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CAS No. : | 1821-12-1 | MDL No. : | MFCD00004403 |
Formula : | C10H12O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OBKXEAXTFZPCHS-UHFFFAOYSA-N |
M.W : | 164.20 | Pubchem ID : | 4775 |
Synonyms : |
4-PBA;Benzenebutyric acid
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.3 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 47.6 |
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) : | -5.58 cm/s |
Log Po/w (iLOGP) : | 1.69 |
Log Po/w (XLOGP3) : | 2.42 |
Log Po/w (WLOGP) : | 2.09 |
Log Po/w (MLOGP) : | 2.29 |
Log Po/w (SILICOS-IT) : | 2.23 |
Consensus Log Po/w : | 2.14 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.49 |
Solubility : | 0.533 mg/ml ; 0.00325 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.85 |
Solubility : | 0.234 mg/ml ; 0.00143 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.98 |
Solubility : | 0.174 mg/ml ; 0.00106 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 |
---|---|---|
42% | With sulfuric acid; iodine; acetic acid; periodic acid In water at 70℃; for 19 h; | A mixture of 4-phenylbutanoic acid (20.0 g, 121.8 mmol), H5IO6 (5.56 g, 24.4 mmol), iodine (13.30 g, 52.4 mmol), 10 M H2SO4 (5.0 mL), water (36 mL) and acetic acid (166 mL) was heated at 70° C. for 19 h. The reaction mixture was cooled and evaporated to dryness. The residue was dissolved in EtOAc (300 mL) and washed with aqueous Na2S2O3 (2*200 mL), brine (2*200 mL), dried over Na2SO4, filtered, and evaporated to leave a yellow solid. The crude product was precipitated from EtOAc/hexane at 0° C. to afford product as light yellow solid (15.0 g, 42percent). 1H NMR (400 MHz, CDCl3) δ 11.0 (brs, 1H), 7.61 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.0 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 2.38 (t, J=7.6 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium hydroxide In water | 0.40 g (2.436 mmol) of 4-phenylbutyric acid are suspended in 30 ml of H2O, and then 0.097 g (2.436 mmol) of sodium hydroxide is added. After the acid has been dissolved, the solution is concentrated by rotary evaporation and twice dewatered azeotropically with toluene. This gives 0.44 g (96.0percent) of sodium 4-phenylbutyrate in solid form. |
88.2% | With sodium hydroxide In ethanol for 4 h; Industrial scale | As shown in Fig. 5, 6000 ml of anhydrous ethanol and 243.6 g of sodium hydroxide were successively charged into 10 L of a four-necked reaction flask. After heating and stirring, 1000 g of phenylbutyric acid prepared in Example 3 was added thereto, stirred and heated to dissolve, (TLC developing solvent: methanol: dichloromethane = 1: 2, Rf = 0.2 for phenylbutyric acid, Rf = 0.1 for sodium phenylbutyrate), and the reaction was terminated for about 4 hours. Add 30g of activated carbon reflux 10 minutes, slightly cold, filter to remove activated carbon. Collect the liquid at 50 ° C. Distillation to remove most of the solvent. A large amount of white solid precipitated. After cooling the residue to 15 ° C, the solid was collected by filtration and washed with 100 ml of absolute ethanol. The solid was dried at 40 ° C for 4 hours and then dried at 60 ° C for 12 hours to give 1000 g of white sodium phenylbutyrate in 88.2percent yield, HPLC purity of 99.77percent (octadecyl silane bonded silica as stationary phase, Glacial acetic acid-methanol-water (1:49:50) as the mobile phase; detection wavelength of 245nm), high-performance liquid chromatography shown in Figure 5, the results shown in Table 8, we can see that a single impurity control Within 0.1percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 4-Phenylbutyric acid With sodium tetrahydroborate In tetrahydrofuran at 60℃; for 0.25h; Stage #2: With iodine In tetrahydrofuran for 5h; | 1.1-1.4; 2-10 1. Intermediate 4-phenyl-butyl alcohol synthesis method, characterized in that the method comprises the following steps: step 1,0.5 g Fe-N/C catalyst 0.8 g NaBH4 and 30 ml tetrahydrofuran were added to a 250 m1 four-necked flask.Mechanically stirred, slowly heated to 60 ° C, held for 15 min; Step 2. Add 3.0 g of 4-phenylbutyric acid to the above system.Constant temperature reaction at this temperature for 15 min,10 ml of 2.4 g of I2 in tetrahydrofuran solution was added dropwise.The system is gradually milky white,And produce a lot of bubbles,Insulation reaction for 5h;Step 3. After the reaction is completed, the reaction is stopped with 5 ml of 3 mol/L HCl.At this time, the upper layer of yellow organic liquid,Lower white solid,After stirring for 15 min, the remaining reaction solution was poured into a single-necked flask.After being steamed to remove tetrahydrofuran, it is orange;Step 4,After adding 30 ml of dichloromethane to dissolve,Filtered to give a pale yellow filtrate.Wash with saturated brine and deionized water in turn,Under the condition of magnetic stirring, water is removed by anhydrous calcium chloride and a small amount of sodium thiosulfate is used to remove iodine.Got a colorless transparent organic liquid,Squeeze the solvent,A pale yellow transparent liquid 4-phenylbutanol was obtained. |
98.4% | Stage #1: 4-Phenylbutyric acid With sodium tetrahydroborate In tetrahydrofuran at 60℃; for 0.25h; Stage #2: With iodine In tetrahydrofuran for 5h; | 1 Example 1 Step 1, in a 250m1 four-necked flask was added 0.5g Fe-N / C catalyst 0.8g NaBH4 and 30ml tetrahydrofuran, mechanically stirred, slowly heated to 60 ° C, kept for 15min;Step 2, adding 3.0 g of 4-phenylbutyric acid to the above system, reacting at this temperature for 15 min, adding 10 ml of 2.4 g of I2 in tetrahydrofuran solution, the system is gradually milky white, and a large number of bubbles are produced, and the reaction is kept for 5 hours;Step 3, after the reaction was completed, the reaction was stopped with 5 ml of 3 mol/L HCl. At this time, the upper yellow organic liquid and the white solid were stirred. After stirring for 15 min, the remaining reaction liquid was poured into a single-necked flask, and then evaporated to remove tetrahydrofuran to give an orange color;Step 4, after adding 30 ml of dichloromethane to dissolve, suction filtration to obtain a pale yellow filtrate, which was washed successively with saturated brine and deionized water, and water-dissolved with anhydrous calcium chloride to remove water and a small amount of sodium thiosulfate to remove iodine. A colorless transparent organic liquid was obtained, and the solvent was evaporated to give a pale yellow transparent liquid 4-phenylbutanol. |
96% | With C25H42N6Rh(1+)*CF3O3S(1-); phenylsilane In tetrahydrofuran at 30℃; for 20h; Inert atmosphere; |
92% | Stage #1: 4-Phenylbutyric acid With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Stage #2: With water In tetrahydrofuran | 1.1 Step 1 Step 1 4-Phenylbutan-1-ol: At 0~10° C., a solution of 4-phenylbutanoic acid (10 g; 60.4 mmol; 1.00 equiv) in tetrahydrofuran (50 mL) was added to a suspension of lithium aluminum hydride (4.6 g; 121 mmol; 2.01 equiv) in tetrahydrofuran (100 mL). The suspension was virgously stirred at ambient temperature for about 2 hours and then quenched by adding water. Standard extractive workup with ethyl acetate afforded the title product as a yellow liquid (8.4 g; 92% yield). 1H NMR (300 MHz, CDCl3) δ: 7.31 (t, J=7.5, 7.2 Hz, 2H), 7.15 (m, 3H), 3.68 (t, J=6.3, 6.3 Hz, 2H), 2.68 (t, J=7.2, 7.8 Hz, 2H), 1.69 (m, 4H). |
91% | With lithium aluminium tetrahydride In diethyl ether | |
89% | With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 4h; | |
84% | With lithium aluminum hydride In diethyl ether at 35℃; for 2h; | |
80% | With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; | |
80% | With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 2h; | |
79% | With lithium aluminium tetrahydride | |
63% | With lithium aluminium tetrahydride In diethyl ether | |
With lithium aluminium tetrahydride; diethyl ether | ||
With lithium aluminium tetrahydride | ||
With lithium aluminium tetrahydride In diethyl ether | ||
With sodium tetrahydroborate; boron trifluoride diethyl etherate | ||
Multi-step reaction with 2 steps 1: 84 percent / AgOTf / CH2Cl2 / 1 h / 20 °C 2: DIBAH / toluene / 0.5 h / 0 °C | ||
Multi-step reaction with 2 steps 1: HCl (gas) 2: LiAlH4 / tetrahydrofuran | ||
With sodium hydroxide In water | 2.a Preparation 2 a. 4-Phenyl-1-butanol.- A solution of 200 g. of 4-phenylbutyric acid in 1500 ml. of anhydrous ether is added with stirring to a suspension of 46.3 g. of lithium aluminum hydride in 1800 ml. of anhydrous ether at a rate sufficient to maintain gentle reflux while the mixture is cooled in an ice bath. Fifteen minutes after the addition is complete the mixture is treated cautiously, under nitrogen, wit 93 ml. of water and then 74 ml. of 10% aqueous sodium hydroxide. The mixture is stirred about 18 hrs. at about 25° C. and dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 171 g. of 4-phenyl-1-butanol; infrared absorption at 3250, 2980, 1610, 1060, 1030, 750 and 700 cm-1; NMR peaks at 7.30 (singlet), 3.61 (triplet), 2.65 (multiplet) and 2.75 (singlet) δ. | |
97.8 %Chromat. | With cobalt(II) oxide; hydrogen at 159.84℃; for 6.5h; Autoclave; | 2.3 Catalytic evaluation and product analysis General procedure: The hydrogenation of carboxylic acids or other substrates was performed in a high-pressure stainless-steel autoclave (Xinyuan Chemical Machinery, Series CJK, 300 mL) with a maximum stirring rate of 1500 r/min. In a typical experiment, 0.2 g of catalyst (or without catalyst for the control experiment), 3 mmol of the substrate, and 100 mL alkane solvent (n-hexane, n-heptane, i-octane, or n-dodecane) were well mixed in the autoclave and purged with pure nitrogen at room temperature. The gas supply and discharge were carried out manually through needle valves. The autoclave was rapidly heated to the desired temperature and hydrogen was introduced at 2 MPa to initiate the reaction. The reaction pressure was kept at 2 MPa with a small negative deviation (∼0.2 MPa) owing to the consumption of hydrogen. Samples of the liquid phase were continuously taken through a sampling tube with a filter at certain intervals. The stirring rate was kept at 750 r/min during the reaction. |
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | ||
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sulfuric acid; iodine; acetic acid; periodic acid; In water; at 70℃; for 19h; | A mixture of 4-phenylbutanoic acid (20.0 g, 121.8 mmol), H5IO6 (5.56 g, 24.4 mmol), iodine (13.30 g, 52.4 mmol), 10 M H2SO4 (5.0 mL), water (36 mL) and acetic acid (166 mL) was heated at 70 C. for 19 h. The reaction mixture was cooled and evaporated to dryness. The residue was dissolved in EtOAc (300 mL) and washed with aqueous Na2S2O3 (2*200 mL), brine (2*200 mL), dried over Na2SO4, filtered, and evaporated to leave a yellow solid. The crude product was precipitated from EtOAc/hexane at 0 C. to afford product as light yellow solid (15.0 g, 42%). 1H NMR (400 MHz, CDCl3) delta 11.0 (brs, 1H), 7.61 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.0 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 2.38 (t, J=7.6 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxalyl dichloride; In dichloromethane; | A solution of 200 mg 4-phenylbutyric acid in dichloromethane was treated with oxalyl chloride (3.0 eq) and was stirred overnight. The solvent and excess oxalyl chloride was removed to give 227 mg of 4-phenylbutanoyl chloride as a clear oil. The presence of the title compound was confirmed by converting it to the methyl ester by dissolving a sample in methanol, and analyzing this by electrospray LC-MS using method A; tR = 3.7 min. The ester is UV-active-only (no ELS signal). This contrasts with the starting material which has an earlier retention time and is ELS- active. | |
With thionyl chloride;N,N-dimethyl-formamide; at 20℃; for 3h; | EXAMPLE 149 Synthesis of N-[4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-pyrimidinyl]-4-phenylbutanamide: 56.2 mg (0.342 mmol) of 4-phenylbutyric acid was dissolved in 1 ml of thionyl chloride. A catalytic amount of DMF was added and stirred at room temperature for 3 hours. After the solvent was evaporated under reduced pressure, 45.4 mg (0.171 mmol) of 4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-pyrimidinamine and 1 ml of pyridine were added and stirred at 50 C. overnight. After the solvent was evaporated under reduced pressure, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound. Yield: 12.3 mg (0.0299 mmol) (18%) MS (ESI, m/z) 412 (M+H)+ 410 (M-H)- 1H-NMR (CDCl3): 2.00 (3H, quint), 2.29 (2H, t), 2.44 (3H, s), 2.58 (3H, s), 2.65 (2H, t), 7.14-7.47 (8H, m), 7.56-7.57 (1H, m). | |
With thionyl chloride; | 4-Phenylbutanoylchloride (prepared from 4-phenylbutanoic acid (0.73 g, 4.4 mmol) and thionyl chloride (0.64 ml, 8.9 mmol) ) was added to a solution of the 5 (R)-methyl-L- proline ethyl ester trifluroacetic acid salt (prepared from Boc-5 (R)-methyl-L-proline ethyl ester (0.90 g, 3.7 mmol) according to procedure E) and triethyl amine (2.1 ml, 15.0 mmol) in dichloromethane at 0 C, where after it was stirred at rt for 3 h. The dichloromethane phase was washed with 30 % citric acid, saturated NACL and saturated NAHC03. The dichloromethane phase was dried and evaporated. Purification by flash chromatography, yield 0.74 g (2.6 mmol). |
With oxalyl dichloride; In dichloromethane; at 20℃; | Trifluoromethyl ketones (27.1 -4) were synthesized by a method depicted in Scheme 6. 4-Phenyl-butyric acid (25.1), 5-phenyl-pentanoic acid (25.2), 6-phenyl-hexanoic acid (25.3) and 5-(4-methoxy-phenyl)-pentanoic acid (25.4) were commercially available starting materials. | |
With thionyl chloride; In benzene; for 2h;Reflux; Inert atmosphere; | A solution of 4-phenylbutyric acid (18.76g, 114.23mmol) in benzene (147mL) was treated with thionyl chloride (25.27mL, 348mmol) and the resulting mixture was refluxed for 2h, then the solvent was removed under vacuum and the resulting brown oil was subjected to the following step without further purification. | |
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20 - 30℃; for 1h; | 4-phenylbutyric acid (300 g, 1.827 mol) was dissolved in dichloromethane (450 ml). Dimethylformamide (3 ml) was added and the reaction mixture was stirred to get a clear solution. Thionyl chloride (172 ml, 2.375 mol) was added drop wise at temperature 20-30 C and stirred for one hour. 4-phenyl butyryl chloride (II) was isolated as oil by removing the solvent and thionyl chloride by distillation under reduced pressure | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; | INTERMEDIATE 4: 4-phenylbutanoyl chlorideOxalyl chloride (6 ml, 68.5 mmol) was added to a solution of 4-phenylbutanoicacid (7 g, 42.6 mmol) in dichloromethane (207 ml) and a few drops of DMF at 0 00. Thereaction was allowed to warm to room temperature overnight then concentrated to givethe title compound as a yellow oil which was used without further purification or characterization. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere; | To an oven-dried 100 mL three-necked flask, 4-phenylbutyric acid (1.6 g, 10 mmol), DMF (5drops) and DCM (20 mL) were added under a N2 atmosphere. Oxalyl chloride (1.0 mL, 12 mmol,1.2 equiv.) was added dropwise at 0 C resulting in vigorous bubbling. The mixture was stirred for 3h at room temperature, and the solvent was then removed in vacuo. The resulting acid chloride wasused immediately without further purification. To a solution of acid chloride in DCM(30 mL), thesolution of 8-amino-5-chroloquinoline (2.1 g, 12 mmol, 1.2 equiv.), Et3N (2.5 mL, 24 mmol, 2equiv.) in DCM (15 mL) were added dropwise to the solution at 0 C, and the solution was thenwarmed to room temperature. After stirring overnight, the reaction system was quenched with sat. aq.NaHCO3 (30 mL) and the organic layer was separated. The aqueous layer was extracted with DCM(2 x 15 mL). The combined organic layers were washed with 1 M HCl aq. (30 mL) and brine (30mL), dried over MgSO4, filtered and evaporated in vacuo. The resulting crude amide was purified bycolumn chromatography on silica gel (eluant: hexane/EtOAc = 4/1) to afford the desired amide as awhite solid (2.5 g, 77%). | |
With oxalyl dichloride; In N,N-dimethyl-formamide; at 0 - 20℃; | Oxalyl chloride (6 ml, 68.5 mmol) was added to a solution of 4-phenylbutanoic acid (7 g, 42.6 mmol) in dichloromethane (207 ml) and a few drops of DMF at 0 C. The reaction was allowed to warm to room temperature overnight then concentrated to give the title compound as a yellow oil which was used without further purification or characterization. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; | Oxalyl chloride (6 ml, 68.5 mmol) was added to a solution of 4-phenylbutanoic acid (7 g, 42.6 mmol) in DCM (207 ml) and a few drops of DMF at 0 C. The reaction was allowed towarm to room temperature overnight then concentrated to give the title compound as a yellow oil which was used without further purification or characterization. | |
With oxalyl dichloride; In dichloromethane; at 0 - 20℃; for 3h; | General procedure: Oxalyl chloride (23 mmol) was added dropwise to a solution of the appropriate phenylalkyl acid (1a-f) (10 mmol) in dry CH2Cl2(18.5 mL) cooled at 0 C. After complete addition, the mixture was stirred at room temperature for 3 h. After this period, the mixture was evaporated to dryness and the obtained phenylalkyl acylchloride was used for the next reaction without further purification. 2N trimethylsilyldiazomethane in dry Et2O (27.3 mL) was added dropwise to a solution of the appropriate phenylalkyl acylchloride (10 mmol) in dry CH3CN (13.5 mL) cooled at 0 C. After stirring at 0 C for 2 h, 48% aqueous HBr (15.3 mL) was added drop wise to the mixture cooled at 0 C. After complete addition, the mixture was stirred at room temperature overnight, then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and NaHCO3 solution, then dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate/light petroleum (1:2). | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 4h; | Synthesis of 4-Phenylbutanoyl chloride (6): To a stirred solution of 4-phenylbutanoic acid 5 (60 g, 0.3654 mol) in DCM (600 mL), DMF (1 mL) and oxalyl chloride (231.9 g, 1.83 mol) were added and allowed the mixture to stir at rt for 4h. The mixture was concentrated under reduced pressure under nitrogen atmosphere to obtain 6 (65 g, crude) as a light brown liquid compound which was used as such in next step. | |
With thionyl chloride; In benzene; at 80℃; for 3h; | 5-Ethylsulphonyl-2-(p-amino-phenyl)benzoxazole (1) was synthesized by heating 0.01mol 4-ethylsulphonyl-2-aminophenol. HCl with 0.01mol p-amino-benzoic acid in 24g polyphosphoric acid was stirred 3h. At the end of the reaction period, the resiude was poured into ice-water, stirred and was neutralized with excess of 10% NaOH solution extracted with benzene. The benzene solution was dried over anhydrous sodium sulphate and evaporated under diminished pressure. The residue was boiled with 200mg charcoal in ethanol and filtered and a crude product was obtained and recrystallized from ethanol-water mixture and compound 1 was dried in vacuo. Benzene butanoic acid (0.5mmol) and thionyl chloride (1.5ml) were refluxed in benzene (5ml) at 80C for 3h excess thionyl chloride was removed in vacuo. The benzenebutanoyl chloride (2) were dissolved in ether (10ml) and this solution added during 1h to a stirred, ice-cold mixture of 5-ethylsulphonyl-2-[p-amino-phenyl]benzoxazole (1), (0.5mmol), sodium bicarbonate (0.5mmol), diethyl ether (10ml) and water (10ml). The mixture was kept stirred overnight at room temperature and filtered. The precipitate was washed with water, 2N HCl and water, respectively and finally with ether to give 3 (Scheme 1 , supporting material) [14]. The product was recrystallized from ethanol-water as needles which are dried in vacuo. The chemical, physical and spectral data of the compound 3 is reported below: 2.2.1 Compound 3: 20 2-[4-(4-phenylbutanamido)phenyl]-5-ethylsulphonyl-benzoxazole C25H24N2O4S, yield: 41.72%, Mp: 250-251C. 1H NMR (400MHz, d-DMSO, (δ ppm) J=Hz): 10.327 (s, 1H), 8.263-8.259 (d, 1H, J4,6=1.6Hz), 8.193-8.171 (d, 2H, J2′,3’=J6′,5’=8.8Hz), 8.051-8.029 (d, 1H, J7,6=8.8Hz), 7.936-7.910 (dd, 1H, J6,4=1,6Hz, J6,7=8.6Hz), 7.882-7.861 (d, 2H, J3′,2’=J5′,6’=8.8Hz), 3.413-3.350 (m, 2H), 7.323-7.195 (m, 5H), 2.668-2.630 (t, 2H), 2.419-2.382 (t, 2H), 1.946-1.909 (m, 2H), 1.128 (t, 3H) MS (70eV)m/z: 449.8 (M++H) | |
With thionyl chloride; at 90℃; for 2h; | General procedure: The corresponding carboxylic acid and an excess of thionyl chloride (2eq. or more) were refluxed at 90 C for 2 h. Subsequently, the excess thionylchloride was removed under vacuum. | |
With thionyl chloride; In dichloromethane; for 3h;Reflux; | General procedure: To the corresponding carboxylic acid (11a-c, 3.0 mmol) in dry dichloromethane, thionyl chloride (3.6 mmol) was added and refluxed for 3 h. After the completion of the reaction, the reaction mixture was evaporated under vacuum and immediately used for the next step | |
With thionyl chloride; for 1h;Heating / reflux; | A mixture of benzenebutanoic acid (0.0131 mol) and SOCl2 (12 ml) was refluxed for 1 hour while stirring. The excess of SOCl2 was removed in vacuo. The residue was diluted with dry benzene (15 ml) and then concentrated (repeated twice). Then, a <n="78"/>solution of acyl chloride in benzene (10 ml) was added dropwise to a mixture of 4-[4- (phenylmethyl)-l-piperazinyl]benzenamine (0.0094 mol), Et3N (2.8 ml) and dry benzene (45 ml) while stirring. The reaction mixture was refluxed for 3 hours at stirring. Sedimentation was observed. The reaction mixture with formed precipitate was concentrated. Then, residue was partitioned between DCM (60 ml) and 10 % aqueous K2CO3 (40 ml). The organic layer was separated, washed with water, dried over MgSO4, and concentrated in vacuum. The residue was triturated with an ether-hexane mixture. The formed precipitate was filtered off and dried on air. Yield: 3.71 g of intermediate 21 (96 %). | |
With thionyl chloride; at 20℃; | Benzenebutanoic acid (0.1670 mol) in thionyl chloride (1.7 mol) was stirred overnight at room temperature. The solution was evaporated and coevaporated twice with toluene. This residu was dissolved in 100 ml of acetonitrile and added dropwise to a suspension of intermediate 2 and NaHCCh in 500 ml acetonitrile which was cooled on a water bath for 15 minutes. The mixture was treated with 2.5 1 water and stirred for 2 hours. The precipitate was recuperated, washed with water and recrystallized from 400 ml boiling ethanol. Yield : 64.2 g of intermediate 3 (88 %) | |
With thionyl chloride; In dichloromethane; at 0 - 20℃; for 10h; | To a solution of 4-phenylbutanoic acid (5 g, 30.45 mmol, 1 equiv.) in dichloromethane (50 mL) was added SOd2 (10.87 g, 91 .35 mmol, 6.63 mL, 3 equiv.) at 0 00. The mixture is stirred at 20 C for 10h. The reaction mixture was concentrated under reduced pressure to give a residue that was dissolved intoluene (15 mL). The solution was concentrated under reduced pressure to afford 4-phenylbutanoylchloride (4.32 g, crude) as a yellow oil, which was used in next step directly. | |
With thionyl chloride; In tetrahydrofuran; for 3h;Reflux; Inert atmosphere; | General procedure: To a solution of p-toluic acid (452 mg, 3.32 mmol) in 10 mL of fresh distilled dry THF was added thionyl chloride (SOCl2, 0.25 mL, 3.25 mmol). The mixture was refluxed 3 hours, and after cooling dried under N2 stream. The residue was dissolved in 10 mL of dry methylene chloride (DCM) and added dropwise to an ice bath cooled solution of 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole(500 mg, 2.75 mmol), and TEA (1.15 mL, 8.25 mmol). Mixture was stirred overnight at room temperature, and then diluted with 20 mL of DCM. The organic phase was washed with saturated aqueous Na2CO3(315 mL), 1N HCl (315 mL) and brine (315 mL), then dried (anhydrous Na2SO4), filtered and concentrated under reduced pressure. The residue oil was purified by chromatography on silica gel (ethyl acetate/n-hexane 70/30 v/v) | |
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 5h; | To a solution of 4-phenylbutanoic acid (3 g, 18.27 mmol, 1 equiv.) and SOCI2 (10.87 g, 91 .35 mmol, 6.63 ml_, 5 equiv.) in dichloromethane (50 ml_) is added one drop of DMF, then the mixture stirred at 20C for 5 h. The solvent is removed in vacuum and toluene (20 ml_) added to the mixture. The mixture is concentrated in vacuo to afford 4-phenylbutanoyl chloride (3.5 g, crude). | |
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 5h; | To a solution of 4-phenylbutanoic acid (3 g, 18.27 mmol) and SOCI2 (10.87 g, 91 .35 mmol, 6.63 ml_) in dichloromethane (50 ml_) is added one drop of DMF, then the mixture stirred at 20C for 5 h. The solvent is removed in vacuum and toluene (20 ml_) added to the mixture. The mixture is concentrated in vacuo to afford 4-phenylbutanoyl chloride (3.5 g, crude). | |
With thionyl chloride; In dichloromethane; at 0 - 20℃; for 10h; | To a solution of 4-phenylbutanoic acid (5 g,30.45 mmolj in dichloromethane (50 mL) was added (0736) SOCI (10.87 g,91 .35 mmol,6.63 mL) at 0 C. The mixture is stirred at 20 C for 10 h. The reaction mixture was concentrated under reduced pressure to give a residue that was dissolved in toluene (15 mL). The solution was concentrated under reduced pressure to afford 4-phenylbutanoyl chloride (4.32 g, crude) as a yellow oil, which was used in next step directly. | |
With oxalyl dichloride; In dichloromethane; at 0℃; for 2h;Reflux; Green chemistry; | Add 10mmol of the compound of formula (I) and 20mL of dichloromethane to the reactor successively, add 20mmol of oxalyl chloride dropwise to the reactor under an ice bath, and then raise the temperature to reflux for 2 hours after the completion of the drop. After the reaction is completed, it is evaporated to dryness in vacuo to obtain the formula (II) The crude 4-phenylbutyryl chloride compound was dissolved in 20mL of toluene, Fe-Al-MCM-41 molecular sieve was added to start the reaction, and the reaction was stirred at 60C for 18 hours. After the reaction was completed, it returned to room temperature and filtered with suction. The molecular sieve catalyst was washed with toluene and recovered, the filtrate was combined, evaporated to dryness in vacuo, and the residue was purified by silica gel column chromatography to obtain the benzocyclohexanone compound of formula (III) with a yield of 95.2%. | |
With thionyl chloride; In dichloromethane; at 0℃; for 5h;Reflux; | General procedure: To a stirred solution of the corresponding acid 12 (1.25mmol) in DCM (5mL), SOCl2 (3.75mmol) was added at 0C. The resulting reaction mixture was refluxed for 5h. After cooling to room temperature, the reaction was concentrated under reduced pressure to afford crude compound. The crude compound was dissolved in pyridine (5mL), and added 3-phenylisoxazol-5-amine 10a (1.25mmol). The resulting reaction mixture was stirred at 80C for 16h. After cooling to rt, the reaction was concentrated under reduced pressure and then diluted with EtOAc. The organic phase was washed with 1N HCl solution (2x times), dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The crude residue was subjected to flash silica gel (230-400 mesh) column chromatography (eluting with 10-15% EtOAc in hexanes) to afford the title compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.4% | With ethanol; sodium hydroxide at 50 - 60℃; for 0.666667h; Green chemistry; Large scale; | 3 Example 1 Preparation of 4-phenylbutyric acid The methyl 4-phenylbutyrate prepared in Example 1 was subjected to hydrolysis,Preparation of phenylbutyric acid by acidification. Preparation of phenylbutyric acid by acidification. The amount of each raw material used in the present example is shown in Table 4. As shown in Figure 3, anhydrous ethanol 6000ml, 450g sodium hydroxide were added into the 10L four-mouth reaction bottle. Heated to 50-60°C. After stirring to dissolve, 1000 g of methyl 4-phenylbutyrate was added. The reaction was stirred at 55°C. The progress of the reaction was monitored by TLC (developing solvent: ethyl acetate: triethylamine 10: 1, 4-phenylbutyric acid Rf = 0.2, methyl 4-phenylbutyrate Rf = 0.75). 40 minutes starting material disappeared. Post-processing: The solvent was removed by distillation under reduced pressure at 50°C. A white solid was obtained. The solid was dissolved by stirring with 10 L of pure water. The pH of the solution was adjusted to 3.5 with concentrated hydrochloric acid. A large number of white solid precipitation. 5°C for 4 hours. Filter. The solid was collected by filtration. Washed three times with pure water (200 ml each). 40°C dry for more than 12 hours blast. 870 g of 4-phenylbutyric acid was obtained, yield was 94.4%, HPLC purity 99.85%, High performance liquid chromatogram shown in Figure 4. The results of the analysis are shown in Table 5. As can be seen, a single impurity are controlled within 0.13%. |
94.4% | With sodium hydroxide In ethanol at 50 - 60℃; for 0.666667h; Large scale; | 3 Example 3, Preparation of phenylbutyric acid As shown in Fig. 3, 450 ml of anhydrous ethanol and 450 g of sodium hydroxide were successively added to 10 L of a four-necked reaction flask, and the mixture was heated to 50 to 60 ° C. After stirring, the mixture was added with methyl 4-phenylbutyrate, C stirring reaction. TLC monitoring reaction process (developing solvent: ethyl acetate: triethylamine 10: 1, phenylbutyric acid Rf = 0.2 4-phenylbutyrate methyl ester Rf = 0.75), 40 min raw material disappeared. Post-treatment: The solvent was removed by distillation under reduced pressure at 50 ° C to give a white solid. The solid was stirred with 10 L of pure water and the pH of the solution was adjusted to 3.5 with concentrated hydrochloric acid. A large amount of white solid was precipitated and allowed to stand at 5 ° C for 4 hours. The solid was collected by filtration and washed three times with pure water (200 ml each). 40 ° C blast drying for more than 12 hours to obtain 870 g of phenylbutyric acid, the yield is 94.4% and the HPLC purity is 99.85%. The high performance liquid chromatogram is shown in Fig. 4, and the results are shown in Table 5. , A single impurity are controlled within 0.13% |
With sodium hydroxide In acetone at 25℃; other temp., ΔH excit., ΔS excit.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | at 20℃; for 11h; | |
99% | With molecular sevies 4A at 20℃; for 11h; | 4 Example 4 [Use of Volatile Alcohol as a Solvent] The catalyst activity of hafnium chloride (IV)•(THF)2 in the esterification reaction of carboxylic acid with volatile alcohol such as methanol was studied. A Soxhlet tube filled with dried molecular sieves 4A (about 1.5 g) was connected to the top of a 5 ml eggplant flask contained with a teflon coated magnetic stirrer, and a cooling tube was further attached over said Soxhlet tube. As it is shown in the following equation, 1 mol % of hafnium choloride (IV)•(THF)2 was added to the carboxylic acid (10 mmol) and methanol (10 mmol), and heating reflux was conducted in the argon for several hours at room temperature. As a result, ester was obtained at a yield of 99%. |
97% | With sulfuric acid Reflux; |
96% | With hydrogenchloride at 20℃; | |
96% | at 20℃; for 1h; | 1 Example 1 : Preparation of methyl 4-phenylbutanoateH2SO4 (7.16 ml, 73.08 mmol) was added to a solution of 4-phenylbutanoic acid (40.0 g, 243.60 mmol) in MeOH (300 ml). The reaction mixture was stirred at room temperature for 1 h, poured into H2O (500 ml) and extracted with CH2CI2 (2x400 ml). The organic layer was washed with NaHCO3 (300 ml, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (10→20% EtOAc/hexanes), to furnish methyl 4-phenylbutanoate (41.95 g, colourless oil, yield: 96%). 1H NMR (CDCI3, 250 MHz) δ ppm: 7.28 (m, 2H), 7.20 (m, 3H), 3.68 (s, 3H), 2.67 (t, J = 7.4 Hz, 2H), 2.35 (t, J = 7.4 Hz, 2H), 1.99 (m, 2H). |
96% | With sulfuric acid for 16h; | |
95% | With dimesitylammonium pentafluorobenzenesulfonate at 22℃; for 24h; | |
95% | at 20℃; for 24h; | |
94% | With thionyl chloride for 2h; Reflux; | |
94.9% | With sulfuric acid for 5h; Reflux; Green chemistry; Large scale; | 1 Example 1 Preparation of methyl 4-phenylbutyrate With industrial grade 4-phenylbutyric acid as raw material, methyl 4-phenylbutyrate was prepared according to the scheme shown in Fig. 1. The amount of each raw material used in the present example is shown in Table 1. As shown in Figure 1, 1000ml of methanol, 1000g of industrial grade 4-phenylbutyric acid were put into 2000ml four-mouth reaction bottle. After stirring, 50 ml of concentrated sulfuric acid was added. Stirring, The reaction was heated to reflux until the starting material disappeared. TLC monitoring reaction (developing solvent: ethyl acetate: triethylamine 10: 1, starting material Rf = 0.2, methyl 4-phenylbutyrate Rf = 0.75). The reaction was complete in about 5 hours. Post-processing: temperature below 40°C. The solvent was removed by distillation under reduced pressure. The residue was cooled to below 20°C. 500 ml of pure water was added. The pH was adjusted to 9 with 4N aqueous sodium hydroxide solution; After stirring for 10 minutes, the layers were allowed to stand. The organic phase was collected. The organic phase was washed successively with 300 ml of a 5% aqueous solution of sodium carbonate, 300ml pure water, stirring and washing for 10 minutes. The organic phase was collected. The organic phase was dried with an appropriate amount of anhydrous magnesium sulfate for 4 hours. The desiccant was removed by filtration. About 1030g methyl 4-phenylbutyrate, yield was 94.9%, purity of 99.7% (detection conditions: with octadecyl silane bonded silica as a filler; 0.05mol / L sodium dihydrogen phosphate solution (adjusted to pH with phosphoric acid to 3.0) - acetonitrile (55:45, volume ratio) as the mobile phase; detection wavelength of 210nm; flow rate of 1.0ml per minute; column temperature of 30°C.). High performance liquid chromatogram shown in Figure 2. The results of the analysis are shown in Table 2. As can be seen, a single impurity are controlled within 0.1%. |
94.9% | With sulfuric acid for 5h; Reflux; Large scale; | 1 Example 1 - Preparation of methyl phenylbutyrate As shown in Fig. 1, 1000 ml of methanol and 1000 g of industrial grade phenylbutyric acid were successively put into a 2000-ml four-necked reaction flask and dissolved in 50 ml of concentrated sulfuric acid. Stirring, heating to reflux reaction to disappearance of raw materials. TLC monitoring reaction (developing solvent: ethyl acetate: triethylamine 10: 1, raw material Rf = 0.2, methyl phenylbutyrate Rf = 0.75), about 5 hours reaction is complete. Post-treatment: temperature below 40 ° C, solvent removal under reduced pressure. The residue was cooled to below 20 ° C, 500 ml of pure water was added and the pH was adjusted to 9 with 4N aqueous sodium hydroxide. After stirring for 10 minutes, the layers were allowed to stand and the organic phase was collected. The organic phase was washed successively with 300 ml of a 5% aqueous solution of sodium carbonate, 300 ml of pure water and stirred for 10 minutes, and the organic phase was collected. The organic phase was dried with anhydrous magnesium sulfate for 4 hours, and then the desiccant was removed by filtration to give about 1030 g of methyl phenylbutyrate in 94.9% yield and 99.7% purity (detection conditions: octadecylsilane bonded silica gel (55:45, volume ratio) as the mobile phase; detection wavelength of 210nm; flow rate of 1.0ml per minute; the flow rate of 1.0ml per minute; Column temperature of 30 ° C.), high-performance liquid chromatography shown in Figure 2, the results shown in Table 2, we can see that a single impurity are controlled within 0.1%. |
92% | With potassium carbonate In acetonitrile at 50℃; Sealed tube; Inert atmosphere; Sonication; | |
92% | With tert.-butylnitrite at 40℃; for 48h; Green chemistry; | |
91% | With thionyl chloride | |
90% | With sulfuric acid In 1,2-dichloro-ethane | |
90% | for 3h; Heating / reflux; | 3E A mixture of 4-phenyl butyric acid (3.64 g, 23.95 mmol), H2SO4 (several drops, catalytic amount) in MeOH (17 ml) was refluxed for 3 hr. TLC showed that no starting material was present. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (30 ml), and washed with sat. NaHCO3 (2 x 20 ml), H20 (2 x 20 ml), and brine (30 ml). The organic layer was dried (MgS04), and filtered. The filtrate was concentrated in vacuo to provide an oil (3.55 g, 90%). 1H NMR (CDCl3. 400 MHz) 6 1.93-2. 03 (m, 2H), 2.46 (t, J= 5. 88 Hz, 2H), 2.67 (t, J= 5.97 Hz, 2H), 3.67 (s, 3H), 7.12- 7.22 (m, 3H), 7.24-7. 33 (m, 2H). |
90% | Stage #1: methanol; 4-Phenylbutyric acid at 20 - 33℃; for 2h; Stage #2: With sulfuric acid at 49℃; | 1.a 1800 g (10.98 moles) of 4-phenylbutyric acid, crystalline in a glass bottle was heated with a heating blanket for 2 h to melt the acid. The liquid was poured in 8 L of methanol in a 22 L reaction flask (3-necked round-bottom flask fitted with stirrer and thermometer adapters). The solution was stirred under Argon, temperature 200C - 330C, and 400 ml_ concentrated sulfuric acid was added in 50 ml. portions. The temperature increased to 490C. The solution was stirred under argon over the week-end and allowed to cool to ambient temperature. The solution was transferred to a quench tank and diluted with 8 L of water. The oil formed was separated and the aqueous phase was extracted with 2 x 1 L of ethyl acetate. The extracts were combined with the oil and the solution concentrated to give 1753 g of clear oil in 90 % yield. |
88% | With sulfuric acid for 18h; Heating; | |
86% | With sulfuric acid for 12h; Reflux; Inert atmosphere; | |
86% | With tert.-butylnitrite at 40℃; for 48h; | 42 Add compound 1ap (0.5 mmol, 82.1mg) and methanol containing 40mol% tert-butyl nitrite to the reaction test tube; then react for 48 hours at 40°C in air; after the reaction, add sodium thiosulfate and stir. After quenching, using a rotary evaporator to remove the solvent, adsorbing on silica gel, and finally performing column chromatography with a mixed solvent of ethyl acetate and petroleum ether to obtain the product 3ap with a yield of 86%. |
78% | With sulfuric acid for 3h; Ambient temperature; | |
77% | With chloro-trimethyl-silane at 0 - 20℃; for 1.5h; Inert atmosphere; | |
76% | With 2-oleamido-5-nitro-pyridinium p-toluenesulfonate In 2,2,4-trimethylpentane at 25℃; for 24h; | General Procedure for Catalytic Esterification Reactions General procedure: A catalyst ranging from 1-10 mol% was added to a mixture of an acid (1 eq.) and an alcohol (1 eq.) in isooctane (4mL). The resultant reactions were carried out at various temperatures and the reaction progresses were monitored by GC and TLC analyses. Then, the solvent was removed in vacuo and the products were isolated, purified by flash chromatography, and characterized by 1H NMR, 13C NMR, IR, and high-resolution mass spectrometry. |
75% | With copper dichloride at 130℃; for 24h; | |
72% | With N-butyl-2,4-dinitroanilinium p-toluenesulfonate In 2,2,4-trimethylpentane for 24h; Reflux; | General procedures of esterification reactions: General procedure: The mixture of a carboxylic acid (2 mmol) and an alcohol (2 mmol) in 4 mL of iso-octane was treated with a various amount of catalyst at a various temperature. GC analyses were employed to monitor the reaction progress. Then, the solvent was removed and the crude mixture was applied onto a flash chromatography to yield a pure final product. A mixture of ethyl acetate and hexane was typically used for flash chromatography purification. |
14% | With 3,4,5-trifluorophenylboronic acid for 28h; Heating; | |
With hydrogenchloride | ||
at 20℃; | 47 Example 47: 4-Phenyl-butyric acid methyl ester A solution of 4-phenyl-butyric acid (10G, 60. 29MMOL) in methanol (200mL) was prepared. To this solution was added hafnium chloride-THF complex (0.6g, 1.2mmol) and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between water and diethyl ether. The aqueous phase was extracted again with ether. The recombined organic layer was extracted with saturated sodium hydrogen carbonate, brine, and water. The solvent was evaporated to dryness, after drying over sodium sulfate and filtration. The resultant oily product was used directly in the next reaction without any further PURIFICATION. 1H-NMR (CDCI3, 300MHZ) : 1.97 (p, J=7.5Hz, 2H); 2.35 (3, J=7.4Hz, 2H); 2.66 (t, J=7.4Hz, 2H); 3.67 (s, 3H); 7.22 (m, 5H) | |
With sulfuric acid Reflux; | ||
With sulfuric acid for 4h; Reflux; | D9 Intermediate D9-methyl 4-phenylbutanoate Intermediate D9-methyl 4-phenylbutanoate To a stirred solution of 4-phenylbutanoic acid (3.28g, 20mmol) in absolute methanol (20ml) was added concd. H2SO4 (2ml) dropwise (heat was released) and the mixture was refluxed for 4h. Then, most of the solvent was evaporated and ice water (30ml) was added to the residue. The resulting mixture was neutralized with a solution of NaOH (10%) and extracted with DCM (60ml) three times. The combined organic phase was dried over MgSO4 and solvent evaporated to dryness to give the title compound as an oil which could be used in next step without further purification. 1H-NMR (CDCl3, 300MHz) δ 1.96 (m, 2H), 2.33 (t, 2H, J=7.5), 2.65 (t, 2H, J=7.5), 3.66 (s, 3H), -7.25 (m, 5H). | |
With sulfuric acid for 4h; Reflux; | Intermediate D9-methyl 4-phenylbutanoate To a stirred solution of 4-phenylbutanoic acid (3.28 g, 20 mmol) in absolute methanol (20 ml) was added concd. H2504 (2 ml) dropwise (heat was released) and the mixture was refluxed for 4 h. Then, most ofthe solvent was evaporated and ice water (30 ml) was added to the residue. The resulting mixture was neutralized with a solution of NaOH (10%) and extracted with DCM (60 ml) three times. The combined organic phase was dried over Mg504 and solvent evaporated to dryness to give the title compound as an oil which could be used in next step without thrther purification. ‘H-NMR (CDC13, 300 MHz) ö 1.96 (m, 2H), 2.33 (t, 2H, J=7.5), 2.65 (t, 2H, J=7.5), 3.66 (s, 3H), 7.25 (m, 5H). | |
With sulfuric acid for 10h; Reflux; | ||
With sulfuric acid for 10h; Reflux; | Methyl-4-phenylbutanoate To methanol solution (20 ml) of 4-phenylbutyric acid (30.51 m) was added concentrated sulfuric acid (1 ml) and refluxed for 10 hours. The solvent was evaporated by vacuum drying, water was added, and the mixture was extracted with ethyl acetate to obtain methyl-4-phenylbutanoate. | |
With sulfuric acid at 20℃; for 12h; Inert atmosphere; | ||
With sulfuric acid at 60℃; for 12h; | ||
With sulfuric acid at 20℃; for 3.08333h; Reflux; | ||
3.4 g | With sulfuric acid at 80℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 2,4,6-triphenylpyrylium tetrafluoroborate; iodine In 1,2-dichloro-ethane at 20℃; for 18h; Irradiation; | |
89% | With hydrogen bromide; (2-(N-methylbenzamido)phenyl)-l 3-iodanediyl diacetate; acetic acid In dichloromethane at 0 - 20℃; for 22h; Irradiation; | |
83% | With tetrabutylammonium tetrafluoroborate at 25℃; for 4.66667h; Electrolysis; |
80% | With potassium bromide In dichloromethane at 30℃; for 8h; | |
77% | With iodobenzene; 3-chloro-benzenecarboperoxoic acid; potassium bromide In 2,2,2-trifluoroethanol at 20℃; for 24h; | |
77% | With 2,4,6-triphenylpyrylium tetrafluoroborate; oxygen; acetic acid; zinc(II) iodide In dichloromethane at 20℃; for 72h; Irradiation; regioselective reaction; | |
75% | With iodobenzene; 3-chloro-benzenecarboperoxoic acid; potassium bromide In 2,2,2-trifluoroethanol at 20℃; for 24h; | |
69% | With ammonium iodide; Oxone; potassium bromide In 2,2,2-trifluoroethanol; acetonitrile at 20℃; for 12h; Green chemistry; | Typical Procedure for the NH4I Promoted Cyclization of Carboxylic Acids 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. |
62% | With tetrabutylammonium tetrafluoroborate In methanol; acetonitrile at 20℃; Electrochemical reaction; regioselective reaction; | |
59% | With dipotassium peroxodisulfate; copper(II) acetate monohydrate; acetic acid In water at 105℃; for 2h; | |
53% | With 2-(1-methoxy-1-methylethyl)iodosylbenzene-trifluoroacetic acid; potassium bromide In dichloromethane at 20℃; for 14h; | |
42% | With sodium bromate; magnesium chloride In acetonitrile at 20℃; for 18h; Inert atmosphere; Irradiation; Sealed tube; | |
41% | With sodium persulfate In water at 85 - 90℃; for 3.5h; | |
37% | With N-hydroxyphthalimide; nitromethane; iodic acid In water at 60℃; for 8h; | |
32% | With ammonium cerium(IV) nitrate; nitric acid In acetonitrile for 8h; Heating; | |
21 %Spectr. | With di-tert-butyl peroxide; cobalt(II) chloride In 1,2-dichloro-ethane at 120℃; for 18h; Inert atmosphere; Molecular sieve; Sealed tube; Glovebox; | Preparation of 5-phenyldihydrofuran-2(3H)-one A DCE solution (1 mL) was prepared under argon consisting of 1j (82.9 mg, 0.5 mmol), CoCl2 (6.5 mg, 0.05 mmol, 10.0 mol%), DTBP (189 μL, 1.0 mmol, 2.0 equiv.), and molecular sieves (4A, 165.0 mg ) in a sealed reaction tube with a stir bar. The mixture was then heated to 120 °C and reacted for 18h, thereafter being filtered through diatomite to remove the catalyst. The residue was extracted by diethyl ether (3 × 5mL). Afterwards, the combined organic filtrate was sampled and analyzed by 1H NMR (CDCl3) with CH2Br2 (43.3 mg, 0.25 mmol) as internal standard. Yield determined by compare integration of the typical 1H NMR signal (δ: 5.51 ppm) for CH-O with that for CH2Br2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: 4-phenylbutanoic acid With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.25h; Stage #2: With hydroxyamino hydrochloride; potassium hydroxide In tetrahydrofuran; methanol at 20℃; for 0.5h; | 1.1 Example 1: Chemical syntheses 1. Synthesis of N-hydroxy-4-phenylbutanamide (Compound 1); [Show Image] A solution of 4-phenylbutyric acid (10.0 g, 60.9 mmol) in anhydrous THF (180 mL) was added ethyl chloroformate (7.0 mL, 73.1 mmol) and triethylamine (11.1 mL, 79.2 mmol) at 0°C. The mixture was stirred at 0°C for 15 min. The solid was filtered off. The filtrate was added to a freshly prepared methanolic hydroxylamine solution (63.0 mL, prepared by adding 6.34 g or 91.4 mmol of hydroxylamine hydrochloride to 30.0 mL of a stirred methanolic solution containing 5.13 g or 91.4 mmol of KOH at 0°C for 15 min). The resulting mixture was stirred at room temperature for 30 min and evaporated in vacuo. The residue was purified by chromatography to give Compound 1 (6.4 g, 58%): mp >300°C; NMR (400 MHz in CDCl3): δ 1.98( m, 2H, PhCH2-CH2-CH2CONHOH), 2.13 (t, 2H, Ph-CH2-CH2CH2CONHOH), 2.64 (t, 2H, PhCH2CH2-CH2- CONHOH), 7.15 (d, 2H, Ar-H), 7.20 (t, 2H, Ar-H), 7.28 (m, 1H, Ar-H), 8.20 (br, 1H, NH). |
58% | Stage #1: 4-phenylbutanoic acid With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.25h; Stage #2: With hydroxyamino hydrochloride; potassium hydroxide In tetrahydrofuran; methanol at 0 - 20℃; for 0.5h; | 1.1 1. Synthesis of N-hydroxy-4-phenylbutanamide (Compound 1) A solution of 4-phenylbutyric acid (10.0 g, 60.9 mmol) in anhydrous THF (180 mL) was added ethyl chloroformate (7.0 mL, 73.1 mmol) and triethylamine (11.1 mL, 79.2 mmol) at 0° C. The mixture was stirred at 0° C. for 15 min. The solid was filtered off. The filtrate was added to a freshly prepared methanolic hydroxylamine solution (63.0 mL, prepared by adding 6.34 g or 91.4 mmol of hydroxylamine hydrochloride to 30.0 mL of a stirred methanolic solution containing 5.13 g or 91.4 mmol of KOH at 0° C. for 15 min). The resulting mixture was stirred at room temperature for 30 min and evaporated in vacuo. The residue was purified by chromatography to give Compound 1 (6.4 g, 58%): mp>300° C.; NMR (400 MHz in CDCl3): δ 1.98 (m, 2H, PhCH2-CH2-CH2CONHOH), 2.13 (t, 2H, Ph-CH2-CH2CH2CONHOH), 2.64 (t, 2H, PhCH2CH2-CH2-CONHOH), 7.15 (d, 2H, Ar-H), 7.20 (t, 2H, Ar-H), 7.28 (m, 1H, Ar-H), 8.20 (br, 1H, NH). |
25% | Stage #1: 4-phenylbutanoic acid With 4-methyl-morpholine; 4-dimethylaminopyridine; hydroxyamino hydrochloride In dichloromethane at 0℃; Stage #2: With 1,3,5-trichloro-2,4,6-triazine In dichloromethane at 20℃; for 24h; |
With hydroxyamino hydrochloride; benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide 1.) DMF, room temperature, 1 h, 2.) CH2Cl2, room temperature, 18 h; Yield given. Multistep reaction; | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydroxyamino hydrochloride; sodium hydroxide / methanol / 1 h / Reflux | ||
Multi-step reaction with 2 steps 1: 0.08 h / 20 °C / Milling 2: hydroxyamino hydrochloride / 0.75 h / 20 °C / Milling | ||
Multi-step reaction with 2 steps 1: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; benzotriazol-1-ol; 4-methyl-morpholine / N,N-dimethyl-formamide / 20 °C 2: trifluoroacetic acid; triethylsilane / dichloromethane / 20 °C | ||
Stage #1: 4-phenylbutanoic acid With 1,1′-carbonyldiimidazole for 1h; Inert atmosphere; Stage #2: With hydroxylamine chloride at 20℃; Inert atmosphere; | ||
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 4 h / 0 - 20 °C / Inert atmosphere 2: hydroxyamino hydrochloride; potassium carbonate / ethyl acetate; lithium hydroxide monohydrate / 12 h / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 4 h / 0 - 20 °C / Inert atmosphere 2: potassium carbonate; hydroxyamino hydrochloride / ethyl acetate; lithium hydroxide monohydrate / 12 h / 0 - 20 °C / Inert atmosphere | ||
Stage #1: 4-phenylbutanoic acid With 1,1′-carbonyldiimidazole In tetrahydrofuran at 20℃; Stage #2: With hydroxyamino hydrochloride at 20℃; | ||
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 0 - 20 °C 2: hydroxyamino hydrochloride; potassium carbonate / ethyl acetate; lithium hydroxide monohydrate / 12 h / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: tetrahydrofuran / 1 h / 20 °C / Schlenk technique; Inert atmosphere 2: hydroxyamino hydrochloride / Inert atmosphere | ||
Stage #1: 4-phenylbutanoic acid With 1,1′-carbonyldiimidazole In tetrahydrofuran for 1h; Stage #2: With hydroxyamino hydrochloride In tetrahydrofuran at 20℃; | ||
Multi-step reaction with 2 steps 1: tetrahydrofuran / 1 h / 20 °C / Inert atmosphere; Schlenk technique 2: hydroxyamino hydrochloride / Inert atmosphere | ||
P.III [Preparation Example 9] Preparation of 4-phenylbutanyl Hydroxamic Acid [Preparation Example 9] Preparation of 4-phenylbutanyl Hydroxamic Acid Prepared from 4-phenylbutyric acid (2 mmol scale) by Method B; White solid (0.34 g, 95%); 1H NMR (600 MHz, CDCl3) δ 8.50 (br, 2H), 7.28-7.24 (m, 2H), 7.18 (t, J=7.4 Hz, 1H), 7.14 (d, J=7.4 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 2.11 (t, J=7.6 Hz, 2H), 1.94 (p, J=7.5 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 171.4, 140.9, 128.4, 128.4, 126.1, 34.9, 32.1, 26.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sulfuric acid; pyrographite In water at 100℃; for 24h; | General procedure for the acidic hydrolysis of ester 1 mediated by activated charcoal General procedure: Aqueous 3M H2SO4 (2.0 mL) was added to a mixture of ester 1b (272 mg, 2.0 mmol) and activated charcoal (400 mg) in a 10 mL flask. The mixture was stirred at 700 rpm at room temperature for 3 minutes. After stirring at 400 rpm at 100 °C for 24 h, Et2O (10 mL) was added. Activated charcoal was removed by filtration and washed with ether. The aqueous phase was extracted with ether three times and the combined ethereal solution was washed with water (2 mL×2), dried, and evaporated. The residue was purified by column chromatography on silica gel using heptane-acetone (3 : 1) as eluent to give 2b (205 mg, 84%). |
With potassium hydroxide In ethanol for 2h; Heating; | ||
With sodium hydroxide In methanol; water Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In toluene for 24h; Heating; | |
97% | With molecular sevies 4A In toluene at 120℃; for 24h; | 7.1 Example 7 [Synthesis of Thioester Using the Catalyst of Hafnium Chloride (IV)•(THF)2] By using the catalyst of hafnium chloride (IV)•(THF)2, the thioester composition reaction from carboxylic acid and thiol was studied. A Soxhlet tube filled with dried molecular sieves 4A (about 1.5 g) was connected to the top of a 5 ml eggplant flask contained with a teflon coated magnetic stirrer, and a cooling tube was further attached over said Soxhlet tube. As shown in the following equation, toluene solvent (2 ml) was added to carboxylic acid (20 mmol) and benzyl thiol (24 mmol), and under the presence or in the absence of 5 mol % of hafnium chloride (IV)•(THF)2, heating reflux was conducted in the argone for 24 hours at 120° C. After the reaction, the mixture solution was purified directly by silica gel column chromatography (eluant hexane:ethylacetate=40:1), and dried under a reduced pressure. The results are shown in Table 4. Furthermore, decane thiol (C10H21SH) was used instead of benzyl thiol, and under the presence of 5 mol % of hafnium chloride (IV)•(THF)2 in the same manner as described above, heating reflux was conducted in the argone for 17 hours at 120° C. The results are also shown in Table 4. As also shown in Table 4, under the presence of hafnium chloride (IV)•(THF)2, thioester was obtained at a high yield. These results revealed that hafnium (IV) compounds such as hafnium chloride (IV)•(THF)2 and the like are useful as a catalyst for thioester synthesis reaction. [TABLE-US-00004] TABLE 4 [CHEMMOL-00034] [CHEMMOL-00035] catalyst reaction Entry R (mol %) time (h) yield (%) 1 benzyl 5 24 97 2 benzyl 0 24 small 3C10H21 5 17 >99 |
With molecular sevies 4A In toluene at 120℃; for 24h; | 7.2 Example 7 [Synthesis of Thioester Using the Catalyst of Hafnium Chloride (IV)•(THF)2] By using the catalyst of hafnium chloride (IV)•(THF)2, the thioester composition reaction from carboxylic acid and thiol was studied. A Soxhlet tube filled with dried molecular sieves 4A (about 1.5 g) was connected to the top of a 5 ml eggplant flask contained with a teflon coated magnetic stirrer, and a cooling tube was further attached over said Soxhlet tube. As shown in the following equation, toluene solvent (2 ml) was added to carboxylic acid (20 mmol) and benzyl thiol (24 mmol), and under the presence or in the absence of 5 mol % of hafnium chloride (IV)•(THF)2, heating reflux was conducted in the argone for 24 hours at 120° C. After the reaction, the mixture solution was purified directly by silica gel column chromatography (eluant hexane:ethylacetate=40:1), and dried under a reduced pressure. The results are shown in Table 4. Furthermore, decane thiol (C10H21SH) was used instead of benzyl thiol, and under the presence of 5 mol % of hafnium chloride (IV)•(THF)2 in the same manner as described above, heating reflux was conducted in the argone for 17 hours at 120° C. The results are also shown in Table 4. As also shown in Table 4, under the presence of hafnium chloride (IV)•(THF)2, thioester was obtained at a high yield. These results revealed that hafnium (IV) compounds such as hafnium chloride (IV)•(THF)2 and the like are useful as a catalyst for thioester synthesis reaction. [TABLE-US-00004] TABLE 4 [CHEMMOL-00034] [CHEMMOL-00035] catalyst reaction Entry R (mol %) time (h) yield (%) 1 benzyl 5 24 97 2 benzyl 0 24 small 3C10H21 5 17 >99 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 99% | With molecualar sevies 4A;tetrachlorobis(tetrahydrofuran)hafnium(IV); In toluene; at 120℃; for 24h; | By combining diversely the carboxylic acid of various structure and alcohol, the scope of substrate application of the tetravalent hafnium compound was examined. A Soxhlet tube filled with dried molecular sieves 4A (about 1.5 g) was connected to the top of a 5 ml eggplant flask contained with a teflon coated magnetic stirrer, and a cooling tube was further attached over said Soxhlet tube. Unless there is a particular point of concern, toluene solvent (2 ml) and 0.1 mol %, 0.2 mol % or 1 mol % of hafnium chloride (IV)?(THF)2 were added to carboxylic acid (10 mmol) and alcohol (10 mmol), and heating reflux was conducted in the argon for several hours at 120C. After the reaction, the mixture solution was purified by direct silica gel column chromatography (eluant hexane:ethyl acetate=4:1 to 8:1), and the solution was dried under reduced pressure. The results are shown in Table 2. In Table 2, the following are shown: for the experiment of Entry 3, toluene solvent (5 ml) was used; for the experiment of Entry 4, 4-phenyl butanoic acid (36 mmol) and toluene solvent (4 ml) were used; for the experiment of Entry 5, the numerical value of yield showed in parenthesis is the value in the case the inventors wanted to use the catalyst; for the experiment of Entry 9, o-xylene solvent (2 ml) was used; for the experiment of Entry 14, enantiomer of carboxylic acid was used and at a yield of 84%, the enantiomer of ester was obtained; for the experiment of Entry of 17, 1,3,5-mesitylene solvent(2 ml) was used; for the experiments of Entry 18 and 19, the lactone value is shown for the yield. [TABLE-US-00002] TABLE 2 [CHEMMOL-00003] HfCl4.(THF)2 reaction entryRCO2H ROH (1 mol %) time (h) yield (%) 1 [CHEMMOL-00004] [CHEMMOL-00005] 0.2 6 97 2 [CHEMMOL-00006] [CHEMMOL-00007] 0.2 24 92 3 [CHEMMOL-00008] [CHEMMOL-00009] 0.1 18 >99 4 [CHEMMOL-00010] EtC(CH2OH)3 0.2 24 >99 5 [CHEMMOL-00011] [CHEMMOL-00012] 0.2 5 94 (36) 6 [CHEMMOL-00013] l-menthol 0.2 36 >99 7 [CHEMMOL-00014] [CHEMMOL-00015] 0.2 13 >99 8 [CHEMMOL-00016] Et3COH 1.0 24 0 9 [CHEMMOL-00017] PhOH 0.2 36 91 10 [CHEMMOL-00018] [CHEMMOL-00019] 0.2 10 92 11 [CHEMMOL-00020] [CHEMMOL-00021] 0.1 18 98 12 [CHEMMOL-00022] [CHEMMOL-00023] 0.2 7 96 13Et2CHCO2H [CHEMMOL-00024] 0.2 60 98 14 [CHEMMOL-00025] [CHEMMOL-00026] 0.2 13 98 15PhCO2H [CHEMMOL-00027] 0.2 15 92 16 [CHEMMOL-00028] [CHEMMOL-00029] 0.2 10 92 17PhCO2H3,5-Me2C5H3OH 1.0 24 95 18 [CHEMMOL-00030] 0.2 10 98 19 [CHEMMOL-00031] 0.2 10 94 [0022] As it is also shown in Table 2, every carboxylic acid reacted with primary and secondary alcohol, under the presence of the catalyst of 0.2 mol % and under, and produced ester quantitatively, but as it is shown from the experiment of Entry 8, it did not react with tertiary alcohol. Furthermore, as it is shown from the experiment of Entry 17, the aromatic substrates (benzoic acid and phenol) showed lower reactivity compared to aliphatic substrates, and when carboxylic acid and alcohol are both aromatics, the ester could be obtained at a high yield, by increasing the catalyst amount up to 1 mol %. Moreover, when the reactivity is low, it is also effective to use a benzene solvent of higher boiling point, for example, o-xylene of the experiment of Entry 9 or 1,3,5-mesitylene of the experiment of Entry 17 and to conduct heating reflux. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In toluene for 17h; Heating; | |
99% | With molecular sevies 4A In toluene at 120℃; for 17h; | 7.3 Example 7 [Synthesis of Thioester Using the Catalyst of Hafnium Chloride (IV)•(THF)2] By using the catalyst of hafnium chloride (IV)•(THF)2, the thioester composition reaction from carboxylic acid and thiol was studied. A Soxhlet tube filled with dried molecular sieves 4A (about 1.5 g) was connected to the top of a 5 ml eggplant flask contained with a teflon coated magnetic stirrer, and a cooling tube was further attached over said Soxhlet tube. As shown in the following equation, toluene solvent (2 ml) was added to carboxylic acid (20 mmol) and benzyl thiol (24 mmol), and under the presence or in the absence of 5 mol % of hafnium chloride (IV)•(THF)2, heating reflux was conducted in the argone for 24 hours at 120° C. After the reaction, the mixture solution was purified directly by silica gel column chromatography (eluant hexane:ethylacetate=40:1), and dried under a reduced pressure. The results are shown in Table 4. Furthermore, decane thiol (C10H21SH) was used instead of benzyl thiol, and under the presence of 5 mol % of hafnium chloride (IV)•(THF)2 in the same manner as described above, heating reflux was conducted in the argone for 17 hours at 120° C. The results are also shown in Table 4. As also shown in Table 4, under the presence of hafnium chloride (IV)•(THF)2, thioester was obtained at a high yield. These results revealed that hafnium (IV) compounds such as hafnium chloride (IV)•(THF)2 and the like are useful as a catalyst for thioester synthesis reaction. [TABLE-US-00004] TABLE 4 [CHEMMOL-00034] [CHEMMOL-00035] catalyst reaction Entry R (mol %) time (h) yield (%) 1 benzyl 5 24 97 2 benzyl 0 24 small 3C10H21 5 17 >99 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In toluene for 13h; Heating; | |
99% | With molecualar sevies 4A In toluene at 120℃; for 13h; | 3.7 Example 3 [Scope of Substrate Application] By combining diversely the carboxylic acid of various structure and alcohol, the scope of substrate application of the tetravalent hafnium compound was examined. A Soxhlet tube filled with dried molecular sieves 4A (about 1.5 g) was connected to the top of a 5 ml eggplant flask contained with a teflon coated magnetic stirrer, and a cooling tube was further attached over said Soxhlet tube. Unless there is a particular point of concern, toluene solvent (2 ml) and 0.1 mol %, 0.2 mol % or 1 mol % of hafnium chloride (IV)•(THF)2 were added to carboxylic acid (10 mmol) and alcohol (10 mmol), and heating reflux was conducted in the argon for several hours at 120°C. After the reaction, the mixture solution was purified by direct silica gel column chromatography (eluant hexane:ethyl acetate=4:1 to 8:1), and the solution was dried under reduced pressure. The results are shown in Table 2. In Table 2, the following are shown: for the experiment of Entry 3, toluene solvent (5 ml) was used; for the experiment of Entry 4, 4-phenyl butanoic acid (36 mmol) and toluene solvent (4 ml) were used; for the experiment of Entry 5, the numerical value of yield showed in parenthesis is the value in the case the inventors wanted to use the catalyst; for the experiment of Entry 9, o-xylene solvent (2 ml) was used; for the experiment of Entry 14, enantiomer of carboxylic acid was used and at a yield of 84%, the enantiomer of ester was obtained; for the experiment of Entry of 17, 1,3,5-mesitylene solvent(2 ml) was used; for the experiments of Entry 18 and 19, the lactone value is shown for the yield. [TABLE-US-00002] TABLE 2 [CHEMMOL-00003] HfCl4.(THF)2 reaction entryRCO2H ROH (1 mol %) time (h) yield (%) 1 [CHEMMOL-00004] [CHEMMOL-00005] 0.2 6 97 2 [CHEMMOL-00006] [CHEMMOL-00007] 0.2 24 92 3 [CHEMMOL-00008] [CHEMMOL-00009] 0.1 18 >99 4 [CHEMMOL-00010] EtC(CH2OH)3 0.2 24 >99 5 [CHEMMOL-00011] [CHEMMOL-00012] 0.2 5 94 (36) 6 [CHEMMOL-00013] l-menthol 0.2 36 >99 7 [CHEMMOL-00014] [CHEMMOL-00015] 0.2 13 >99 8 [CHEMMOL-00016] Et3COH 1.0 24 0 9 [CHEMMOL-00017] PhOH 0.2 36 91 10 [CHEMMOL-00018] [CHEMMOL-00019] 0.2 10 92 11 [CHEMMOL-00020] [CHEMMOL-00021] 0.1 18 98 12 [CHEMMOL-00022] [CHEMMOL-00023] 0.2 7 96 13Et2CHCO2H [CHEMMOL-00024] 0.2 60 98 14 [CHEMMOL-00025] [CHEMMOL-00026] 0.2 13 98 15PhCO2H [CHEMMOL-00027] 0.2 15 92 16 [CHEMMOL-00028] [CHEMMOL-00029] 0.2 10 92 17PhCO2H3,5-Me2C5H3OH 1.0 24 95 18 [CHEMMOL-00030] 0.2 10 98 19 [CHEMMOL-00031] 0.2 10 94 [0022] As it is also shown in Table 2, every carboxylic acid reacted with primary and secondary alcohol, under the presence of the catalyst of 0.2 mol % and under, and produced ester quantitatively, but as it is shown from the experiment of Entry 8, it did not react with tertiary alcohol. Furthermore, as it is shown from the experiment of Entry 17, the aromatic substrates (benzoic acid and phenol) showed lower reactivity compared to aliphatic substrates, and when carboxylic acid and alcohol are both aromatics, the ester could be obtained at a high yield, by increasing the catalyst amount up to 1 mol %. Moreover, when the reactivity is low, it is also effective to use a benzene solvent of higher boiling point, for example, o-xylene of the experiment of Entry 9 or 1,3,5-mesitylene of the experiment of Entry 17 and to conduct heating reflux. |
92% | With N-butyl-2,4-dinitroanilinium p-toluenesulfonate In 2,2,4-trimethylpentane for 19h; Reflux; | General procedures of esterification reactions: General procedure: The mixture of a carboxylic acid (2 mmol) and an alcohol (2 mmol) in 4 mL of iso-octane was treated with a various amount of catalyst at a various temperature. GC analyses were employed to monitor the reaction progress. Then, the solvent was removed and the crude mixture was applied onto a flash chromatography to yield a pure final product. A mixture of ethyl acetate and hexane was typically used for flash chromatography purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In toluene for 24h; Heating; | |
92% | With molecualar sevies 4A In toluene at 120℃; for 24h; | 3.2 Example 3 [Scope of Substrate Application] By combining diversely the carboxylic acid of various structure and alcohol, the scope of substrate application of the tetravalent hafnium compound was examined. A Soxhlet tube filled with dried molecular sieves 4A (about 1.5 g) was connected to the top of a 5 ml eggplant flask contained with a teflon coated magnetic stirrer, and a cooling tube was further attached over said Soxhlet tube. Unless there is a particular point of concern, toluene solvent (2 ml) and 0.1 mol %, 0.2 mol % or 1 mol % of hafnium chloride (IV)•(THF)2 were added to carboxylic acid (10 mmol) and alcohol (10 mmol), and heating reflux was conducted in the argon for several hours at 120°C. After the reaction, the mixture solution was purified by direct silica gel column chromatography (eluant hexane:ethyl acetate=4:1 to 8:1), and the solution was dried under reduced pressure. The results are shown in Table 2. In Table 2, the following are shown: for the experiment of Entry 3, toluene solvent (5 ml) was used; for the experiment of Entry 4, 4-phenyl butanoic acid (36 mmol) and toluene solvent (4 ml) were used; for the experiment of Entry 5, the numerical value of yield showed in parenthesis is the value in the case the inventors wanted to use the catalyst; for the experiment of Entry 9, o-xylene solvent (2 ml) was used; for the experiment of Entry 14, enantiomer of carboxylic acid was used and at a yield of 84%, the enantiomer of ester was obtained; for the experiment of Entry of 17, 1,3,5-mesitylene solvent(2 ml) was used; for the experiments of Entry 18 and 19, the lactone value is shown for the yield. [TABLE-US-00002] TABLE 2 [CHEMMOL-00003] HfCl4.(THF)2 reaction entryRCO2H ROH (1 mol %) time (h) yield (%) 1 [CHEMMOL-00004] [CHEMMOL-00005] 0.2 6 97 2 [CHEMMOL-00006] [CHEMMOL-00007] 0.2 24 92 3 [CHEMMOL-00008] [CHEMMOL-00009] 0.1 18 >99 4 [CHEMMOL-00010] EtC(CH2OH)3 0.2 24 >99 5 [CHEMMOL-00011] [CHEMMOL-00012] 0.2 5 94 (36) 6 [CHEMMOL-00013] l-menthol 0.2 36 >99 7 [CHEMMOL-00014] [CHEMMOL-00015] 0.2 13 >99 8 [CHEMMOL-00016] Et3COH 1.0 24 0 9 [CHEMMOL-00017] PhOH 0.2 36 91 10 [CHEMMOL-00018] [CHEMMOL-00019] 0.2 10 92 11 [CHEMMOL-00020] [CHEMMOL-00021] 0.1 18 98 12 [CHEMMOL-00022] [CHEMMOL-00023] 0.2 7 96 13Et2CHCO2H [CHEMMOL-00024] 0.2 60 98 14 [CHEMMOL-00025] [CHEMMOL-00026] 0.2 13 98 15PhCO2H [CHEMMOL-00027] 0.2 15 92 16 [CHEMMOL-00028] [CHEMMOL-00029] 0.2 10 92 17PhCO2H3,5-Me2C5H3OH 1.0 24 95 18 [CHEMMOL-00030] 0.2 10 98 19 [CHEMMOL-00031] 0.2 10 94 [0022] As it is also shown in Table 2, every carboxylic acid reacted with primary and secondary alcohol, under the presence of the catalyst of 0.2 mol % and under, and produced ester quantitatively, but as it is shown from the experiment of Entry 8, it did not react with tertiary alcohol. Furthermore, as it is shown from the experiment of Entry 17, the aromatic substrates (benzoic acid and phenol) showed lower reactivity compared to aliphatic substrates, and when carboxylic acid and alcohol are both aromatics, the ester could be obtained at a high yield, by increasing the catalyst amount up to 1 mol %. Moreover, when the reactivity is low, it is also effective to use a benzene solvent of higher boiling point, for example, o-xylene of the experiment of Entry 9 or 1,3,5-mesitylene of the experiment of Entry 17 and to conduct heating reflux. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 4-Phenylbutyric acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; Stage #2: N,O-dimethylhydroxylamine*hydrochloride In dichloromethane at 20℃; for 16h; | 4.2 General Procedure A: synthesis of Weinreb amides 1 [11] General procedure: To a solution of carboxylic acid (1 equiv) in dichloromethane (2.5 mL/mmol) was added carbonyldiimidazole (1.3 equiv) portionwise at room temperature under vigorous stirring. After 1 h, N,O-dimethylhydroxylamine hydrochloride (2 equiv) was added and the reaction mixture was stirred overnight. Aqueous HCl (2 M, 10 mL/mmol) was added and the mixture was stirred for 15 min at room temperature. The phases were separated and the aqueous layer was extracted with CH2Cl2 (3 2.5 mL/mmol). The combined organic phases were washed with saturated aq. NaHCO3 (10 mL/mmol) and brine (10 mL/mmol), dried over MgSO4 and concentrated under vacuum. The resulting crude product was purified by column chromatography (eluent pentane/Et2O or pentane/EtOAc). |
96% | Stage #1: 4-Phenylbutyric acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 1h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride In dichloromethane at 20℃; for 16h; | |
94% | Stage #1: 4-Phenylbutyric acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 1h; Inert atmosphere; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With triethylamine In dichloromethane for 0.166667h; Inert atmosphere; |
90% | With dmap; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 16h; Inert atmosphere; | |
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; | 9.9A Example 9; (2S,3R)-3-amino-2-hydroxy-6-phenylhexanoic acid; Example 9A; 4-phenylbutanal A solution of 4-phenylbutyric acid (1.64 g, 10.0 [MMOL),] [N, O-DIMETHYL HYDROXYLAMINE] hydrochloride (1. [58] g, 16 mmol), [1- (3-DIMETHYLAMINOPROPYL)-3-ETHYLCARBODIIMIDE] hydrochloride (2. [06 G,] 10.7 mmol), [1-HYDROXYBENZOTRIAZOLE] (1.56 [G,] 11.6 [MMOL), AND N-] methylmorpholine (2.8 mL, 26 mmol) in dichloromethane (40 mL) at room temperature was stirred for 16 hours, diluted with dichloromethane, washed sequentially with aqueous [NAHC03,] brine, 10% [KHS04,] and brine, dried [(MGS04),] filtered, and concentrated. A mixture of the concentrate and lithium aluminum hydride (9.0 mmol, 1 equiv. ) in diethyl ether (49 [ML)] at room temperature was stirred for 90 minutes, treated with 1M [NAHS04,] diluted with diethyl ether, washed sequentially with 10% [KHS04,] and brine, dried [(MGS04),] filtered, and concentrated to provide the desired product. MS (ESI) m/e 148 [(M+H) +.] | |
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; | 9.A 4-phenylbutanal 4-phenylbutanal A solution of 4-phenylbutyric acid (1.64 g, 10.0 mmol), N,O-dimethyl hydroxylamine hydrochloride (1.58 g, 16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.06 g, 10.7 mmol), 1-hydroxybenzotriazole (1.56 g, 11.6 mmol), and N-methylmorpholine (2.8 ML, 26 mmol) in dichloromethane (40 ML) at room temperature was stirred for 16 hours, diluted with dichloromethane, washed sequentially with aqueous NaHCO3, brine, 10% KHSO4, and brine, dried (MgSO4), filtered, and concentrated.A mixture of the concentrate and lithium aluminum hydride (9.0 mmol, 1 equiv.) in diethyl ether (49 ML) at room temperature was stirred for 90 minutes, treated with 1M NaHSO4, diluted with diethyl ether, washed sequentially with 10% KHSO4, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 148 (M+H)+. | |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dimesitylammonium pentafluorobenzenesulfonate In n-heptane at 80℃; for 48h; | |
90% | With N-(2,6-diisopropylphenyl)-N-(2,4,6-mesityl)ammonium pentafluorobenzenesulfonate In n-heptane at 80℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dimesitylammonium pentafluorobenzenesulfonate In n-heptane at 80℃; for 48h; | |
90% | In n-heptane at 80℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With (1S)-10-camphorsulfonic acid at 80℃; for 22h; | |
84% | With dimesitylammonium pentafluorobenzenesulfonate In n-heptane at 80℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With chlorotriphenylphosphinegold(I); silver trifluoromethanesulfonate In 1,2-dichloro-ethane at 80℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With dmap; P(p-C6H4F)3 In 1,4-dioxane at 65℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile for 8h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With air; potassium carbonate In water at 46.84℃; for 24h; | |
94% | Stage #1: 4-phenyl-butan-1-ol With Oxone; sodium ortho-iodobenzenesulfonate In acetonitrile at 70℃; for 1h; Stage #2: With water In acetonitrile for 5h; | |
94% | With potassium peroxymonosulfate; 2-Iodo-5-methylbenzenesulfonic acid In nitromethane at 70℃; for 8h; | 7 8.9mg (0.03mmol) of 2-iodo-5-methylbenzenesulfonic acid prepared by Preparation Example 2, 2.04g (3.3mmol) of powdered Oxone (registered trademark) were added to 3.75ml of nitromethane, and 450mg (3mmol) of 4-phenylbutanol was added dropwise for two hours, and the mixture was heated at 70 C while being stirred for six hours. The later treatment was carried out in the same way as in Example 1, and then 4-phenylbutanoic acid was obtained. The yield of the obtained 4-phenylbutanoic acid was determined and the result is shown in Table 1. |
94.6% | With sodium hypochlorite; sodium chlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In aq. phosphate buffer; water; acetonitrile at 0 - 40℃; for 6h; Large scale; | 1 EXAMPLE 1 Preparation of 4-phenyl-1-butyric acid 1-butanol (1 kg, 6.66 mol) and TEMPO (72.8 g, 466 mmol, 0.07 eq.) were dissolved in acetonitrile (5 L) at ambient temperature. In a 12 L 3-neck round bottom flask, a potassium phosphate buffer was prepared by dissolving potassium phosphate monobasic (996 g, 7.32 mol) and potassium phosphate dibasic (1276 g, 7.33 mol) in water (10 L), and the prepared buffer was transferred into the reaction mixture at ambient temperature. Two other solutions were prepared separately including an aqueous solution of sodium chlorite by dissolving sodium chlorite (1.28 kg, 11.32 mol, 1.7 eq.) in water (4 L) and bleach solution by diluting 8.25% bleach (110 mL, 122 mmol, 0.02 eq.) in water (200 mL). The temperature of the reaction mixture was adjusted to 10- 40°C followed by adding the prepared aqueous solution of sodium chlorite (900 mL) and the diluted bleach (60 mL) in sequence. The remaining of the two solutions was then slowly added simultaneously and separately over four hours while maintaining the temperature of the reaction mixture at 10-40°C. It was noted that after the addition, the temperature of the reaction mixture kept increasing to 30 °C, and maintained at 30 °C for about two hours before starting to slowly cool down to 20 °C. The mixture was agitated at 20 °C overnight, and the conversion was > 99.9%. Temperature of the reaction mixture was adjusted to below 0-20°C followed by pH adjustment to 9.8 with 25% aqueous sodium hydroxide (prepared from 50% aqueous sodium hydroxide with water, 1/1 v/v; -1360 mL). An aqueous solution of sodium sulfite was prepared by dissolving sodium sulfite (2 kg, 15.87 mol, 2.4 eq.) in water (10 L), and slowly transferred into reaction mixture over one hour while maintaining the temperature at below 15 °C (note that the peak for 3-BPA increases to about 6-7A% immediately after the sodium sulfite quench). The resulting light cloudy mixture was stirred at 15 to 30°C overnight (to bring the levels of the 3- BPA peak back down to about 1.5A %) and then cooled to 0-10°C (to maximize precipitation of the inorganic salts). The suspension was stirred at 0-10°C for two hours and then the solids removed by filtration through a Celite pad (250 g). The filtered cake was washed with cold water (1 L x 3). The combined filtrate was washed with MTBE (10 + 5 L). The resulting colorless aqueous phase was cooled to 0-10°C, and agitated overnight (no further precipitation of inorganic material was noted). It is essential to perform the acidification on a chilled solution, in order for the 4-PBA to precipitate. To the chilled solution was slowly added 6N aqueous HC1 (1 L) over two hours to adjust pH to about 6.5. At this stage, 4-PBA seed (10 g, 60.9 mmol) was added to induce crystallization to form a thin suspension. Additional 6N aqueous HC1 (2.6 L) was slowly added over two hours to adjust the pH to 3. The resulting suspension was agitated at 5 °C overnight, and then filtered to collect the solid. The wet cake was washed with ice cold water (2 L), and dried under vacuum with nitrogen purge to provide 4-PBA as white solid, which was dried in the open air, in glass trays over 3 days. The total amount of the crude 4-PBA was 1034.1 g (94.6% isolation yield) with 99.7 A% purity by HPLC analysis, 210 nm and >99 A% by 260 nm (1 mg/mL acetonitrile solution). No 3-BPA was detected by both wavelengths. DSC analysis gave the melting point 52 °C. Next, the 4-PBA was analyzed by HPLC using with the concentration of 5 mg/mL in mobile phase A and acetonitrile (80/20 v/v). The purity was 99.7 A% with 93 %w/w. Under this analysis 3-BPA was identified in 0.04 A% along with four other impurities in the range of 0.04 to 0.1 A%. The weight assay of 3-BPA was calculated as 0.002 %w/w using 0.04% 3-BPA solution. Final Karl Fischer analysis was 0.14 %w/w of water content. |
76% | With 5-fluoro-2-azaadamantane N-oxyl; acetic acid; sodium nitrite at 20℃; for 2.5h; | |
68% | Stage #1: 4-phenyl-butan-1-ol With Ru(η(2)-2-(2'-pyridyl)phenyl)Cl(CO)(PPh3)2; potassium hydroxide In toluene at 120℃; for 6h; Schlenk technique; Inert atmosphere; Stage #2: With hydrogenchloride In water | |
Multi-step reaction with 2 steps 1: TEMPO; poly[4-(diacetoxyiodo)styrene] / acetone / 3 h / 20 °C 2: aq. TEMPO; poly[4-(diacetoxyiodo)styrene] / acetone / 24 h / 20 °C | ||
With oxygen; sodium t-butanolate; 1,3-bis[(2,6-diisopropyl)phenyl]imidazolinium chloride In dichloromethane at 20℃; for 30h; Molecular sieve; | 4.3. General procedure for the oxidation of the long chainalcohol 3a-3h General procedure: Under Oxygen atmosphere, alcohol (2 mmol), precatalyst(SIMesHCl or SIPrHCl, 0.06 mmol), NaOtBu (960.5 mg, 10 mmol),and 1 g 3 A molecular sieve were added to dichloromethane(20 mL). This solution was allowed to stir for 30 h. After filtratingthrough a pad of Celite, the cake was added to hydrochloric acid(2N, 50 mL) and extracted with ethyl acetate (50 mL3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. | |
94 %Chromat. | With oxygen; potassium carbonate In water at 90℃; for 20h; Green chemistry; | |
75 %Spectr. | With potassium peroxymonosulfate at 41 - 43℃; for 16h; Milling; | 3.1. PS-TEMPO/Oxone/Stainless Steel General procedure: To a customized 3.0 mL stainless steel vial was added 250 mg (0.99 mmol/g) of PS-TEMPO, 0.314 gOxone (0.5 mmol), and 0.25 mmol of alcohol. A 3/16” stainless steel ball was added to the vial.The vial was shaken at 18Hz for 16 h in a Spex8000M Mixer/Mill (Metuchen, NJ, USA). The resultingmixture was gravity ltered with one of three polar solvents (acetone, ethyl acetate, and ethanol),depending on the solubility of the desired product. The solvent was removed under reduced pressure,aording the carboxylic acid product. The PS-TEMPO was recovered, dried and used in the subsequentreactions. 1H NMR spectroscopy using a Bruker Avance 400 spectrometer was performed to assess theextent and purity of the reaction products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride; In water; acetic acid; at 95 - 110℃; for 20h;Heating / reflux; | EXAMPLE 16 To a mixture of 2000 mL of acetic acid and 1500 mL of 6N hydrochloric acid was added 500 g of Diester {PhCH2CH2CH(COOEt)2). The temperature of the mixture was raised to the range of about 95 to 110 C. and refluxed for about 20 hrs. The progress of the reaction was monitored by chromatography, and at completion the acetic acid and water were removed by distillation at atmospheric pressure. The residue was dissolved in water using 10% sodium hydroxide. The aqueous solution was then washed with methylene chloride and the pH was adjusted with concentrated hydrochloric acid to a pH of about 1. The product was extracted with 1700 ml of hexane and the eluate was cooled to -10 C. The resulting precipitated crude 4-phenylbutyric acid was isolated by filtration and dried under vacuum at about 30 C. Yield 280 g (90%). The crude 4-phenyl butyric acid so isolated was dissolved in 1500 mL hexane at a temperature of about 30 to 50 C. and then cooled to about -10 C. and then stirred for about one hour to precipitate. The pure 4-phenyl butyric acid was then isolated by filtration and dried under vacuum without heating. (Purity>99%.) ; EXAMPLE 17 To a mixture of 2000 mL of acetic acid and 1500 mL of 6N hydrochloric acid added 500 g of Diester {PhCH2CH2CH(COOEt)2}. The temperature of the mixture was raised to between about 95 to about 110 C. and refluxed for about 20 hrs. The progress of the reaction mixture was monitored by chromatography and at completion the acetic acid and water were removed by distillation at atmospheric pressure. The residue was dissolved in water using 10% sodium hydroxide. The aqueous solution was washed with methylene chloride and the pH was adjusted with concentrated hydrochloric acid to about one. The product was extracted with 1700 ml of hexane and the solution was cooled to -10 C. The precipitated crude 4-phenylbutyric acid was isolated by filtration and dried under vacuum at about 30 C. Yield 280 g (90%). The crude 4-phenyl butyric acid was then fractionally distilled under vacuum at about 170 C. (Purity>99%.) |
EXAMPLE 16; Preparation of 4-phenylbutyric Acid; To a mixture of 2000 mL of acetic acid and 1500 mL of 6N hydrochloric acid was added 500 g of Diester {PhCH2CH2CH(COOEt)2). The temperature of the mixture was raised to the range of about 95 to 110 C. and refluxed for about 20 hrs. The progress of the reaction was monitored by chromatography, and at completion the acetic acid and water were removed by distillation at atmospheric pressure. The residue was dissolved in water using 10% sodium hydroxide. The aqueous solution was then washed with methylene chloride and the pH was adjusted with concentrated hydrochloric acid to a pH of about 1. The product was extracted with 1700 ml of hexane and the eluate was cooled to -10 C. The resulting precipitated crude 4-phenylbutyric acid was isolated by filtration and dried under vacuum at about 30 C. Yield 280 g (90%). The crude 4-phenyl butyric acid so isolated was dissolved in 1500 mL hexane at a temperature of about 30 to 50 C. and then cooled to about -10 C. and then stirred for about one hour to precipitate. The pure 4-phenyl butyric acid was then isolated by filtration and dried under vacuum without heating. (Purity>99%.); EXAMPLE 17; To a mixture of 2000 mL of acetic acid and 1500 mL of 6N hydrochloric acid added 500 g of Diester {PhCH2CH2CH(COOEt)2 }. The temperature of the mixture was raised to between about 95 to about 110 C. and refluxed for about 20 hrs. The progress of the reaction mixture was monitored by chromatography and at completion the acetic acid and water were removed by distillation at atmospheric pressure. The residue was dissolved in water using 10% sodium hydroxide. The aqueous solution was washed with methylene chloride and the pH was adjusted with concentrated hydrochloric acid to about one. The product was extracted with 1700 ml of hexane and the solution was cooled to -10 C. The precipitated crude 4-phenylbutyric acid was isolated by filtration and dried under vacuum at about 30 C. Yield 280 g (90%). The crude 4-phenyl butyric acid was then fractionally distilled under vacuum at about 170 C. (Purity>99%.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: acetic acid; platinum / Hydrogenation 2: H2SO4; toluene / Kochen unter Abscheidung des azeotrop abdestillierenden Wassers und Hydrogenolyse des Reaktionsprodukts an Kupferchromit bei 250grad/210 at |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.1% | In dichloromethane; | B. 4-Phenylbutanoyl chloride. To a mixture of 4-phenylbutanoic acid (12.0 g, 0.73 mol) in 60 ml of dichloromethane was added oxalyl chloride (12.8 ml, 0.15 mol). This was then stirred at room temperature until gas evolution ceased (2 hrs.). The reaction mixture was then evaporated to yield a yellow oil (13.1 g, 98.1%) which was used without further purification. IR (neat) 1799.6 cm-1 C=O (acid chloride). |
Example 102 4-Phenylbutyryl chloride (2d) Using an analogous method (G2), the title compound was obtained from 4-phenylbutyric acid (1d) and oxalyl chloride, ca. yield of the crude product 100% (yellow oil). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In hydrogenchloride; hexane; water; isopropyl alcohol; acetonitrile; Petroleum ether; | EXAMPLE 3 1-(1-Hydroxy-4-phenyl-1-buten-1-yl)-4-(4-imidazolyl)piperidine (Dihydrochloride) (Compound 59) 2.03 g (0.0132 mol) of triethylamine are added dropwise at 0 C. to a solution of 2.16 g (0.0132 mol) of 4-phenylbutyric acid in 70 ml of acetonitrile. After 30 minutes' stirring, 1.43 g (0.0132 mol) of ethyl chloroformate are added in such a way that the temperature remains between 0 C. and 5 C. After 30 minutes, stirring, the solution is poured into 60 ml of acetonitrile and 15 ml of water containing 1.99 g (0.0132 mol) of 4-(4-imidazolyl)piperidine. After being heated to 80 C. for 1 hour, the solution is concentrated under reduced pressure and the oily residue is taken up with 20 ml of water and then extracted with 70 ml of ethyl acetate. The residual oil obtained crystallises on adding an ethyl ether/petroleum ether (30:20) mixture. After recrystallisation in an ether/hexane (30:20) mixture a white powder (Compound 42) is obtained. M.p. 102 C. Mass=3.2 g Yield=81% 3.2 g (0.81 mol) of the base obtained (Compound 42) are then added to 20 ml of isopropanol in the presence of 2.1 equivalents of concentrated hydrochloric acid. The precipitate is drained and washed with 10 ml of isopropyl alcohol and then with 15 ml of ethyl ether. After drying, the precipitate is recrystallized in acetonitrile. The compound of the title is obtained in the form of a white powder. M.p. 126 C. Yield=55% Analysis: C, H, N, Cl. Recrystallisation in acetonitrile (70)+ethyl ether (30). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium hydroxide; In water; | 0.40 g (2.436 mmol) of 4-phenylbutyric acid are suspended in 30 ml of H2O, and then 0.097 g (2.436 mmol) of sodium hydroxide is added. After the acid has been dissolved, the solution is concentrated by rotary evaporation and twice dewatered azeotropically with toluene. This gives 0.44 g (96.0%) of sodium 4-phenylbutyrate in solid form. |
88.2% | With sodium hydroxide; In ethanol; for 4.0h;Industrial scale; | As shown in Fig. 5, 6000 ml of anhydrous ethanol and 243.6 g of sodium hydroxide were successively charged into 10 L of a four-necked reaction flask. After heating and stirring, 1000 g of phenylbutyric acid prepared in Example 3 was added thereto, stirred and heated to dissolve, (TLC developing solvent: methanol: dichloromethane = 1: 2, Rf = 0.2 for phenylbutyric acid, Rf = 0.1 for sodium phenylbutyrate), and the reaction was terminated for about 4 hours. Add 30g of activated carbon reflux 10 minutes, slightly cold, filter to remove activated carbon. Collect the liquid at 50 C. Distillation to remove most of the solvent. A large amount of white solid precipitated. After cooling the residue to 15 C, the solid was collected by filtration and washed with 100 ml of absolute ethanol. The solid was dried at 40 C for 4 hours and then dried at 60 C for 12 hours to give 1000 g of white sodium phenylbutyrate in 88.2% yield, HPLC purity of 99.77% (octadecyl silane bonded silica as stationary phase, Glacial acetic acid-methanol-water (1:49:50) as the mobile phase; detection wavelength of 245nm), high-performance liquid chromatography shown in Figure 5, the results shown in Table 8, we can see that a single impurity control Within 0.1%. |
With sodium carbonate; In methanol; at 60.0℃; for 0.75h; | About 200 g of 4-phenylbutyric acid was dissolved in 1200 mL of methanol, then 65 g sodium carbonate was added and the mixture heated to about 60 C. for about 45 min. The solution is concentrated to about 1/10th of its original volume and 7000 mL of acetone was added with stirring for about 40 min at about 0 C. The precipitated sodium-4-phenylbutyrate was filtered and washed with acetone, and dried under vacuum at 30 C. |
With sodium carbonate; In methanol; at 60.0℃; for 0.75h; | EXAMPLE 18; Preparation of Sodium 4-phenylbutyrate; About 200 g of 4-phenylbutyric acid was dissolved in 1200 mL of methanol, then 65 g sodium carbonate was added and the mixture heated to about 60 C. for about 45 min. The solution is concentrated to about 1/10th of its original volume and 7000 mL of acetone was added with stirring for about 40 min at about 0 C. The precipitated sodium4-phenylbutyrate was filtered and washed with acetone, and dried under vacuum at 30 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-Phenylbutyric acid With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dimethyl sulfoxide at 30℃; for 3h; Stage #2: 7-aminoheptanoic acid With sodium hydrogencarbonate In water; dimethyl sulfoxide at 30℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With palladium on activated carbon; hydrogen In methanol at 20℃; for 1h; Schlenk technique; | |
95% | With palladium 10% on activated carbon; W(OTf)<SUB>6</SUB>; hydrogen at 50℃; for 12h; | 40 Preparation of phenylbutyric acid from γ-phenyl-γ-butyrolactone 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, γ- 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 reaction temperature was changed to 50 ° C, and the yield 95%, the purity of the product is 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 |
95% | With palladium on activated carbon; W(OTf)<SUB>6</SUB>; hydrogen In acetic acid at 50℃; for 12h; |
68% | With potassium fluoride; palladium diacetate; chlorobenzene In tetrahydrofuran; water at 20℃; for 1h; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75 %Chromat. | In methanol; diethyl ether at 0 - 20℃; | 4.3. General procedure for the oxidation of the long chainalcohol 3a-3h General procedure: To the solution of the mixture in diethyl ether (5 mL) andmethanol (4 mL) in ice bath, a solution of trimethysilyldiazomethanein diethyl ether (2 mL, 2 M, 4 mmol) was added dropwisewhile stirring, and stirring for 2 h, then ice bath was removed andstirring overnight. Upon removal of residual solvents and trimethylsilylspecies, the product was obtained and the product wasdetected by GCeMS. The original spectra of GCeMS were given inthe Supplementary data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dicyclohexyl-carbodiimide In dichloromethane at 60℃; for 58h; | General procedure for the synthesis of compounds 3a-3j General procedure: A solution of fluorescein (1) (0.664 g, 2 mmol), carboxylic acid (2) (4 mmol), DCC (4 mmol, 0.825) in CH2Cl2 (5 ml) was heated at 60 °C for 24-48 h. After the completion, the DCU was filtered off. The organic layer was washed with water (25 ml) and saturated NaHCO3 solution (25 ml), dried over Na2SO4 and concentrated to give the crude product. The crystalline pure product was obtained by further recrystalization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: tribenzylamine With iodine; triphenylphosphine In dichloromethane at 0℃; for 0.166667h; Stage #2: 4-Phenylbutyric acid In dichloromethane at 25℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With 2,2,6,6-tetramethylpiperidinium triflate; In neat liquid; at 120℃; for 15h;Green chemistry; | General procedure: Place carboxylic acid (2.0 mmol), alcohol (2.2 mmol), 5 mol% ( 0.1 mmol) of catalyst into a round-bottom flask containing a teflon-coated magnetic stir bar, then stir the system at 120 C under solvent-free condition (Scheme 1). Trace thereaction by GC or 1H NMR analysis. When the catalyst precipitated completely from the reaction medium at the end of the reaction, separated it by centrifugation, then washed it three times with petroleum ether. The pure ester was obtained by the column chromatography, indentified by 1H NMR and 13C NMR analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-iodo-succinimide; iodine In 1,2-dichloro-ethane at 100℃; for 8h; Sealed tube; Darkness; | |
90% | With N-iodo-succinimide; iodine In 1,2-dichloro-ethane at 100℃; for 8h; Darkness; | |
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C 2: 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride; sodium iodide; 2,4,6-trimethyl-pyridine / acetone / 45 °C / Irradiation; Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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 dichloromethane at 20℃; | 2 4.2.1 General procedure for synthesis of target compounds (11a-11r) General procedure: Oseltamivir, 1-[Bis (dimethylamino) methylene]-1H-1, 2, 3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.5 equiv), N,N-diisopropylethylamine (DIPEA) (2.5 equiv), corresponding acid (1.5 equiv) and 10mL CH2Cl2 were charged in a 50mL round bottom flask. The mixture was stirred at room temperature until starting material was consumed, as indicated by TLC analysis. The organic layer was washed successively by 1N HCl aqueous solution, saturated aq.NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the intermediate 10a-10r. To 10mL methanol was added corresponding 10, and then was added 1N NaOH (2.5 equiv) and H2O (V(methanol): V(H2O)=5:1). The reaction mixture was stirred at room temperature. After reaction completed, the methanol was evaporated in vacuo and acidified with 1N HCl to pH 1-2. The precipitate was filtered and dried to furnish a solid. If no precipitate, 2×10mL CH2Cl2 were added, the combined organic layer was washed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain corresponding 11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With iron(III) trifluoromethanesulfonate; water; palladium diacetate; triphenylphosphine In 1,4-dioxane at 120℃; for 15h; Sealed tube; Inert atmosphere; Autoclave; Overall yield = 89 %; regioselective reaction; | ||
With sulfuric acid; α,α′-bis(2-pyridyl(tert-butyl)phosphino)-o-xylene; water; palladium(II) acetylacetonate; acetic acid at 20 - 100℃; for 20h; Inert atmosphere; Autoclave; Overall yield = 99 percent; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With formic acid; bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In tetrahydrofuran at 100℃; Inert atmosphere; Sealed tube; Overall yield = 87 %; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 61% 2: 18% | With formic acid; bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,2-dichloro-ethane at 100℃; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Stage #1: C13H11N4O3PolS; 4-Phenylbutyric acid With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate In ethyl acetate at 20℃; for 3h; Molecular sieve; Stage #2: 2-amino-5-iodobenzoic acid In N,N-dimethyl-formamide at 20℃; Molecular sieve; | 4.1.9. 5-iodo-2-(4-phenylbutanoylamino)benzoic acid (23) 4-phenylbutanoic acid (690 mg, 4.2 mmol, 3 eq) was dissolvedin EtOAc dried over molecular sieves (15 mL), with PyBrop (1.96 g,4.2 mmol, 3 eq) and DIEA (1.46 mL, 8.4 mmol, 6 eq). The solutionwas added to the HOBt resin (1-Hydroxybenzotriazole-6-sulfonamidomethyl polymer-bound, 1.4 mmol, 1 eq) and the resinwas shaked for 3 h at RT. After the first activation step the resin was washed 3 times with DMF. The second activation step was performed under the same conditions and the resin was washed 5 times with DMF then twice with DCM and dried. The polymer bound activated ester (146 mg, 0.25 mmol, 1.25 eq) and 2-amino-5-iodo-benzoic acid (52 mg, 0.2 mmol, 1 eq) were dissolved in DMF dried over molecular sieves (1 mL). The mixture was stirred overnight at RT. The conversion was around 70%. The supernatant was separated from the resin by filtration. The polymeric beads werewashed 3 times with DMF, the washing solutions were recovered and combined with the supernatant previously recovered. The solvent was evaporated in vacuo. The residue was purified by preparative HPLC to give 5-iodo-2-(4-phenylbutanoylamino)benzoicacid. Yield: 46%. 1H NMR (DMSO-d6): d (ppm) 13.91 (brs, OH),11.06 (s, NH), 8.30 (d, J 8.8 Hz, 1H), 8.21 (d, J 2.2 Hz, 1H), 7.90(dd, J 8.8 Hz, J 2.2 Hz, 1H), 7.34e7.14 (m, 5H), 2.63 (t, J 7.5 Hz,2H), 2.40 (t, J 7.5 Hz, 2H), 1.92 (quin, J 7.5 Hz, 2H). 13C NMR(DMSO-d6): d (ppm) 171.6, 168.6, 142.6, 142.0, 140.8, 139.4, 128.8,128.8, 126.3, 122.7, 119.4, 86.2, 37.3, 34.9, 27.0. HRMS (TOF, ES-) m/z[M H]- calculated for C17H15NO3I 408.0097, found 408.0111. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In ethyl acetate at 20℃; for 12h; | General procedure for the synthesisof amides (2-5) or esters (1, 6)in the presence of 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate(TBTU) General procedure: The compounds were synthesized by following the describedprotocol [42]. Briefly, 4-phenylbutyric acid (4-PBA)(1 mmol, 1 eq, 164.2 mg) was dissolved in ethyl acetate(EtOAc) (30 ml) and TBTU (1 mmol, 1 eq, 321 mg) andtriethylamine (TEA) (2 mmol, 2 eq, 0.27 ml) were added.The mixture was stirred until a clear solution was achieved;then the appropriate amine (2 mmol, 2 eq) was added. Afterhaving been stirred for 12 h at room temperature, the mixture was washed with H2O(3 × 50 ml) and the organic phasewas separated, dried over anhydrous Na2SO4,filtered, andevaporated at reduced pressure to obtain a crude product.Appropriate purification of the crude mixture afforded correspondingcompounds 1-6. The compounds were also characterizedby HRMS and NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-(3-(((ethylimino)methylene)amino)propylidene)-N-methylmethanaminium chloride In dichloromethane at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; C27H25O3P; lithium chloride; palladium dichloride In 1,4-dioxane at 70℃; for 24h; Sealed tube; Overall yield = 63 percent; Overall yield = 0.052 g; regioselective reaction; |
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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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