolidine-2-carboxylic acid (300 mg, 0.47 mmol) in THF (5 mL) was added 1, 1'-carbonyldiimidazole (115 mg, 0.71 mmol) at rt. The mixture was stirred at 60 for 30 min, and 4- (hydroxymethyl) benzoic acid (143 mg, 0.94 mmol) was added dropwise. After the addition, the mixture was stirred at 70 for 24 h and concentrated. The residue was diluted with water (10 mL) . The resulting mixture was extracted with EtOAc (10 mL × 3) . The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with DCM/MeOH (v/v) 30/1 to give the title compound as a white solid (141 mg, 38) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
AM-PS (0.1 mmol, 118 mg, loading 0.85 mmol g-1) was swelled in DMF for 10 min. To a solution of Rink amide linker (217 mg, 0.4 mmol) and Cl-HOBt (68 mg,0.4 mmol) in DMF (3 mL) was added DIC (62 mul, 0.4 mmol) and the solution was added to the drained resin. The mixture was allowed to stand for 90 min, drained, and washed with DMF. The Kaiser test was negative. The Fmoc group was removed with 20% piperidine (25 min), washed with DMF, and a solution of HMBA (46 mg, 0.3 mmol), Cl-HOBt (101 mg,0.6 mmol), and DIC (63 muL, 0.4 mmol) was added. The reaction was left to proceed overnight, at which point a negative Kaiser test was obtained. Fmoc-Ile-OH (106 mg, 0.3 mmol) was dissolved in DMF (3 mL), DIC (63 muL, 0.4 mmol) was added, and the resultant solution was added to the resin. A solution of DMAP (122 muL, 10 mgmL-1, 0.01 mmol) was added and the mixture shaken for 1 h. The resin was drained and washed with DMF and the procedure repeated twice more to ensure complete esterification. Any remaining hydroxyl groups were capped with 20% (v/v) acetic anhydride in DMF with a catalytic amount of DMAP (0.01 mmol) for 30 min. A total of 203 mg of resin was collected, on which the peptide was elongated as described to afford resin-bound linear peptide. Cyclisation and resin cleavage afforded lassomycin-HMBA-NH2 (125 mg, 62% yield, 64% purity; m/z (ESI-MS) 500.7, (M+4H)4+ requires 500.8). Crude lassomycin-HMBA-NH2 (15 mg, 7.65 mmol) was dissolved in methanol (7.65 mL), cooled to 0 C, and NaOMe (165 mg, 3.06 mmol) was added to give a final concentrationof 0.4 M. The solution was stored at 0 C for 1 h, quenched with TFA (0.58 mL) to give a final TFA concentration of 1M, concentrated under a stream of nitrogen, dissolved in 50% aq.CH3CN containing 0.1 %TFA, and lyophilised. In parallel, a second portion (14 mg) was also subjected to the above conditions. Pooling of both batches and purification by HPLC afforded lassomycin-OMe 1 (4.12 mg, 20% yield). m/z (ESI-MS) 470.9, (M+4H)4+ requires 471.0; 627.5, (M+3H)3+ requires 627.7. Deconvolution yields a mass of 1879.60.07 Da. The calculated mass is 1880.2 Da. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; 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 tetrahydrofuran; at 10 - 35℃; for 1h; | A solution of (R)-3-amino-N-(3-(cyclopropylmethyl)-7-fluoro-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)piperidine-1-carboxamide (0.209 g, 0.50 mmol), 4-(hydroxymethyl)benzoic acid (0.091 g, 0.60 mmol), HATU (0.570 g, 1.50 mmol), DIEA (0.323 g, 2.50 mmol) and DMAP (0.061 g, 0.50 mmol) in THF (5 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0?100% ethyl acetate/hexane), and crystallization from ethyl acetate gave (R)-N-(3-(cyclopropylmethyl)-7-fluoro-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)-3-(4-(hydroxymethyl)benzamide)piperidine-1-carboxamide (0.276 g, 100.0%) as a white powder. 1H NMR (300 MHz, CDCl3):delta 0.40-0.50(4H,m), 1.24-1.32(1H,m), 1.59(6H,d,J=6.0 Hz), 1.65-2.10(4H,m), 2.25(1H,brs), 3.42-3.50(1H,m), 3.55(1H,dd,J=3.0 Hz,12.0 Hz), 3.65-3.75(1H,m), 3.85-3.95(1H,m), 3.93(2H,d,J=6.0 Hz), 4.16(1H,brs), 4.74(2H,s), 4.91(1H,brs), 6.79(1H,brs), 6.74-6.82(1H,m), 7.07(1H,d,J=12.0 Hz), 7.46(2H,d,J=9.0 Hz), 7.79(2H,d,J=9.0 Hz), 8.38(1H,d,J=9.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 12h; | 0.152 g of <strong>[3006-96-0]4-hydroxymethylbenzoic acid</strong> was added to 20 mL of dichloromethane,0.162 g of HOBT, 0.42 mL of triethylamine, 0.230 g of EDCI · HCl,5- (2,5-dimethylphenoxy) -dimethylpentan-1-amine, 0.235 g,Stirred at room temperature for 12 hours,10 ml of methylene chloride was added to the reaction solution, washed with dilute hydrochloric acid, washed with saturated sodium bicarbonate, washed with saturated sodium chloride and dried over anhydrous magnesium sulfate to give 0.24 g of the title compound as a yield of 65.0%. |
57.2% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 12h; | General procedure: To a solution of benzoic acid (0.122 g) and 5-(2,5-dimethylphenoxy)-2,2-dimethylpentan-1-amine 4 (0.235 g) in DCM (15 mL) were added triethylamine (0.42 mL), HOBT (0.162 g), and EDCIHCl (0.230 g). The reaction mixture was stirred at room temperature for 12 h, and then washed with diluted HCl, saturated with NaHCO3 and brine, dried over MgSO4, filtrated, concentrated and the residue was purified by chromatography to afford compound BI-9. Yield 75.1%, mp: 111.5-111.7oC; 1H NMR (400 MHz, DMSO-d6) delta: 8.31 (t, J = 6.2 Hz, 1H), 7.84 (d, J = 7.1Hz, 2H), 7.49-7.45 (m, 3H), 6.97 (d, J = 7.5 Hz, 1H), 6.71 (s, 1H), 6.62 (d, J = 7.5 Hz, 1H), 3.90 (t, J = 6.4 Hz, 2H), 3.17 (d, J = 6.2 Hz, 2H), 2.24 (s, 3H), 2.07 (s, 3H), 1.81 - 1.64 (m, 2H), 1.45 - 1.30 (m, 2H), 0.91 (s, 6H); ESI-MS m/z: 338 [M-H] +. 340 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; ammonium hydroxide; copper(I) bromide; at 120℃; for 24h; | The reactants used were p-methylbenzyl alcohol (i.e., R1 in the formula (I) as the para-COOH) 1.0 mmol(1.8 mmol / L) 3.0 mL, the amount of copper bromide used in the catalyst was 8 mol% (11.5 mg), the amount of TEMPO was 5 mol% (7.8 mg), the amount of TEMPO was 5 mol% The reaction temperature was 120 and the reaction time was 24h. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain the target product in 29.4 mg yield of 88%. |
60% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; ammonium acetate; oxygen; nitric acid; acetic acid; at 50℃; under 760.051 Torr; for 12h;Sealed tube; | General procedure: 0.5 mmol substrate, 1.5 mmol NH4OAc, 0.15 mmol TEMPO, 2 mL AcOH and 0.15 mmol HNO3 weresuccessively added to a dried 45 mL tube filled with 1atm oxygen. Then the reaction tube was sealed andplaced in a constant-temperature oil bath to perform the reaction for 12 h. Once the reaction time wasreached, the mixture was cooled to room temperature. Then the mixture was alkalized to pH 7-8 with sodiumhydroxide aqueous solution. GC analysis of organic phase provided the GC yields of the products.Subsequently, the crude product from another parallel experiment was purified by column chromatography,and identified by 1H-NMR, 1C-NMR or GC-MS |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.9% | 3.37 g of 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propionyl chloride was dissolved in 25 mL of 1,4-dioxane, 1.52 g of <strong>[3006-96-0]4-hydroxymethylbenzoic acid</strong> was added to 20 mL of mixed solvent of 1,4-dioxane: water / 1: 1, 10 mL of 2N sodium hydroxide was added at 0 C. The mixture was stirred for 30 minutes. The solution was added dropwise to the solution at 0 C. Stirring was continued for 10 hours. The mixture was acidified, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The residue was purified by column chromatography to obtain 3.25 g of the title compound in a yield of 71.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With tetramethyl ammoniumhydroxide; sodium iodide; In dimethyl sulfoxide; at 60℃; | General procedure: The syntheses of 1a,b and the starting dibromides 3 and 4were previously published. The previously reported esteri-cation was the basis of a standard ester coupling methodin which 1 equiv. of the dibromide (3 or 4), 2.2 equiv. ofthe head group benzoic acid, and 0.2 equiv. of NaI, weredissolved in DMSO before 2.2 equiv. of tetramethylammoniumhydroxide pentahydrate was added. The reaction washeated at 60C for 12-18h, cooled and subject to compoundspecic workup and characterisation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With tetramethyl ammoniumhydroxide; sodium iodide; In dimethyl sulfoxide; at 60℃; | General procedure: The syntheses of 1a,b and the starting dibromides 3 and 4were previously published. The previously reported esteri-cation was the basis of a standard ester coupling methodin which 1 equiv. of the dibromide (3 or 4), 2.2 equiv. ofthe head group benzoic acid, and 0.2 equiv. of NaI, weredissolved in DMSO before 2.2 equiv. of tetramethylammoniumhydroxide pentahydrate was added. The reaction washeated at 60C for 12-18h, cooled and subject to compoundspecic workup and characterisation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With iodine; dimethyl sulfoxide In nitromethane at 130℃; for 24h; Schlenk technique; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; at 280℃; under 4500.45 Torr;Autoclave; | General procedure: The reaction of hydrogenation of 4-CBA was carried out ina 100 ml Premex stirred autoclave reactor. In a typical run,0.2 g or 0.1 g catalyst, 0.7 g 4-CBA and 70 ml deionizedwater were loaded and reacted at 0.6 MPa and 280 C. Inorder to eliminate diffusion effect as soon as possible, the as-prepared Pd/TNT and commercial Pd/C were crushedinto 300-400 mesh powder, and the agitation speed maintainedat 800 rpm, according to our previous experimentfor Pd/C catalyst. Upon termination at some intervals, thereactant and products were determined by an Agilent 1100Series HPLC equipped with a Hypersil ODS C18 columnusing acetonitrile-methanol-water ternary mixture as gradientelution mobile phase. The conversion of 4-CBA (T) withselectivity to products (S) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; at 280℃; under 4500.45 Torr;Autoclave; | The reaction of hydrogenation of 4-CBA was carried out ina 100 ml Premex stirred autoclave reactor. In a typical run,0.2 g or 0.1 g catalyst, 0.7 g 4-CBA and 70 ml deionizedwater were loaded and reacted at 0.6 MPa and 280 C. Inorder to eliminate diffusion effect as soon as possible, the as-prepared Pd/TNT and commercial Pd/C were crushedinto 300-400 mesh powder, and the agitation speed maintainedat 800 rpm, according to our previous experimentfor Pd/C catalyst. Upon termination at some intervals, thereactant and products were determined by an Agilent 1100Series HPLC equipped with a Hypersil ODS C18 columnusing acetonitrile-methanol-water ternary mixture as gradientelution mobile phase. The conversion of 4-CBA (T) withselectivity to products (S) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With dipotassium hydrogenphosphate; [4,4?-bis(1,1-dimethylethyl)-2,2?-bipyridine-N1,N1?]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; triphenylphosphine; In dichloromethane; water; at 20℃;Inert atmosphere; Irradiation; | Firstly weighing (30.4 mg, 0.2 mmol),photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6(2.3 mg, 0.002 mmol), K2HPO4(7.0 mg, 0.04 mmol), and Ph3P (62.9 mg, 0.24 mmol) are added to a reaction tube, pumping air through the vacuum line three times, in the argon atmosphere, adding DCM/H2O (2.0 ml, 4:1 v/v), then carefully added (31.5 mg, 0.3 mmol), then put into 5 W blue LEDs lamp irradiation, react at room temperature for 36 - 60h. Add 20 ml water, and the DCM extraction (3x 10 ml) the aqueous phase, combined with the organic phase. The organic phase by absolute Na2SO4 after drying and steaming and to remove the solvent, dry sample, column chromatography (300 - 400 item of chromatographic analysis silica gel) (petroleum ether - ethyl acetate) to obtain the product 32.8 mg, Yield 68%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With dipotassium hydrogenphosphate; [4,4?-bis(1,1-dimethylethyl)-2,2?-bipyridine-N1,N1?]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; 2,4,6-Triisopropylthiophenol; water-d2; triphenylphosphine; In dichloromethane; at 20℃; for 36h;Irradiation; Inert atmosphere; Sealed tube; | Weighed first (35.2mg, 0.2mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.3mg, 0.002mmol), Kappa2EtaRhoOmicron4 (34.8mg, 1.0equinu.), and Rhoh3Rho (0.22mmol, 57.6mg, 1.1equiv.) was added to the reaction tube, and the gas was exchanged three times through a vacuum line. Under an argon atmosphere, DCM/D2O (2.0 mL, 1: 1 nu/nu) was added. Then, 2,4,6-triisopropylthiophenol (0.03 mmol, 7.1 mg) was carefully added, and then the tube was sealed and placed under a 5W blue LEDs lamp and allowed to react at room temperature for 36 hours. At the end of the reaction. The reaction completed, the mixture was quenched with water, and extracted with DCM (3x10mL). Rotary evaporated organic phase was dried over anhydrous Na2SO4 the solvent was removed by dry-like, column chromatography (300-400 mesh silica gel chromatography) (eluent: petroleum ether - ethyl acetate, volume ratio: 40-10: 1) to give 19.2 mg, 70 % yield of product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: Fmoc-Lys(tert-butoxycarbonyl) With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.75h; Stage #2: With piperidine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #3: Fmoc-Asp(OtBu)-Ser(ψMe,Mepro)-OH; N-(fluoren-9-ylmethoxycarbonyl)glycine; Fmoc-Val-OH; Fmoc-Leu-OH; N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-alanine; 3-hydroxymethyl-benzoic acid; Fmoc-Gly-Ser(ψMe,MePro)-OH; N-Fmoc L-Phe; Fmoc-Ser(tBu)-OH; Fmoc-(tBu)Asp-OH; Fmoc-Glu(OtBu)-OH; Fmoc-Ile-OH; Fmoc-Tyr(tBu)-OH; N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-methionine; L-Asn(Trt); Fmoc-L-Gln(Trt)-OH; Fmoc-His(Trt)-OH; Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine Further stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; | To a solution of 4-nitrophenyl chloroformate (745 mg, 3.6 mmol), Et3N (505 muL, 3.6 mmol) in 4 mL of DCM at 0 C was added dropwise a solution of 4-(hydroxymethyl)benzoic acid 10 (186 mg, 1.2 mmol) in 4 mL of DCM and 2 mL of DMF. The reaction was stirred at r. t. for 7 h30. The reaction was quenched with NaHCO3, the aqueous layer was extracted with DCM (3×20 mL), the organic layers were combined, dried with MgSO4, and concentrated under reduced pressure. The crude product was purified over silica gel with cyclohexane-EtOAc: 100-0 to 60-40 to give the expected product (217 mg, yield: 74%). 1H NMR (300 MHz, CDCl3) delta 8.33-8.26 (m, 4H), 7.46-7.36 (m, 4H), 5.42 (s, 2H). 13C NMR (75 MHz, CDCl3) delta 163.69, 155.52, 152.36, 145.52, 140.56, 130.80, 129.00, 128.30, 125.33, 122.58, 69.76. HRMS (ESI): m/z Calcd for C15H10NO7, [M-H]+: 316.0457, found: 316.0456. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With triethylamine; In acetonitrile; at 0 - 20℃;Inert atmosphere; | 3.05 g (20 mmol) of 4 -hydroxymethyl benzoic acid and 3.04 (66 mmol) triethylamine were dissolved in 50 mL of dry acetonitrile. The solution was degassed with Ar and cooled down to below 0 C. Subsequently, 2.30 g (22 mmol) of freshly distilled methacryloyl chloride were dissolved in 20 mL dry acetonitrile, degassed and added dropwise under argon atmosphere to the reaction solution. After addition, the reaction was stirred another hour at a temperature below 0 C, then warmed to room temperature and stirred overnight. On the next day, the reaction solution was stabilized with 250 ppm BHT, and the solvent was evaporated. Then, the slurry was dissolved again in CH2C12 and the organic phase was washed with 10 vol% HC1 (3x25 mL) and brine (3x25 mL). The organic layer was dried over Na2S04, filtrated, and stabilized with 50 ppm phenothiazine, before the solvent was removed again. The received white crude solid was purified by means of column chromatography (Si02, PE:EE = 1: 1) to yield 1.91 g (43%) of white crystals. NMR (400 MHz, DMSO-d6, d, ppm): 12.97 (s, 1H; -COOH), 7.96 (d, 2H; Ar-H), 7.51 (d, 2H; Ar-H), 6.11 (s, 1H; = (s, 3H; CH2=CH2-CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With chloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]copper(I); potassium methanolate; In N,N-dimethyl acetamide; at 70℃; for 24h;Schlenk technique; Sealed tube; | In the glove box, to a 50 mL Schlenk bottle equipped with a stir bar was added 4-hydroxymethylphenylboronic acid (1 mmol, 152.0 mg), potassium methoxide (2 mmol, 2 equivalents, 140.2 mg), Cu (IPr) Cl (0.03 mmol, 0.03 equivalents, 14.6 mg), 5 mL of solvent N, N-dimethylacetamide. Remove the capped Schlenk bottle from the glove box, fully evacuate, fill the reaction system with carbon dioxide and seal it well, and then stir the reaction mixture at 70 C. for 24 hours. After cooling to room temperature, it was acidified by adding 1 mol / L hydrochloric acid, and extracted with ethyl acetate, and washed once with brine. The organic phase was collected and concentrated in vacuo. The liquid mixture was dropped on a silica gel column and purified by column chromatography. As petroleum ether / ethyl acetate, the desired product 4-hydroxymethylbenzoic acid was obtained with a yield of 73%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 1h; Sealed tube; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With silver(l) oxide In hexane; dichloromethane at 20 - 60℃; for 12h; Inert atmosphere; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With C21H25IN2Ru; potassium hydroxide In m-xylene at 145℃; for 12h; Schlenk technique; | 2.4.1. A typical reaction under the optimized reaction condition General procedure: To a 25mL Schlenk flask, an NHC-Ru complex (one of [Ru-1]-[Ru-7], 1.56 μmol), an alcohol (25mmol), KOH (1.68g, 30mmol), a stirring bar, and m-xylene (3.0mL) were added. The flask was equipped with a reflux condenser, and the reaction mixture was stirred at a refluxing temperature in open air. After the assigned reaction period, the flask was cooled to room temperature. Water (10mL) and ethyl acetate (20mL) were added, and the two layers were separated. The organic layer was collected, and the aqueous layer was further extracted with ethyl acetate (3× 20mL). Subsequently, the organic layers were combined, dried over Na2SO4, concentrated via a rotary evaporator, dried with a vacuum pump to afford the unreacted alcohol, which was weighed to obtain its yield. Afterwards, 3N HCl (around 12mL) was added to the aqueous layer, which was extracted with ethyl acetate (3× 20mL). The organic layers were combined, dried over Na2SO4, concentrated and dried to afford the desired carboxylic acid, which was weighed to determine its yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With aluminum(III) oxide; ammonia In toluene at 210℃; for 18h; | 2 Comparative Example 2 Add sodium carbonate and deionized water to the reaction kettle, and under the condition of rotating speed of 250r/min,Stir until the sodium carbonate is completely dissolved,Add tetraethylammonium bromide and 4-bromomethylbenzoic acid, under the condition of temperature of 115 ,The reflux reaction was carried out for 1.8h to obtain 4-hydroxymethylbenzoic acid. The saturated toluene solution of 4-hydroxymethyl benzoic acid and ammonia was added into the reactor and stirred, completely dissolved,Add activated alumina, under the condition of pressure of 6MPa and temperature of 210,Carry out reflux reaction for 18h to obtain aminotoluene acid,The yield was 75% (see Patent Document CN111574388A, Example 2). |
Tags: 3006-96-0 synthesis path| 3006-96-0 SDS| 3006-96-0 COA| 3006-96-0 purity| 3006-96-0 application| 3006-96-0 NMR| 3006-96-0 COA| 3006-96-0 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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