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CAS No. : | 306-08-1 | MDL No. : | MFCD00004350 |
Formula : | C9H10O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QRMZSPFSDQBLIX-UHFFFAOYSA-N |
M.W : | 182.17 | Pubchem ID : | 1738 |
Synonyms : |
Vanilacetic acid;HVA;Homovanillic acid, HVA, NSC 16682, Vanilacetic Acid;NSC 16682;Vanillacetic acid
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 46.5 |
TPSA : | 66.76 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.18 cm/s |
Log Po/w (iLOGP) : | 1.18 |
Log Po/w (XLOGP3) : | 0.33 |
Log Po/w (WLOGP) : | 1.03 |
Log Po/w (MLOGP) : | 0.79 |
Log Po/w (SILICOS-IT) : | 1.08 |
Consensus Log Po/w : | 0.88 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.32 |
Solubility : | 8.7 mg/ml ; 0.0478 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.3 |
Solubility : | 9.22 mg/ml ; 0.0506 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.73 |
Solubility : | 3.41 mg/ml ; 0.0187 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.49 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; at 20℃; for 4h;Reflux; | [0191] Sulfuric acid (5.8 mL, 0.11 mol) was added to a homogeneous solution of homovanillic acid 11 (400 g, 2.2 mol) in methanol (2.0 L) at room temperature. The solution was heated to reflux and stirred for 4 hours. The solvent was removed in vacuo to furnish the methyl ester as a viscous brown oil which was used directly in the subsequent step. *H NMR (CDC13) delta 6.87 - 6.77 (m, 3H), 3.89 (s, 3H), 3.69 (s, 3H), 3.55 (s, 2H). | |
With chloro-trimethyl-silane; at 25℃; for 24h; | General procedure: To a suspension of acidic phenols 1a-d (0.05mmol) in TMCS (0.1mmol), the alcohol (1.0mL) was added and the reaction mixture was stirred at 25C. After 24h, the reaction was stopped and evaporated under reduced pressure to afford 2a-l in quantitative yield without the need of purification: | |
With sulfuric acid; at 90℃; for 7h; | Excess of the corresponding alcohol. <strong>[306-08-1]Homovanillic acid</strong> (1.5-3 g) was stirred in the respectivealcohol (100 mL) with 0.2-0.5 equivalents of sulfuric acid for 7 h at 90 C (heating block temperature).Most of the alcohol was removed in vacuo, then sat. aq. NaHCO3 solution and EtOAc were added.The organic phase was separated and the aqueous phase extracted with EtOAc. The combined organiclayer was washed with sat. aq. NaHCO3 solution and water or alternatively with sat. aq. NaCl solution,dried over NaSO4 and the solvent removed in vacuo. The product was obtained after purification bycolumn chromatography on silica in 90% to quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In acetonitrile; for 4h;Reflux; | A solution of commercially available acid 17 (5.0g, 27.5mmol), K2CO3 (7.58g, 54.9mmol), and benzyl bromide (6.5mL, 54.9mmol) in acetonitrile (150mL) was refluxed for 4h. The reaction was cooled to rt, filtered, and the solvent evaporated under reduced pressure. The resulting crude product was purified on a silica gel column eluting in 10% ethyl acetate-petroleum ether to afford 18 as a pale yellow solid (9.4g, 95%). Mp 50-53C; 1H NMR (500MHz, CDCl3): delta 7.42 (m, 2H), 7.33 (m, 8H), 6.81 (d, 2H, J=7.9Hz), 6.74 (dd, 1H, J=8.2, 1.9Hz), 5.14 (s, 2H), 5.13 (s, 2H), 3.84 (s, 3H), 3.59 (s, 2H); 13C NMR (125MHz, CDCl3): delta 171.5, 149.6, 147.3, 137.1, 135.8, 128.55 (×2), 128.54, 128.3, 128.2, 127.8, 127.2 (×2), 126.9, 121.4, 114.1 (×2), 112.9 (×2), 71.1, 66.6, 55.9, 40.9; HRESIMS: calcd for C23H22O4Na [M+Na]+ 386.1444; found 386.1446. |
With caesium carbonate; In water; ethyl acetate; acetonitrile; | (i) Benzyl 4-benzyloxy-3-methoxyphenylacetate Cs2CO3 (17.88 g; 54.9 mmol) was added to a solution of homovanillic acid (2.0 g; 11 mmol) in CH3CN, whereafter BnBr (4.3 g; 24.15 mmol) was added dropwise over 10 minutes. The mixture was refluxed overnight, filtered through Hyflo and concentrated. The resulting mixture was dissolved in EtOAc (100 mL), water (30 mL) was added, and the aqueous layer was separated. The organic phase was washed with citric acid solution (5%, 1*20 mL) and brine, dried (Na2SO4), and evaporated to yield 4.25 g (quant.) of the sub-title compound. 1H-NMR (300 MHz; CDCl3): delta 7.43 (d, 2H); 7.34 (m, 8H); 6.82 (d, 2H); 6.74 (dd, 1H); 5.33 (s, 4H); 3.84 (s, 3H); 3.59 (s, 2H). | |
37 g | With potassium carbonate; In acetone;Reflux; | 15 g of the compound of the formula 1b, 65 g of potassium carbonate and 300 ml of acetone were mixed and stirred.41.5 g of benzyl bromide was added dropwise to the system at a constant rate, and after the addition, the temperature was raised to reflux overnight.After the reaction is over, drop to room temperature and take care.The filtrate was collected and concentrated under reduced pressure.Obtaining 37 g of the compound of formula 2,No need to purify, go directly to the next step.Hydroxy protection reaction |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium hydroxide; In ethanol; water; at 80℃; for 48h;Inert atmosphere; | To a solution of nitrile 17 (50 mg, 0.31 mmol) in EtOH (2 mL) and H2O (1 mL), was added NaOH (49 mg, 1.21 mmol) and the resultant solution was heated at 80C for 2 d. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (2 mL) and was poured on a slurry of conc. HCl and ice. The organic layer was separated and the aqueous mixture was extracted with ethyl acetate (3x5 mL). The combined organic extracts were dried (MgSO4) and the solvent was removed under reduced pressure to yield the title compound (50 mg, 89%) as a yellow oil which required no further purification. RF (2:1 hexanes, ethyl acetate) 0.24; dH (400 MHz; MeOD; Me4Si) 3.57 (2H, s, CH2Ar), 3.88 (3H, s, OCH3), 6.75-6.88 (3H, m, 2-, 5- and 6-H); Spectroscopic data were in accordance with literature values. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With ammonium acetate; In diethylene glycol; at 190℃; for 0.133333h;microwave irradiation; | Example XII; Synthesis of l-(4'-hydroxy-3-methoxy)phenyl-2-(l'-naphthyI)ethene; (From formula I where R8=OH3 R1+ R2 = phenyl, R3, R4, R5, R6, R7, R9, R10=H) A mixture of 1-naphthaldehyde (0.0160mol), 4-hydroxy-3-methoxyphenylacetic acid (0.0181mol), ammoniumacetate (0.0246mol) and diethylene glycol (3 ml) were taken in a 100 ml round bottom flask fitted with a condenser. The flask was shaken well and placed inside the microwave oven and irradiated (monomode, 250W, 190 0C) for 8 minutes in parts After completion the reaction was worked up as in example I and provided viscous liquid; 53% yield; solid, (m.p. 83-86 0C); 1H NMR (CDCl3) delta 8.22 (IH5 d, J=Z 68 Hz), 7.85 (IH, d, J=8.23 Hz), 7.77 (3H, m), 7.51 (3H, m), 7.11 (2H, m), 7.08 (IH, d, J=I 7.05 Hz), 6.95 (IH, d, J=8.23 Hz), 5.74 (IH, s), 3.91 (3H, s); 13C NMR (CDCl3) delta 146.8, 145.8, 135.3, 133.8, 131.7, 131.4, 128.7, 127.8, 126.0, 125.8, 123.8, 123.6, 123.0, 120.6, 114.7, 108.6 and 56.0. HREIMS data: m/z [M+H]+ for C19H17O2, calculated =277.3440; observed =277.3441. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: ethyl acetate; ozone / und anschliesende Hydrierung an Palladium/Kohle 2: potassium permanganate; magnesium sulfate; aqueous acetone | ||
Multi-step reaction with 2 steps 1: KMnO4; water 2: NaOH-solution |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; | <strong>[306-08-1]Homovanillic acid</strong> (182 mg, 0.999 mmol) dissolved in DMF (3 ml) was cooled in an ice- bath. [N-HEXYLBENZYLAMINE] (201 mg, 1.049 mmol) was added and then TBTU (337 mg, 1.049 mmol) followed by DIPEA (407 mg, 3.147 [MMOL).] The mixture was stirred at room temperature overnight and evaporated. Sodium hydrogencarbonate aqueous solution (sat.) was added into the residue. The mixture was then extracted with ethyl acetate (x2). The extracts were combined and washed with water and brine and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column [(ISOLUTE&COMMAT; ] SI, 5g/15 [ML)] using DCM and then MeOH/DCM (1: 99) as eluant gave 264 mg the desired product, yield 74%. [1H] NMR (rotamers, 400 MHz, [CDC13)] : 8 0.83-0. 89 [(M,] 3H), 1.20-1. 29 [(M,] 6H), 1. [44-1. 56] [(M,] 2H), 3.18, 3.37 (t, t, 2H), 3.60, 3.71 (s, s, 2H), 3.81 (s, br, 3H), 4.50, 4.61 (s, s, 2H), 5.98 (s, br, 1H), 6. [62-6. 85 (M,] 3H) and 7.11-7.36 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With hexamethylenetetramine; at 90℃; for 4h; | A mixture of 4-hydroxy-3-methoxyphenylacetic acid (6a; 1.0 g; 5.49 mmol) and hexamethylenetetramine (0.808 g; 5.76 mmol) and TFA (7 mL) were stirred and heated at 90 C. for 4 h. The reaction was cooled and excess TFA removed in vacuo and 35 mL of ice and water was added to the residue. The resulting dark brown solution was stirred at rt for 20 m. The aqueous solution was extracted with Et2O (40 mL) and the extract was dried (Na2SO4), filtered and evaporated to afford 0.70 g of 6b (61%; m.s. (M+H)+=211.13; mw=210). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Step 1 A mixture of 4-hydroxy-3-methoxyphenylacetic acid (6a; 1.0 g; 5.49 mmol) and hexamethylenetetramine (0.808 g; 5.76 mmol) and TFA (7 ML) were stirred and heated at 90 C. for 4 h.The reaction was cooled and excess TFA removed in vacuo and 35 ML of ice and water was added to the residue.The resulting dark brown solution was stirred at rt for 20 m.The aqueous solution was extracted with Et2O (40 ML) and the extract was dried (Na2SO4), filtered and evaporated to afford 0.70 g of 6b (61%; m.s. (M+H)+=211.13; mw=210). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In 1,4-dioxane; water; at 65℃; for 7h; | With vigorous stirring, gaseous chlorodifluoromethane is introduced at 65OR-INTO a solution of homovanillic acid (0.91 g, 5 MMOL) and potassium hydroxide (2.8 g, 50 MMOL) in water (5.6 mi) and dioxane (10 ML). After 1 h, potassium hydroxide (28 g, 500 MMOL) in water (56 ML) is added dropwise over a period of 5 h to the solution, which continues to be treated with gas. The mixture is stirred for another hour and then cooled. The solution is acidified with citric acid (about 25 G) and extracted three times with ethyl acetate (in each case 20 ML). The combined organic phases are washed twice with water (in each case 20 ML), and with saturated sodium chloride solution (20 ML), and dried over magnesium sulphate, and the solvent is removed using a rotary evaporator. The amorphous residue is recrystallized from toluene (15 ML), result- ing in the recovery of HOMOVANILLIC acid (0. 28 G). The mother liquor is concentrated using a rotary evapora- tor and the amorphous residue is RECRYSTALLIZED from water (30 ml), filtered off with suction and washed with water (10 ML). Drying gives the title compound (0. 384 G) as colourless crystals. MS: calc. : C, OH, OF204 (232.05), found: [MH] 232 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-methyl-1H-imidazole; 1-(mesitylene-2-sulfonyl)-3-nitro-1H-1,2,4-triazole; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h; | 300 mg of 4-hydroxy-3-methoxy-phenylacetic acid and 570 mul DIEA were dissolved in 5 ml DCM and added to 0.5 g 2-chlorotrityl-chloride resin (1.5 mmol/g). The suspension was agitated for 1 h at RT and resin was washed with DCM. Resin was resuspended in a solution of 190 mg 3-maleimidopropionic acid, 333 mg MSNT and 73 mul N-methyl imidazole in 3 ml DCM and agitated for 1h. After washing of the resin with DCM, cleavage was performed by agitation of the resin for 30 min in 10 ml 4/1 (v/v) DCM/TFA. Solvent was removed under nitrogen flow and compound 6 was purified by RP-HPLC. MS [MNa]+ (MW+Na calculated): 356 g/mol (356 g/mol) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sulfuric acid; for 18h;Heating / reflux; | EXAMPLE 15 Methyl homovanillate (6); [00198] To a stirred solution of homovanillic acid (100 g, 0.55 mol) in dry methanol (1.0 L) was added trimethyl orthoformate (25 mL) and concentrated sulfuric acid (5 mL). The solution was heated at reflux for 18 hours, at which point the reaction was complete by TLC analysis. Following cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in toluene (1.0 L) and this solution was washed with water (2 x 200 mL), saturated aqueous sodium bicarbonate solution (250 mL), saturated aqueous sodium chloride solution and dried over magnesium sulfate. After clarification, the filtrate was concentrated to dryness under reduced pressure and the residue was distilled (120-125 C/0. 5 mm Hg vacuum) to afford 92 g of 6 in 85% yield, as a colorless oil. The NMR was consistent with the structure |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With hexamethylenetetramine; at 90℃; for 4h; | A mixture of 4-hydroxy-3-methoxyphenylacetic acid (20; 1.0 g; 5.49 mmol, SCHEME 2) and hexamethylenetetramine (0.808 g; 5.76 mmol) and TFA (7 mL) were stirred and heated at 90 C. for 4 h. The reaction was cooled and excess TFA removed in vacuo and 35 mL of ice and water was added to the residue. The resulting dark brown solution was stirred at rt for 20 min. The aqueous solution was extracted with Et2O (40 mL) and the extract was dried (Na2SO4), filtered and evaporated to afford 0.70 g of 22a (61%): ms (M+H)+=211.13; mw=210. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In dichloromethane; | Step 1) Synthesis of N-{3-(3,4-dimethylphenyl)propyl}-4-hydroxy-3-methoxyphenylacetamide A mixture of 1.39 g of 3-(3,4-dimethylphenyl)propylamine obtained in Preparation Example 1, 1.50 g of 4-hydroxy-3-methoxyphenylacetic acid and 0.60 g of powdered 4 A molecular sieve was stirred for 4 hours at a temperature within the range of 150-160 C. and dissolved in 10 ml of dichloromethane. The resultant mixture was purified by column chromatography to provide 2.43 g(yield 90%) of the title compound, having the characteristics of: NMR(CDCl3) delta1.72(m, 2H, CH2), 2.21(s, 6H, 2ArCH3), 2.49(t, J=7 Hz, 2H, ArCH2), 3.22(q, J=7 Hz, 2H, ArCH2), 3.47(s, 2H, CH2 CO), 3.87(s, 3H, OCH3), 5.44 (s, 1H, NH), 5.78(s, 1H, OH), 6.68-7.04(m, 6H, ArH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With hydrogenchloride; tin(ll) chloride; In water; at 80℃; for 4h; | First, stannous chloride dihydrate (250 mmol, 2 eq) was dissolved in 120 ml of concentrated hydrochloric acid.To be completely dissolved, the compound 2-(3-ethoxy-4-hydroxyphenyl)-2-hydroxyacetic acid (94 mmol, 1 eq) was added to a hydrochloric acid solution of stannous chloride dihydrate and reacted at 80 C for 4 h. The reaction was stopped, cooled to room temperature, and a white solid was precipitated and crystallised from distilled water to give 16.3 g of 2-(3-ethoxy-4-hydroxyphenyl)acetic acid as a white solid. |
75% | EXAMPLE 2 The reaction was carried out in the same manner as in Example 1 except that acetic acid was used in place of 20 N sulfuric acid for adjustment to pH 1.5. As the result, conversion of 4-hydroxy-3-methoxymandelic acid was found to be 75% and yield of 4-hydroxy-3-methoxyphenylacetic acid 62%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | molecular sieve; In dichloromethane; | Step 1) Synthesis of N-{3-(3,4-dimethylphenyl)propyl}-4-hydroxy-3-methoxyphenylacetamide A mixture of 1.39g of 3-(3,4-dimethylphenyl)propylamine obtained in Preparation Example 1, 1.50g of 4-hydroxy-3-methoxyphenylacetic acid and 0.60g of powdered 4A molecular sieve was stirred for 4 hours at a temperature within the range of 150-160C and dissolved in 10ml of dichloromethane. The resultant mixture was purified by column chromatography to provide 2.43g(yield 90%) of the title compound, having the characteristics of: NMR(CDCl3)delta 1.72(m, 2H, CH2), 2.21(s, 6H, 2ArCH3), 2.49(t, J=7Hz, 2H, ArCH2), 3.22(q, J=7Hz, 2H, ArCH2), 3.47(s, 2H, CH2CO), 3.87(s, 3H, OCH3), 5.44 (s, 1H, NH), 5.78(s, 1H, OH), 6.68-7.04(m, 6H, ArH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | sulfuric acid; In diethyl ether; at 20℃; for 24.0833h; | Compound 16. Butyric acid 4-[4-(4-chloro-phenyl)-thiazol-2-ylcarbamoyl]-methyl}-2-methoxy-phenyl ester (B240816) Butyric acid 4-carboxymethyl-2-methoxy-phenyl ester (B240809) 4-Hydroxy3-methoxyphenylacetic acid (974 mg, 5.3 mmol) was mixed with butyric acid anhydride (.3.5 mL), followed by addition of H2SO4 (0.1 mL). After stirring for 5 min, it became a yellow solution. Ether (20 mL) was added to it. The reaction was continued for 24 hours at RT. The mixture was poured into 50 mL of ice-water. The mixture was extracted with EtOAc (2×50 mL). The EtOAc solution was dried over Na2SO4. After filtration, the concentrated oily residue was purified by chromatography (CHCl3-3% MeOHl in CHCl3) to afford a yellowish white solid (961 mg, Y=72%). The structure of tie compound was confirmed by NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In dichloromethane at 0 - 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
<strong>[306-08-1]Homovanillic acid</strong> (55 mg, 0.3 mmol) was mixed with DCM (7.5 ml), HOBt hydrate(78 mg, 0.51 mmol), and EDAC (75 mg, 0.39 mmol). After 5 min mPeg(5000)-NH2 (0.50 g, <n="45"/>0.1 mmol) was added, followed by the addition of DIPEA (0.22 ml, 1.24 mmol). The resulting mixture was stirred at room temperature for 24 h. Aminomethylpolystyrene (1.53 g; loading: approx 1 mmol/g) and more DCM (10 ml) were added. After 2 h the mixture was filtered, the resin rinsed with DCM, and the combined filtrates were concentrated under reduced pressure. The residue was redissolved in DCM (2.5 ml), and the product precipitated with diethyl ether. This redissolution-precipitation cycle was repeated two times, and the resulting solid was dried under reduced pressure to yield 505 mg of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In dimethyl sulfoxide; at 80℃; for 4h; | Cs2CO3 (15.5 g, 47.5 mmol) was added to (24.1) (3 g, 14.4 mmol) and 3-methoxy-4- hydroxyphenylacetic acid (2.63 g, 14.4 mmol) in DMSO (30 mL) at room temperature. The mixture was then stirred at 80 0C for 4 h. After cooling, the reaction mixture was treated with water (50 mL), 3N HCl (35 mL) and EtOAc (100 mL). The product was insoluble in EtOAc, but stayed in the organic layer. So the organic layer was washed with water 4 times to get rid of all the salts, and the organic layer was separated, concentrated and dried under vacuum to afford 24.2. MS ESI (pos.) m/z: 355.1 (M+H). 1H NMR (DMSO-d6) delta 8.99 (dd, IH); 8.24 (m, 2H); 7.77 (dd, IH); 7.29 (d, IH); 7.21 (d, IH); 7.18 (d, IH); 6.96 (dd, IH); 3.73 (s, 3H); 3.65 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 4-fluoro-3-nitroaniline (3.45 g, 22.1 mmol), 4-hydroxy-3-methoxyphenylacetic <n="53"/>acid (4.03 g, 22.1mmol) and cesium carbonate (18.Og, 55.3mmol) in methylsulfoxide (40 mL) was heated to 120 C (external temperature, oil bath) overnight. After 16 h the reaction was poured into water and the pH adjusted to <4 by addition of citric acid. The aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water then brine. The organic separation was stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a dark brown oil. The product was isolated by chromatography on silica gel, eluting with an ethyl acetate/hexane gradient, to afford an orange foamy solid. LC-MS ESI (neg.) m/z: 317.0 (M-H). 1H NMR (400 MHz) (CDCl3) delta 7.27 (d, J=8.4 Hz, IH); 6.93 (s, IH); 6.84-6.79 (m, 4H); 5.90 (br s, 2H); 3.85 (s, 3H); 3.63 (s, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; sodium hydrogencarbonate; In methanol; | A solution of homovanillic acid 10 (2 g, 11 mmol) and sulfuric acid (500 ml, 9.4 mmol) in methanol (100 ml) was refluxed for 3 hours. After cooling, a sodium bicarbonate solution was added to the reaction mixture. The product was extracted with CH2Cl2 (2*50 ml). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give methyl 4-hydroxy-3-methoxyphenylacetate 9 (2 g, 94%) in the form of a colorless oil. 1H NMR (CDCl3, 300 MHz) delta 7.00-6.70 (m, 3H), 5.82 (br s, OH), 3.87 (s, 3H), 3.70 (s, 3H), 3.56 (s, 2H). 13C NMR (CDCl3, 75 MHz) delta 172.6, 146.6, 144.8, 125.7, 122.1, 114.5, 111.8, 55.9, 52.1, 40.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; | To the solution of A (1.82 g, 10 mmol), B (1.81 g, 10 mmol) in DCM (30 mL) was added EDCI (2.83 g, 12 mmol) and Et3N (1.0 g, 9.93 mmol) at 20 C. and the solution was stirred overnight. TLC analysis indicated the completion of the reaction. Water was added, and the organic layer was collected, dried and concentrated to get 2.85 g of C. | |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; | To the solution of A (1 82 g, 10 mmol), B (1 81 g, 10 mmol) in DCM (30 ralphaL) was added EDCI (2 83 g, 12 mmol) and Et3N (1 0 g, 9 93 mmol) at 200C and the solution was stirred overnight TLC analysis indicated the completion of the reaction Water was added, and the organic layer was collected, dried and concentrated to give 2 85 g of C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.5% | With magnesium sulfate;novozyme 435; In toluene; at 50℃; for 16h;Enzymatic reaction; | 8-Methyl-1-nonanol (752 mg, 4.74 mmol), homovanillic acid (907 mg, 4.98 mmol) and Novozyme 435 (100 mg) were measured and placed in a flask (25 ml). Toluene (5 ml) and anhydrous magnesium sulfate (1 g) were added, and the mixture was stirred with heating in an oil bath at 50 C. for 16 hr. The reaction mixture was allowed to cool to room temperature, toluene (25 ml) was added, and Novozyme 435 and the precipitated insoluble material were removed by filtration. Toluene (50 ml) was added, and the mixture was washed with 5% aqueous sodium hydrogen carbonate solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (chloroform:n-hexane:ethyl acetate=1:1:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give 8-methylnonyl homovanillate (1.25 g, yield 81.5%) as a colorless oil.1H-NMR (CDCl3,delta): 0.86 (6H, d, J=6.64 Hz), 1.12-1.35 (10H, m), 1.45-1.65 (3H, m), 3.53 (2H, s), 3.88 (3H, s), 4.08 (2H, t, J=6.76 Hz), 5.56 (1H, s), 6.73-6.88 (3H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; In dichloromethane; at 0℃; | To the solution of 2-(4-hydroxy-3-methoxyphenyl)acetic acid 182-1 (364 mg, 2 mmol) and TEA (404 mg, 4 mmol) in DCM (40 mL) was added triflic anhydride (564 mg, 2mmol) slowly at 0C. The reaction was warmed up to room temperature after addition and stirred for 1 hour at room temperature. The reaction mixture was then partitioned between DCM and water. The organic phase was washed with brine and dried over Na2SO4. The solvent was removed by rotary evaporation to give 2-(3-methoxy-4- (trifluoromethylsulfonyloxy)phenyl)acetic acid 182-2 (590 mg, 95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sulfuric acid; for 2h;Reflux; | The compound 2-(3-ethoxy-4-hydroxyphenyl)acetic acid (a3) (5.5 g, 28 mmol) was dissolved in 50 ml of ethanol, concentrated sulfuric acid (1 ml) was added, and the mixture was reacted under reflux for 2 h. The reaction was completed by a thin-layer chromatography plate, and the solvent was evaporated to dryness under reduced pressure. The solvent was dissolved in ethyl acetate, washed with saturated brine (1×), washed with saturated sodium hydrogen carbonate (1×), and brine (1×), The residue was dried with MgSO 4, filtered and evaporated |
With sulfuric acid; at 90℃; for 7h; | Excess of the corresponding alcohol. <strong>[306-08-1]Homovanillic acid</strong> (1.5-3 g) was stirred in the respectivealcohol (100 mL) with 0.2-0.5 equivalents of sulfuric acid for 7 h at 90 C (heating block temperature).Most of the alcohol was removed in vacuo, then sat. aq. NaHCO3 solution and EtOAc were added.The organic phase was separated and the aqueous phase extracted with EtOAc. The combined organiclayer was washed with sat. aq. NaHCO3 solution and water or alternatively with sat. aq. NaCl solution,dried over NaSO4 and the solvent removed in vacuo. The product was obtained after purification bycolumn chromatography on silica in 90% to quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 26.1: (4-Hydroxy-3-methoxy-phenyl)-acetic acid A mixture of (4-hydroxy-3-methoxy-phenyl)-acetic acid ethyl ester (2 g, 9.51 mmol) and LiOH monohydrate (1.2 g, 28.5 mmol) in MeOH (20 ml) and water (10 ml) was stirred at RT for 14 h. The reaction mixture was concentrated under vacuum, diluted into water and neutralized by the addition of HCl 2 M in water (14.3 ml). The resulting slurry was extracted with DCM (3*) and AcOEt (2*) and the combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (1.67 g, 9.17 mmol, 96%) as a brownish solid, which was used in the next step without further purification. HPLC: AtRet=0.77 min; LC-MS: m/z 183.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 3.43 (s, 2H), 3.74 (s, 3H), 6.61-6.66 (m, J=8.1, 2.0, 1H), 6.67-6.72 (m, 1H), 6.81 (d, J=2.0, 1H), 8.81 (s, 1H), 12.17 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h; | Intermediate 1.4: (4-lsopropoxy-3-methoxy-phenyl)-acetic acid isopropyl esterTo the stirred solution of (4-hydroxy-3-methoxy-phenyl)-acetic acid (24.9 g, 137 mmol) in DMF (274 ml) was added K2C03 (56.7 g, 410 mmol) and 2-iodo-propane (34.2 ml, 342 mmol). The suspension was stirred for 3 h at 60 C. The cooled reaction mixture was concentrated and the residue was extracted between EtOAc (2x) and water (3x). The organic phases were washed with brine and dried over Na2S04, filtered and evaporated. Purification of the residue by normal phase column chromatography, eluting with EtOAc - hexane 1 :5, gave the title compound as a beige oil (27.0 g, 100 mmol, 73%): HPLC: B = 5.59 min; 1H NMR (400 MHz, DMSO-c 6): 1.20 - 1.22 (dd, 12H), 3.50 (s, 2H), 3.70 (s, 3H), 4.46 (m, 1 H), 4.87 (m, 1 H), 6.71 (d, 1 H), 6.85 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 12.5h;Inert atmosphere; | General procedure: To a solution of 5[38] (370 mg, 1 mmol) and TEA (350 muL, 2 mmol) in dry DMF (10 mL) were added the opportune phenolic acid (caffeic acid, syringic, p-coumaric, o-coumaric, 3,4-dihydoxyphenil-acetic, sinapic, m-coumaric, homovanillic or ferulic respectively) (1 mmol) and BOP (442 mg, 1 mmol). The reaction mixture was stirred at 0 C for 30 min and then for 12 h at room temperature under argon atmosphere. After evaporation of the solvent, the residue was dissolved in AcOEt and washed with HCl 1N, sat.d aq. NaHCO3 solution and H2O. The organic phase was dried, filtered and evaporated to give a crude residue purified by chromatography over silica gel to afford the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; | Synthesis of N-benzyloxy-N-heptyl-2-(4-hydroxy-3-methoxyphenyl)acetamide, Compound 14a (R=n-hexyl) A flask was charged with a solution of homovanillic acid (13) (182 mg, 1.0 mmol), HOBt (142 mg, 1.05 mmol), N-benzyloxyheptylamine 12a (232 mg, 1.05 mmol) and 10 mL of dry CH2Cl2. To the stirred solution was added EDC, HCl (211 mg, 1.1 mmol), and stifling continued overnight. The reaction solution was diluted with CH2Cl2 and extracted with 1N HCl, saturated NaHCO3 and saturated NaCl, and the resulting organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting first with CH2Cl2, then CH2Cl2/EtOH (98:2) and finally CH2Cl2/MeOH (98:2) to give 358 mg (93%) of a clear oil: Rf=0.33 (dichloromethane/methanol, 98:2, v/v); 1H NMR (CDCl3) delta 7.38-7.33 (m, 5H)6.80 (d, 3J=8.0 Hz, 1H), 6.74 (bs, 1H), 6.68 (dd, 3J=8.0 Hz, 4J=1.5 Hz), 5.48 (bs, 1H, -OH), 4.74 (s, 2H), 3.78 (s, 3H), 3.62 (bs, 4H), 1.60-1.58 (m, 2H), 1.26-1.17 (m, 8H) and 0.84 (t, 3J=7.0 Hz, 3H). Exact mass (FAB+) calculated for C23H32NO4 [M+H] 386.2356. Found 386.2309. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 4.5h;Inert atmosphere; | Synthesis of N-benzyloxy-N-octyl-2-(4-hydroxy-3-methoxyphenyl)acetamide, 14b (R=n-heptyl) Amine 12b (247 mg, 1.05 mmol) was weighed into a round bottom flask containing a stirring bar and previously purged with N2. To the flask were added homovanillic acid (13) (182 mg, 1.0 mmol) and HOBt (142 mg, 1.05 mmol). The system was placed under a positive N2 pressure, and dry dichloromethane (10 mL) was added via a rubber septum. Stirring at room temperature continued until most of the material had dissolved, except for the HOBt. Once the EDC, HCl (211 mg, 1.1 mmol) was added, a clear solution obtained quickly, and the reaction solution was stirred for 4.5 hours, after which time TLC indicated completion of reaction. The reaction solution was diluted with CH2Cl2 and extracted with water, 1N HCl, saturated NaHCO3 and saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with CH2Cl2, CH2Cl2/EtOH (98:2) and finally CH2Cl2/MeOH (98:2) to give 375 mg (94%) of a clear oil: Rf=0.36 (dichloro-methane/methanol, 98:2, v/v); 1H NMR (CDCl3) delta 7.4-7.31 (m, 5H), 6.80 (d, 3J=8.0 Hz, 1H), 6.74 (bs, 1H), 6.68 (dd, 3J=8.0 Hz, 4J=1.9 Hz), 5.49 (bs, 1H, -OH), 4.69 (s, 2H), 3.78 (s, 3H), 3.67-3.58 (m, 4H), 1.63-1.55 (m, 2H), 1.30-1.15 (m, 10H) and 0.85 (t, 3J=7.0 Hz, 3H). Exact mass (FAB+) calculated for C24H34NO4 [M+H] 400.2482. Found 400.2501. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | General procedure: To a solution of the appropriate carboxylic acid (2 equiv.), diamine (1 equiv.) and PyBOP (2 equiv.) in DMF (1.0 mL) was added TEA (6 equiv.). The reaction mixture was allowed to stir under N2 at room temperature for 22 h. The crude product was concentrated under vacuum and subjected to purification by combinations of reversed-phase C2, C8 and/or C18 flash column chromatography using H2O (+0.05% TFA) - MeOH solvent mixtures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | General procedure: To a solution of the appropriate carboxylic acid (2 equiv.), diamine (1 equiv.) and PyBOP (2 equiv.) in DMF (1.0 mL) was added TEA (6 equiv.). The reaction mixture was allowed to stir under N2 at room temperature for 22 h. The crude product was concentrated under vacuum and subjected to purification by combinations of reversed-phase C2, C8 and/or C18 flash column chromatography using H2O (+0.05% TFA) - MeOH solvent mixtures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | General procedure: To a solution of the appropriate carboxylic acid (2 equiv.), diamine (1 equiv.) and PyBOP (2 equiv.) in DMF (1.0 mL) was added TEA (6 equiv.). The reaction mixture was allowed to stir under N2 at room temperature for 22 h. The crude product was concentrated under vacuum and subjected to purification by combinations of reversed-phase C2, C8 and/or C18 flash column chromatography using H2O (+0.05% TFA) - MeOH solvent mixtures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 22h;Inert atmosphere; | General procedure: To a solution of the appropriate carboxylic acid (2 equiv.), diamine (1 equiv.) and PyBOP (2 equiv.) in DMF (1.0 mL) was added TEA (6 equiv.). The reaction mixture was allowed to stir under N2 at room temperature for 22 h. The crude product was concentrated under vacuum and subjected to purification by combinations of reversed-phase C2, C8 and/or C18 flash column chromatography using H2O (+0.05% TFA) - MeOH solvent mixtures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 22h;Inert atmosphere; | General procedure: To a solution of the appropriate carboxylic acid (2 equiv.), diamine (1 equiv.) and PyBOP (2 equiv.) in DMF (1.0 mL) was added TEA (6 equiv.). The reaction mixture was allowed to stir under N2 at room temperature for 22 h. The crude product was concentrated under vacuum and subjected to purification by combinations of reversed-phase C2, C8 and/or C18 flash column chromatography using H2O (+0.05% TFA) - MeOH solvent mixtures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | To a solution of homovanillic acid (50 mg, 0.27 mmol), 2-morpholinoethanamine (36 muL, 0.27 mmol) and PyBOP (143 mg, 0.54 mmol) in DMF (0.5 mL) was added TEA (114 muL, 0.82 mmol). The reaction mixture was allowed to stir under N2 at room temperature for 22 h. The crude product was concentrated under vacuum to give a pale orange gum. The crude material was subjected to reversed-phase C2 and C8 flash column chromatography with the desired product eluting in H2O (0.05% TFA) which was concentrated to yield 22 as a pale yellow oil (82 mg, 73%): Rf (10% MeOH/DCM) 0.33; Purity 99.3% tR 1.24 min; IR numax (ATR) 3275, 1668, 1515, 1199, 1023, 556 cm-1; 1H NMR (DMSO-d6, 400 MHz) delta 9.88 (1H, br s, OH), 8.19 (1H, t, J = 5.6 Hz, NH-9), 6.82 (1H, d, J = 1.8 Hz, H-2), 6.69 (1H, d, J = 8.1 Hz, H-5), 6.64 (1H, dd, J = 8.1, 1.8 Hz, H-6), 3.96-3.94 (2H, m, H2-14 or H2-16), 3.74 (3H, s, OMe-15), 3.63 (2H, br t, J = 11.6 Hz, H2-14 or H2-16), 3.46-3.39 (4H, m, H2-13 or H2-17 and H2-10), 3.32 (2H, s, H2-7), 3.17 (2H, t, J = 5.6 Hz, H2-11), 3.08 (2H, br m, H2-13 or H2-17); 13C NMR (DMSO-d6, 100 MHz) delta 171.5 (C-8), 147.4 (C-3), 145.3 (C-4), 126.5 (C-1), 121.4 (C-6), 115.3 (C-5), 113.3 (C-2), 63.3 (C-14 and C-16), 55.6 (C-15), 55.2 (C-11), 51.3 (C-13 and C-17), 42.0 (C-7), 33.4 (C-10); (+)-HRFABMS m/z 295.1653 [M+H]+ (calcd for C15H23N2O4, 295.1658). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | General procedure: To a solution of the appropriate carboxylic acid (2 equiv.), diamine (1 equiv.) and PyBOP (2 equiv.) in DMF (1.0 mL) was added TEA (6 equiv.). The reaction mixture was allowed to stir under N2 at room temperature for 22 h. The crude product was concentrated under vacuum and subjected to purification by combinations of reversed-phase C2, C8 and/or C18 flash column chromatography using H2O (+0.05% TFA) - MeOH solvent mixtures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | To a solution of homovanillic acid (50 mg, 0.27 mmol), N,N-dimethylethane-1,2-diamine (30 muL, 0.27 mmol) and PyBOP (143 mg, 0.54 mmol) in DMF (0.5 mL) was added TEA (114 muL, 0.82 mmol). The reaction mixture was allowed to stir under N2 at room temperature for 22 h. The crude product was concentrated under vacuum to give a pale orange gum. The crude material was subjected to reversed-phase C8 flash column chromatography eluting in H2O-MeOH solvents and then silica gel flash column chromatography with the desired product eluting in the 3% MeOH/DCM fraction. Solvent was removed to give the desired product 23 as a yellow oil (22 mg, 22%): Rf (10% MeOH/DCM) 0.18; Purity 99% tR 3.16 min; IR numax (ATR) 3285, 2919, 1669, 1514, 1274, 1124, 1026, 829, 798, 719 cm-1; 1H NMR (DMSO-d6, 400 MHz) delta 8.81 (1H, br s), 8.04 (1H, br t, J = 5.8 Hz, H-9), 6.82 (1H, s, H-2), 6.68 (1H, d, J = 8.0 Hz, H-5), 6.63 (1H, d, J = 8.0 Hz, H-6), 3.73 (3H, s, OMe-15), 3.29 (2H, s, H2-7), 3.27 (2H, td, J = 5.9, 5.8 Hz, H2-10), 2.75 (2H, t, J = 5.9 Hz, H2-11), 2.50 (6H, s, H3-13 and H3-14); 13C NMR (DMSO-d6, 100 MHz) delta 171.0 (C-8), 147.3 (C-3), 145.2 (C-2), 126.8 (C-1), 121.3 (C-6), 115.2 (C-5), 113.3 (C-2), 56.9 (C-11), 55.5 (C-15), 43.6 (C-13 and C-14), 42.0 (C-7), 35.3 (C-10); HREIMS m/z 252.1476 [M]+ (calcd for C13H20N2O3, 252.1474). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water;HUSY (Si/Al=15); at 250℃; under 5250.53 Torr; for 2h;Inert atmosphere;Product distribution / selectivity; | In an autoclave (batch reactor) lignin (0.5 g), HUSY (Si/Al=15) (0.5 g) and mixture of water and organic solvent (30 g) were charged. After flushing the reactor with nitrogen gas for 3 times, nitrogen (7 bar) was charged. Reactor was heated up to 230° C. under the stirring (100 rpm). After attaining the desired temperature of 230° C. stirring was increased up to 500 rpm. Reaction was stopped after 30 minutes. Analysis of reaction mixture was done by GC, GC-MS. The lignin used in these examples were organosolv or dealkaline.Yield: >25percentMass balance: >90percent.The effect of reaction temperature and reaction time on depolymerization reaction is demonstrated by the results presented in Table 8 using SiO2-Al2O3 as catalyst*. TABLE 8 Exp. Time Lignin Product yield, Mass balance, No. (min.) conversion percentpercentNo. percent 1. 30 85 26 80 2. 60 85 41 86 3. 90 92 50 84 4. 120 95 70 85 Lignin, 0.5 g; HUSY (Si/Al = 15), 0.5 g; N2 Pressure, 7 bar (at)RT; Temperature, 250° C.No.Monomer and dimer products soluble in water/organic solvents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 48h; | General procedure: To a cooled (0 C) solution of freshly prepared tyrosol (138 mg, 1 mM) and phenolic acids (1 mM equiv) in dry THF (3.5 mL) were added triphenylphosphine (280 mg, 1 mM) and diisopropylazodicarboxylate (208 muL, 1 mM). After stirring for 48 h at rt, the reaction was worked up by removal of the solvent, and the residue was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified on Sephadex LH-20 (35 mL after CH2Cl2 swelling) using CH2Cl2 to remove the Mitsunobu byproducts, followed by normal phase chromatography to isolate the esters 4-10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 98% | With Agaricus bisporus; oxygen; In aq. phosphate buffer; dichloromethane; at 25℃; for 24h;pH 7; | General procedure: The reactions were performed under both homogeneous and heterogeneous conditions in CH2Cl2/buffer. As a general procedure, phenol (0.05mmol), tyrosinase (600IU) and the optimal amount of the Na-phosphate buffer 0.1M, pH 7 (CH2Cl2/buffer ratio ca. 1:0.1) were suspended in CH2Cl2 (2.5mL) at 25C for 24h, and the mixture stirred under O2 atmosphere. The reactions were monitored by thin layer chromatography (TLC, n-hexane/EtOAc=2.0:1.0). After the disappearance of the substrate, the organic layer was recovered (eventually after filtration for immobilized enzyme), and evaporated under reduced pressure. The crude was treated with Na2S2O4 in equal volume of H2O and THF (2.0mL) with stirring for 5min. The mixture was diluted with EtOAc (4.0mL) and separated from H2O. The organic layer was dried on anhydrous Na2SO4 and evaporated under reduced pressure. When necessary the crude was purified by flash-chromatography. The products were characterized by 1H and 13C NMR, GC-MS (after silylation) and Elemental Analysis. GC-MS analysis was performed on a GC-MS QP5050 Shimadzu apparatus using an SPB column (25m×0.25mm and 0.25mm film thickness) and an isothermal temperature profile of 100C for 2min, followed by a 10Cmin-1 temperature gradient to 280C for 25min. The injector temperature was 280C. Chromatography-grade helium was used as the carrier gas with a flow of 2.7 mL×min-1. Mass spectra were recorded with an electron beam of 70eV. Quantitative analyses were performed by using dodecane as the internal standard. MS values are referred to full silylated derivatives with the only exception of 3c and 3d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro-trimethyl-silane; at 25℃; for 24h; | General procedure: To a suspension of acidic phenols 1a-d (0.05mmol) in TMCS (0.1mmol), the alcohol (1.0mL) was added and the reaction mixture was stirred at 25C. After 24h, the reaction was stopped and evaporated under reduced pressure to afford 2a-l in quantitative yield without the need of purification: | |
With sulfuric acid; at 90℃; for 7h; | Excess of the corresponding alcohol. <strong>[306-08-1]Homovanillic acid</strong> (1.5-3 g) was stirred in the respectivealcohol (100 mL) with 0.2-0.5 equivalents of sulfuric acid for 7 h at 90 C (heating block temperature).Most of the alcohol was removed in vacuo, then sat. aq. NaHCO3 solution and EtOAc were added.The organic phase was separated and the aqueous phase extracted with EtOAc. The combined organiclayer was washed with sat. aq. NaHCO3 solution and water or alternatively with sat. aq. NaCl solution,dried over NaSO4 and the solvent removed in vacuo. The product was obtained after purification bycolumn chromatography on silica in 90% to quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; at 70℃; | <strong>[306-08-1]Homovanillic acid</strong> (from Acros Organic) was used without further purification. Sodium homovanillate was prepared by dissolving the powder of homovanillic acid in the water solution of sodium hydroxide (Aldrich) in a stoichiometric ratio. The mixed solution was slowly condensed at 70C to about 30% of starting volume. Then the solution was left at the room temperature for 24-48h until the sample crystallized in the solid-state. The remaining solvent was removed by drying under reduced pressure at 105C. Obtained salt was anhydrous - in the IR spectra of solid state sample the lack of bands characteristic for crystallizing water was observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | General procedure: General Procedure A for Rink Amide Resin Activation. Rink amide resin (Advanced ChemTech) was mixed with DCM (1 mL per 100 mg resin) and then shaken for 30 minutes. After activation, resin was washed three times with DMF (1 mL per 100 mg resin). [0079] General Procedure B for the Removal of the Fmoc Group from the Rink Amide Resin. Rink amide resin was mixed with 20% piperidine in DMF (1 mL per 100 mg resin) and shaken for 30 minutes, and then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times) sequentially. The removal of the Fmoc group was confirmed by the ninhydrin test.General Procedure C for the Removal the Alloc Group from the Rink Amide Resin. The resin (200 mg) was washed with DCM (2 mL, 5 times) and shaken under 2 overnight with a solution of tetrakis(triphenylphosphine)palladium(0) (10 mg), AcOH (0.5 mL), and NMM (0.2 mL) in DCM (10 mL). The resin was then washed with DMF (2 mL, 3 times), isopropanol (2 mL, 3 times), and DCM (2 mL, 3 times). The removal of the Alloc group was confirmed by the ninhydrin test.General Procedure E for the Coupling of Carboxylic Acids to the Rink Amide Resin. Carboxylic acids (5 equiv, 0.5 M in DMF) were first mixed with HBTU (5 equiv, 0.5 M in DMF), HOBt (5 equiv, 0.5 M in DMF), and NMM (15 equiv, 1.5 M inDMF). The mixed solution was then added to the resin and shaken for 2 hours. The resin was then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times). The completion of the coupling reaction was confirmed by the ninhydrin test. [0083] General Procedure F for Peptide Cleavage from the Rink Amide Resin. The resin was washed with DCM (1 mL per 100 mg resin, 5 times) and subsequently shaken with a solution of 95% TFA, 2.5% TIS, and 2.5% H20 (1 mL per 100 mg resin) for 2 hours. The resin was removed by filtration, and the TFA was evaporated under vacuum. The crude peptide was obtained after trituration with diethyl ether (5 mL per 100 mg resin, 2 times) Compound 8 was synthesized using standard Fmoc chemistry on the Rink amide resin (Figure 18). The resin (200 mg, 0.7 mmol/g loading) was first activated by DCM (General procedure A). The Fmoc group on the resin was removed by piperidine in DMF (General procedure B). The resin was then coupled with Fmoc-Dpr(Boc)-OH. The Fmoc group on the resin was removed by piperidine in DMF (General procedure B). The resin was then coupled with <strong>[147290-11-7]<strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>-OH</strong>. The Fmoc group was removed (General procedure B) and Fmoc-Phe-OH was attached to resin (General procedure E). The Fmoc group was again removed (general procedure B) and the amine group on the F2Pmp residue was coupled with BMBA (general procedure E). The resin was treated with Pd(0) for the deprotection of Alloc group (general procedure C). 3- Iodobenzoic acid (mlBA) was attached to resin (general procedure E). The resin was treated with TFA (general procedure F) to give the crude peptide intermediate, which was treated with a mixture of HVA (0.5 M in DMF, 100 muGamma), HBTU (0.5 M in DMF, 100 muGamma), HOBt (0.5 M in DMF, 100 muGamma) and NMM (1.5 M in DMF, 100 muGamma) to give the crude product 8. The crude product was purified by HPLC to afford 8 (15.8 mg, 12% yield). The assignment of proton NMR utilized additional information from COSY. 1H NMR (500 MHz, DMSO-d6): S= 8.70 (d, J= 8.1 Hz, 1 H, BMBA-NH), 8.60-8.55 (m, 1 H, mlBA- NH), 8.35 (d, J= 6.9 Hz, 1 H, Phe-NH), 8.19 (s, 1 H, mlBA-ArH), 8.04-7.95 (m, 2 H, Orn-NH, BMBA-ArH), 7.91-7.83 (m, 3 H, mlBA-ArH, HVA-NH), 7.67 (d, J= 7.5 Hz, 1 H, BMBA-ArH), 7.40-7.15 (m, 9 H, BMBA-ArH, Phe-ArH, -CONH2 , mlBA-ArH), 6.77 (s, 1 H, HVA-ArH), 6.63 (d, J= 7.6 Hz, 1 H, HVA-ArH), 6.58 (d, J= 7.6 Hz, 1 H, HVA- ArH), 4.78-4.72 (m, 1 H, Phe-CaH), 4.30-4.22 (m, 2 H, Dpr-CaH, Orn-CaH), 3.70 (s, 3 H, HVA-OCH3), 3.40-3.35 (m, 1 H, Dpr-CpHH'), 3.35-3.18 (m, HVA-CH2-CO, Dpr-CpHH', Omicronpiiota-OmicrondeltaEta2, Phe-CpHH'), 3.04-2.96 (m, 1 H, Phe-CpHH'), 2.35 (s, 3 H, BMBA-Ar-CH3), I.81-1.74 (m, 1 H, Orn-CpHH'), 1.68-1.52 (m, 3 H, Orn-CpHH', Orn-CYH2). 13C MR (125 MHz, DMSO-d6 ): S= 171.79, 171.39, 171.25, 171.17, 164.70, 164.52, 147.13, 144.94, 140.65, 139.46, 138.30, 136.49, 135.51, 133.34, 130.75, 130.32, 129.00, 127.92, 126.62, 126.54, 126.10, 123.78, 121.26, 1 15.05, 1 13.13, 94.53, 55.37, 54.77, 53.01, 52.80, 41.74, 40.57, 36.68, 28.99, 25.46, 22.26. MS (ESI): calculated for [M], 954, found [M+H]+ 955. HPLC purity analysis: > 95% (UV, lambda = 254 nm). Figure 18 depicts the synthesis of Compound 8: (a) 30% piperidine/DMF; (b) Fmoc-Dpr(Boc)-OH/HBTU/HOBt/NMM; (c) <strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>- OH/HBTU/HOBt/NMM; (d) Fmoc-Phe-OH/HBTU/HOBt/NMM; (e) 3-bromo-4- methylbenzoic acid/HBTU/HOBt/NMM; (f) Pd(0)/NMM/AcOH; (g) 3 -iodobenzoic acid/HBTU/HOBt/NMM; (h) 95% TFA/H2O/TIS; (i) homovanillic acid/HBTU/HOBt/NMM. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | General procedure: General Procedure A for Rink Amide Resin Activation. Rink amide resin (Advanced ChemTech) was mixed with DCM (1 mL per 100 mg resin) and then shaken for 30 minutes. After activation, resin was washed three times with DMF (1 mL per 100 mg resin). [0079] General Procedure B for the Removal of the Fmoc Group from the Rink Amide Resin. Rink amide resin was mixed with 20% piperidine in DMF (1 mL per 100 mg resin) and shaken for 30 minutes, and then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times) sequentially. The removal of the Fmoc group was confirmed by the ninhydrin test.General Procedure C for the Removal the Alloc Group from the Rink Amide Resin. The resin (200 mg) was washed with DCM (2 mL, 5 times) and shaken under 2 overnight with a solution of tetrakis(triphenylphosphine)palladium(0) (10 mg), AcOH (0.5 mL), and NMM (0.2 mL) in DCM (10 mL). The resin was then washed with DMF (2 mL, 3 times), isopropanol (2 mL, 3 times), and DCM (2 mL, 3 times). The removal of the Alloc group was confirmed by the ninhydrin test.General Procedure E for the Coupling of Carboxylic Acids to the Rink Amide Resin. Carboxylic acids (5 equiv, 0.5 M in DMF) were first mixed with HBTU (5 equiv, 0.5 M in DMF), HOBt (5 equiv, 0.5 M in DMF), and NMM (15 equiv, 1.5 M inDMF). The mixed solution was then added to the resin and shaken for 2 hours. The resin was then washed with DMF (1 mL per 100 mg resin, 3 times), isopropanol (1 mL per 100 mg resin, 3 times), and DCM (1 mL per 100 mg resin, 3 times). The completion of the coupling reaction was confirmed by the ninhydrin test. [0083] General Procedure F for Peptide Cleavage from the Rink Amide Resin. The resin was washed with DCM (1 mL per 100 mg resin, 5 times) and subsequently shaken with a solution of 95% TFA, 2.5% TIS, and 2.5% H20 (1 mL per 100 mg resin) for 2 hours. The resin was removed by filtration, and the TFA was evaporated under vacuum. The crude peptide was obtained after trituration with diethyl ether (5 mL per 100 mg resin, 2 times). Compound 7 was synthesized using standard Fmoc chemistry on the Rink amide resin (Figure 17). The resin (200 mg, 0.7 mmol/g loading) was first activated by DCM (General procedure A). The Fmoc group on the resin was removed by piperidine in DMF (General procedure B). The resin was then coupled with Fmoc-Dpr(Boc)-OH. The Fmoc group on the resin was removed by piperidine in DMF (General procedure B). The resin was then coupled with <strong>[147290-11-7]<strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>-OH</strong>. The Fmoc group was removed (General procedure B) and Fmoc-F2Pmp-OH was attached to resin (General procedure E). The Fmoc group was again removed (general procedure B) and the amine group on the F2Pmp residue was coupled with BMBA (general procedure E). The resin was treated with Pd(0) for the deprotection of Alloc group (general procedure C). 3-Iodobenzoic acid (mlBA) was attached to resin (general procedure E). The resin was treated with TFA (general procedure F) to give the crude peptide intermediate, which was treated with a mixture of HVA (0.5 M in DMF, 100 LL), HBTU (0.5 M in DMF, 100 LL), HOBt (0.5 M in DMF, 100 LL) and NMM (1.5 M in DMF, 100 mu,) to give the crude product 7. The crude product was purified by HPLC to afford compound 7 (21.5 mg, 14% yield). The assignment of proton NMR utilized additional information from COSY. 1H NMR (500 MHz, CD3OD): delta= 8.16 (s, 1 H, mlBA-ArH), 7.92 (s, 1 H, BMBA-ArH), 7.86 (d, J= 7.9 Hz, 1 H, mlBA-ArH), 7.78 (d, J= 7.9 Hz, 1 H, mlBA-ArH) 7.64 (d, J= 8.2 Hz, 1 H, BMBA-ArH), 7.58-7.52 (m, 3 H, BMBA-ArH, F2Pmp-ArH), 7.39 (d, J= 7.9 Hz, 2 H, F2Pmp-ArH) 7.27 (d, J= 8.2 Hz, 1 H, BMBA-ArH), 7.21-7.16 (m, 1 H, mlBA-ArH), 6.81- 6.78 (m, 1 H, HVA-ArH), 6.71-6.63 (m, 2 H, HVA-ArH), 4.83-4.80 (m, 1 H, F2Pmp- CH), 4.48-4.42 (m, 1 H, Dpr- CH), 4.30-4.24 (m, 1 H, Orn- CH), 3.77 (s, 3 H, HVA- OCH3), 3.63-3.58 (m, 1 H, Dpr- CpHH'), 3.51-3.45 (m, 1 H, Dpr- CpHH'), 3.41 - 3.33 (m, 5 H, Orn-C5H2, F2Pmp-CpHH', HVA-CH2-CO-), 3.16-3.09 (m, 1 H, F2Pmp-CpHH'), 2.39 (s, 3 H, BMBA-Ar-CH3). 1.92-1.85 (m, 1 H, Orn-CpHH'), 1.75-1.62 (m, 3 H, Orn-CpHH', Orn-CYH2). 13C MR (125 MHz, CD30D): delta= 175.72, 174.20, 174.15, 168.85, 168.48, 148.97, 146.60, 143.20, 141.53, 141.41, 137.67, 137.41, 134.42, 132.45, 131.95, 131.35, 130.25, 127.83, 127.63, 127.60 127.53, 125.65, 122.83, 1 16.30, 1 13.84, 101.39, 94.73, 56.73, 56.43, 55.33, 43.37, 42.17, 4Figure 17 depicts the synthesis of Compound 7: (a) 30% piperidine/DMF; (b) Fmoc-Dpr(Boc)-OH/HBTU/HOBt/NMM; (c) <strong>[147290-11-7]Fmoc-Orn(Alloc)</strong>- OH/HBTU/HOBt/NMM; (d) Fmoc-F2Pmp-OH/HBTU/HOBt/NMM; (e) 3-bromo-4- methylbenzoic acid/HBTU/HOBt/NMM; (f) Pd(0)/NMM/AcOH; (g) 3 -iodobenzoic acid/HBTU/HOBt/NMM; (h) 95% TFA/H2O/TIS; (i) homovanillic acid/HBTU/HOBt/NMM.0.39, 37.76, 29.54, 26.96, 23.03. MS (ESI): calculated for [M], 1084, found [M+H]+ 1085. HPLC purity analysis: > 95% (UV, lambda = 254 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With boron trifluoride diethyl etherate; at 90℃; for 1.5h;Inert atmosphere; | General procedure: In a two-neck round-bottom flask a mixture of 3,5-dimethoxyphenol (1) (6 mmol, 1.00 equiv.), 3,4-disubstitutedphenyl acetic acid (2a-d) (6 mmol, 1.00 equiv.) and BF3*Et2O(48 mmol, 8.00 equiv.) was stirred at 90 C for 90 min under argon. The reaction mixturewas poured into 10% aqueous NaOAc (100 mL)and allowed to stir at room temperature for 24 h, forming a brown precipitate. The precipitate was filtered and washed with H2O(2 x 20 mL). The precipitate was resuspended with EtOAc, driedover Na2SO4 and finally concentrated in vacuo. The residue waspurified by FC using a mixture of Petroleum Ether/EtOAc as eluent,to obtain the corresponding deoxybenzoin (3a-d) (Supplementary Material). |
With boron trifluoride diethyl etherate; at 90℃; for 1.5h;Inert atmosphere; | A mixture of 3,5-dimethoxyphenol (1,3 mmol, 463 mg), 3,4-dihydroxyphenylacetic acid (2, 3 mmol, 504,5 mg) and BF3?Et20 (15,3 mmol, 1,94 ml) was stuffed at 90C for 90 mm underArgon. The reaction mixture was poured into 10% aqueous NaOAc solution (lOOml) and allowed to stand 4h. The solution was extracted with EtOAc. The combined organic layers were washed with saturated solution of NaHCO3, dried over Na2SO4 and finally concentrated under reduced pressure. The residue was purified by column chromatography using hexane-EtOAc mixture as eluent to obtain 9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | 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 tetrahydrofuran at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.2% | With acetyl chloride; at 60℃; for 3h; | 4-Hydroxy-3-methoxyphenylaceticacid (1.3 g, 7.1 mmol) and acetyl chloride (130 mul, 1.5 mmol)were dissolved in 1-propanol (25.87 ml), and the reaction mixture was stirredat 60C. After 3 h, the reaction mixture was evaporated. The resulting residuewas purified by Wakogel C-200 ( Phi2.0 x 20.7 cm) and eluted with hexane/ethyl acetate (8:2, v/v) to givepropyl-4-hydroxy-3-methoxyphenylacetate (1.25 g, 78.2%). 1H NMR (CD3OD,600 MHz) delta: 0.90 (3H, t, J = 7.2 Hz); 1.62 (2H, sext, J= 7.2 Hz); 3.51 (2H, s); 3.82 (3H, s); 4.02 (2H, t, J = 6.6 Hz); 6.67 (1H, dd, J= 1.8, 7.8 Hz); 6.71 (1H, d, J = 7.8Hz); 6.83 (1H, d, J = 1.8 Hz). 13CNMR (CD3OD, 150 MHz) delta: 10.67, 23.03,41.62, 56.34, 67.46, 113.89, 116.13, 122.88, 127.03, 146.68, 148.90, 174.13. ESI-HRMS[M-H]-: calcd. for C12H15O4:223.0976, found 223.0978. HPLC: rt 6.6 min, 98.7% purity. |
With sulfuric acid; at 90℃; for 7h; | Excess of the corresponding alcohol. <strong>[306-08-1]Homovanillic acid</strong> (1.5-3 g) was stirred in the respectivealcohol (100 mL) with 0.2-0.5 equivalents of sulfuric acid for 7 h at 90 C (heating block temperature).Most of the alcohol was removed in vacuo, then sat. aq. NaHCO3 solution and EtOAc were added.The organic phase was separated and the aqueous phase extracted with EtOAc. The combined organiclayer was washed with sat. aq. NaHCO3 solution and water or alternatively with sat. aq. NaCl solution,dried over NaSO4 and the solvent removed in vacuo. The product was obtained after purification bycolumn chromatography on silica in 90% to quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In N,N-dimethyl-formamide; for 24h;Reflux; Inert atmosphere; | To a solution of homovanillic acid 18 (1.1 g, 6.0 mmol) in dry DMF (30 mL), was added K2CO3 (2.7 g, 19 mmol), followed by 2-bromopropane (2.6 mL, 28 mmol) dropwise and the resultant suspension was heated at reflux for 24 h. Water (30 mL), conc. HCl (30 mL) and ethyl acetate (20 mL) were added and the organic layer was separated. The aqueous mixture was extracted further with ethyl acetate (3x20 mL) and the combined organic extracts were dried (MgSO4), and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (2:1 ethyl acetate, hexanes) to yield the title compound (1.6 g, quantitative) as a yellow oil. RF (2:1 hexanes, ethyl acetate) 0.81; dH (300 MHz; CDCl3; Me4Si) 1.22 (6H, d, J 6.3 Hz, C(O)OCH(CH3)2), 1.35 (6H, d, J 6.1 Hz, 4-OCH(CH3)2), 3.51 (2H, s, CH2Ar), 3.84 (3H, s,OCH3), 4.49 (1H, sept., J 6.1 Hz, 4-OCH(CH3)2), 5.01 (1H, sept.,J 6.3 Hz, C(O)OCH(CH3)2), 6.76-6.85 (3H, m, 2-, 5- and 6-H); dC(75 MHz; CDCl3) 21.7 (C(O)OCH(CH3)2), 22.0 (4-OCH(CH3)2), 41.2 (CH2Ar), 55.8 (OCH3), 68.0 (C(O)OCH(CH3)2), 71.3 (4-OCH(CH3)2),112.9 (C-2),115.7 (C-5), 121.2 (C-6), 127.1 (C-1), 146.2 (C-4), 150.2 (C-3), 171.3 (C(O)OCH(CH3)2); IR: nmax(film)/cm-1; 2979, 2937, 1728, 1509, 1229, 1141, 1036, 792, 705; m/z (ESI) 289 (M+Na, 100%); HRMS (ESI): found (M+Na): 289.1407 C15H22NaO4 requires 289.1410. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 6h; | General procedure: To a solution of 2-(3,4-dimethoxyphenyl)acetic acid 5 (0.77g, 3.93mmol) in CH2Cl2, 2-thiophene ethylamine (0.50g, 3.93mmol), EDC-HCl (N-ethyl-N?-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1.13g, 5.90mmol), HOBt (hydroxybenzotriazole, 0.69g, 5.11mmol) and triethylamine (0.40g, 3.93mmol) were added. The mixture was stirred for 6hat room temperature, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was recrystallized from ethyl acetate to afford 6 (1.6g, 86%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.3% | With sulfuric acid; In toluene; for 2h;Dean-Stark; Reflux; | The present Example provides a synthesis of 2-Phenoxyethyl 2-(4-hydroxy-3- methoxyphenyl)acetate. 1.82 g (10 mmol) of 2-(4-hydroxy-3-methoxyphenyl) acetic acid and 50 ml oftoluene were added to a one neck, round bottom flask, equipped with a Dean-Stark trap and condenser. While this suspension was stirred at room temperature, 1.38 g (10 mmol) of 2-phenoxyethanol was added followed by 0.10 g (1 mmol) of concentrated sulfuric acid. The mixture was then refluxed for 2 hours and the water formed was collected in the trap. The reaction mixture was then cooled to room temperature, diluted with ethylacetate, and quenched with saturated NaHCO3. Once the phases were separated, the organic phase was washed once more with saturated NaHCO3 and brine. The organic layer was then dried over Mg504, filtered, and concentrated under reduced pressure. The crude product was first isolated by automated silica gel chromatography (Biotage SP1, 12-100% ethyl acetate/hexane) and finally purified via Kugelrohr distillation(100C-120C 0.45 Torr) to afford 2.33 g (77.3%) of 2-phenoxyethyl 2-(4-hydroxy-3- methoxyphenyl)acetate, which crystallized to an off-white solid (mp 56C).?HNMR (400 IVIHz, CDC13) ppm 3.58 (s, 2H) 3.82 (s, 3H) 4.16 (m, 2H) 4.44 (m, 2H) 5.57 (s, 1H) 6.83 (m, 5H) 6.97 (m, 1H) 7.27 (m, 2H). ?3C NMR (101 MHz, CDC13) ppm 40.87, 55.93, 63.30, 65.92, 111.79, 114.44, 114.70, 121.31, 122.25,125.61, 129.62, 144.87, 146.55, 158.53, 171.96. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.3% | This Example provides a synthesis of (E)-3,7-Dimethylocta-2,6-dien-1-yl 2-(4- hydroxy-3 -methoxyphenyl)acetate.1.82 g (10 mmol) 2-(4-hydroxy-3-methoxyphenyl) acetic acid and 5 mL of anhydrous dimethyl formamide were added to a two neck, round bottom flask, equippedwith a nitrogen gas inlet. The resulting amber solution was stirred under nitrogen and cooled to 0 C in an ice bath. When the desired temperature was reached, 2.06 g (10 mmol) of N,N?-dicyclohexylcarbodiimide was added to the solution followed by 0.12 g (1 mmol) of 4-dimethylaminopyridine. This suspension was stirred for 30 minutes before a solution of 1.54 g (10 mmol) (E)-3,7-dimethylocta-2,6-dien-1-ol in 50 mL ofanhydrous dichloromethane was added drop-wise over a period of 30 minutes. This mixture was allowed to warm to room temperature and stirred for an additional 24 hours. The mixture was then filtered through a pad of Celite filter aid and the pad was then washed 3 times with an additional 10 mL of fresh dichloromethane. The combined filtrate was then concentrated under reduced pressure. The crude product was firstisolated by automated silica gel chromatography (Biotage SP1, 10-80 % ethyl acetate/hexane) and finally purified via Kugelrohr distillation to afford 1.00 g (31.3%) of (E) -3, 7-Dimethylocta-2, 6-dien- 1 -yl 2-(4-hydroxy-3 -methoxyphenyl)acetate as a colorless oil.?HNMR (400 IVIFIz, CDC13) ppm 1.58 (m, 4H) 1.67 (s, 6H) 2.05 (m, 4H) 3.53(s, 2H) 3.86 (s, 3H) 4.59 (d, 2H) 5.06 (m, 1H) 5.32 (m, 1H) 5.54 (s, 1H) 6.75 (m, 1H)6.80 (d, 1H) 6.84 (m, 1H). ?3C NIVIR (101 MHz, CDC13) ppm 16.57, 17.77, 25.76,26.37, 39.60, 41.06, 55.95, 61.88, 111.80, 114.40, 118.23, 122.21, 123.78, 125.98,131.94, 142.52, 144.79, 146.51, 172.03. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50 g | With sodium carbonate; In toluene; at 60℃; | 30 g of the compound of the formula 1b, 120 g of sodium carbonate and 600 ml of toluene were mixed and stirred.82 g of benzyl chloride was added dropwise to the system at a constant rate, and after the addition, the temperature was raised to 60 C to react overnight.After the reaction is over, drop to room temperature and take care.The filtrate was collected and concentrated under reduced pressure.50 g of the compound of formula 2 were obtained, which was directly taken to the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.8% | 4-hydroxy-3-methoxyphenylacetic acid was weighed according to a molar ratio of 1:1:1.5:0.1.4-methylbenzyl alcohol, dicyclohexylcarbodiimide and 4-dimethylaminopyridine,First add 4-hydroxy-3-methoxyphenylacetic acid and 4-methylbenzyl alcohol to a three-necked flask.And add dichloroethane, stir and mix, then heat to 55 C,Subsequently, dicyclohexylcarbodiimide and 4-dimethylaminopyridine were added, and the reaction was stirred for 4 h;After the reaction is completed, dichloroethane is distilled off under reduced pressure, and the reactant is added to water, stirred and mixed, and then allowed to stand for separation, the oil phase is collected, and the oil phase is dried in an oven.The dried oil phase is mixed with a mass ratio of 1:10 and tetrahydrofuran, mixed, placed in an ice water bath, and sodium borohydride is added in an amount of 3% by mass of the oil phase, and the reaction is carried out under a nitrogen atmosphere for 2 hours.After the reaction, tetrahydrofuran is recovered, and the reaction liquid is added to water, and filtered with suction to obtain a residue, washed, and dried.After recrystallization, you can get1-(4-hydroxy-3-methoxyphenyl)-3-(4-methylphenyl)propan-2-one,The purity was 95.2%, and the yield was 96.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 45% | With sulfuric acid; In toluene; for 5h;Reflux; | <strong>[306-08-1]Homovanillic acid</strong> (2.0 g) is provided with 2-ethyl-1-butanol (equimolar) in toluene (100 mL), concentrated sulphuric acid (0.1 g) is added and heated for 5 h at the water separator until boiling. It was washed twice with saturated aqueous NaHCO3 solution, diluted with 50 mL acetic acid, washed once with water or electively saturated aqueous NaHCO3 solution and the solvent was removed in the vacuum. The product was obtained after column chromatographic purification on silica gel with a yield of approximately 45%. (0083) 1H-NMR (400 MHz, CDCl3): delta=6.85 (d, J=8.1 Hz, 1H), 6.81 (d, J=1.9 Hz, 1H), 6.76 (dd, J=8.1, 1.9 Hz, 1H), 5.56 (s, 1H), 4.01 (d, J=5.8 Hz, 2H), 3.88 (s, 3H), 3.53 (s, 2H), 1.49 (h, J=6.2 Hz, 1H), 1.38-1.25 (m, 4H), 0.86 (t, J=7.5 Hz, 6H). (0084) 13C-NMR (100 MHz, CDCl3): delta=10.97 (2C), 23.26 (2C), 40.26, 41.14, 55.86, 66.86, 111.68, 114.29, 122.12, 125.98, 144.67, 146.41, 172.07. (0085) GCMS: m/z (%)=266 [M+] (28), 182 (18), 137 (100), 122 (8), 107 (2), 94 (6), 85 (3), 77 (2), 66 (5), 57 (4), 43 (28). |
With sulfuric acid; In toluene; for 5h;Heating; Dean-Stark; | Dean-Stark apparatus. <strong>[306-08-1]Homovanillic acid</strong> (1.5-3 g) and the respective alcohol (equimolar) were dissolved in toluene (100 mL), a catalytic amount (1-2 drops) of conc. sulfuric acid was added and the reaction mixture was boiled for 5 h. After washing with sat. aq. NaHCO3 solution and water (2x) oroptionally sat. aq. NaCl solution, the solvent was removed in vacuo. The product was obtained after purification by column chromatography on silica in about 70% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 70℃; for 4h; | To a suspension of (4-hydroxy-3-methoxyphenyl)acetic acid (6.18 g, 33.93 mmol), 2-(3-methoxyphenyl)ethan-1-amine (5.13 g, 33.93 mmol), HOBt (5.50 g, 40.71 mmol) and TEA (4.12 g, 40.71 mmol) in DMF (68 mL) was added EDCl (7.80 g, 40.71 mmol). The resulting suspension was stirred (70 C, 4 hr). The reaction mixture was cooled (RT) and partitioned with EtOAc (70 mL) and H2O (70 mL). The aqueous layer was extracted with EtOAc (70 mL). The combined organic layers were washed with 1 M HCl (2*100 mL), saturated NaHCO3 (2*100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound as an amber oil (9.39 g, 88%): 1H NMR (CDCl3, 400 MHz) delta7.14 (t, J=8.6 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.72-6.75 (m 1H), 6.59-6.65 (m 4H), 5.80 (br s, 1H), 5.46 (br t, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.46 (q, J=6.8 Hz, 2H), 3.45 (s, 2H), 2.70 (t, J=6.8 Hz, 2H). 13C NMR (CDCl3, 100 MHz) delta 171.44, 159.78, 146.90, 145.02, 140.23, 129.55, 126.41, 122.28, 120.98, 114.80, 114.40, 111.78, 111.73, 55.88, 55.13, 43.51, 40.52, 35.42 ppm. LCMS m/z (relative intensity) 316.0 [M+1]+ (100); 338.0 [M+Na]+ (15). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; at 90℃; for 7h; | General procedure: Homovanillinic acid (1.5-3 g) was stirred with the respective alcohol (100 ml) and 0.2-0.5 equivalent of sulphuric acid for 7 h at 90 C. (heating block temperature). Majority of the alcohol was removed under vacuum, saturated aqueous NaHCO3 solution and EtOAc were added, the organic phase separated and the aqueous phase extracted once with EtOAc. The combined organic phases were washed once with saturated aqueous NaHCO3 solution and with water or alternately with saturated aqueous NaCl solution, dried over NaSO4 and the solvent was removed under vacuum. The product was obtained by column chromatography on silica gel with a 90% to quantitative yield. | |
With sulfuric acid; at 90℃; for 7h; | Excess of the corresponding alcohol. <strong>[306-08-1]Homovanillic acid</strong> (1.5-3 g) was stirred in the respectivealcohol (100 mL) with 0.2-0.5 equivalents of sulfuric acid for 7 h at 90 C (heating block temperature).Most of the alcohol was removed in vacuo, then sat. aq. NaHCO3 solution and EtOAc were added.The organic phase was separated and the aqueous phase extracted with EtOAc. The combined organiclayer was washed with sat. aq. NaHCO3 solution and water or alternatively with sat. aq. NaCl solution,dried over NaSO4 and the solvent removed in vacuo. The product was obtained after purification bycolumn chromatography on silica in 90% to quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In toluene; for 5h;Reflux; | General procedure: <strong>[306-08-1]Homovanillic acid</strong> (1.5-3 g) was provided with the respective alcohol (equimolar) in toluene (100 ml), conc. sulphuric acid was added to it and heated to the boiling point at the water separator for 5 h. It was washed once with saturated aqueous NaHCO3 solution, twice with water or alternately with saturated aqueous NaCl solution and the solvent was removed under vacuum. The product was obtained by column chromatography on silica gel with a yield of about 70%. | |
With sulfuric acid; In toluene; for 5h;Heating; Dean-Stark; | Dean-Stark apparatus. <strong>[306-08-1]Homovanillic acid</strong> (1.5-3 g) and the respective alcohol (equimolar) were dissolved in toluene (100 mL), a catalytic amount (1-2 drops) of conc. sulfuric acid was added and the reaction mixture was boiled for 5 h. After washing with sat. aq. NaHCO3 solution and water (2x) oroptionally sat. aq. NaCl solution, the solvent was removed in vacuo. The product was obtained after purification by column chromatography on silica in about 70% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.3 g | A 500 mL round bottom flask was charged with (25 g, 0.137 mol) of high vanillic acid, 150 ml of DMF was dissolved, (66 g, 0.477 mol) of anhydrous K2CO3 was added, and BnBr (34 mL, 0.286 mol) was added dropwise at room temperature. After 5 h, TLC showed complete. 500mL EA, 500mL water was added to the reaction solution, and the organic phase was separated. The aqueous phase was extracted with EA (100 ml*2), and the EA phase was combined, followed by 200 mL of water. washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated and column chromatography (PE: EA = 20: 1) to give the product 42g, yield 85%. (34 g, 90 mmol) of the above product was stirred in anhydrous methanol, and stirred for 5 min, then (30 g, 540 mmol) KOH was added, and the reaction mixture was clarified and stirred at room temperature for 4 h TLC. The reaction solution was concentrated, methanol was removed, and 300 mL of water and 200 mL of diethyl ether were added to the reaction mixture. The aqueous phase was separated, and the organic impurities in the aqueous phase were extracted with 100 ml of diethyl ether, and the aqueous phase was neutralized with 6N HCl to a pH of about 4. Large amount of solid precipitated, 300mL EA was added, and extracted twice (Or directly filter, wash, dry the product), combine EA phase, wash with 100ml water, wash with 100ml saturated sodium chloride, Dry over anhydrous sodium sulfate, filter, concentrate, recrystallize with (PE: EA), ie, dissolve the appropriate amount of EA under reflux, add PE to precipitate, dissolve and dissolve, and then static filter to obtain 23.3 g of product, yield 91.4% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; at 90℃; for 7h; | Excess of the corresponding alcohol. <strong>[306-08-1]Homovanillic acid</strong> (1.5-3 g) was stirred in the respectivealcohol (100 mL) with 0.2-0.5 equivalents of sulfuric acid for 7 h at 90 C (heating block temperature).Most of the alcohol was removed in vacuo, then sat. aq. NaHCO3 solution and EtOAc were added.The organic phase was separated and the aqueous phase extracted with EtOAc. The combined organiclayer was washed with sat. aq. NaHCO3 solution and water or alternatively with sat. aq. NaCl solution,dried over NaSO4 and the solvent removed in vacuo. The product was obtained after purification bycolumn chromatography on silica in 90% to quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Methyl 1-(3-methoxy-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)cyclopentane-1-carboxylate [S34]. To a 300 mL flask added 2-(4-hydroxy-3-methoxyphenyl)acetic acid 1.8218 g (10 mmol, 1.0 equiv.), 2.54 mL TMSCl (20 mmol, 2.0 equiv.) and 100 mL MeOH. The reaction was sitrred under room temperature for 24 hours before diluted with 100 mL DCM and extracted with 100 mL brine. The organic layer was dried with Na2SO4 and concentrated. The crude compound was redissolved in 50 mL anhydrous DCM, and treated with 1.809 g (12 mmol, 1.2 equiv.) TB SCl, 1.020 g (15 mmol, 1.5 equiv.) imidazole and 122 mg (1 mmol, 0.1 equiv.) DMAP. The reaction was stirred overnight, worked up with water and extracted with DCM. The combined organic layer was washed with brine and dried with Na2SO4. The crude product was dissolved in 15 mL anhydrous DMF and transferred to a 50 mL flamed dried flask. 632 mg (95% purity, 25 mmol, 2.5 equiv.) of NaH was added in portions at 0 C. and the reaction was allowed to stir for 1 hour at 0 C. 1.18 mL (10.0 mmol, 1.0 equiv.) of 1,4-dibromobutane was added dropwise at 0 C. and the reaction was allowed to stir overnight at room temperature. The reaction was quenched carefully with 10 mL water and extracted with 30 mL EtOAc three times, washed with 50 mL brine, dried with MgSO4, filtered, and concentrated. The product was dissolved in 2 mL THF and added 1.5 mL 1M TBAF solution and stirred overnight then concentrated. The previous aqueous layer was acidified with 3M HCl then extract with 30 mL EtOAc three times. The combined organic layer was washed with 50 mL brine, dried with MgSO4, filtered, and concentrated to get 378 mg of crude phenol compound. The crude was dissolved in 5 mL anhydrous DCM, cooled to 0 C. and treated with 0.31 mL (1.8 mmol, 1.2 equiv.) of triflate anhydride and 0.18 mL (2.27 mmol, 1.5 equiv.) of pyridine. The reaction was then stirred for 5 hours at room temperature before quenched with 10 mL water. 15 mL DCM was used to extract the reaction 3 times and the combined organic layer was dried with Na2SO4 and concentrated. Flash column chromatography on silica (50 mm fritted glass column, 200 mL SiO2) using 5% EtOAc/hexanes?10% EtOAc/hexanes as eluent gave 542.2 mg (1.42 mmol) of pure product as a colorless oil (14% yield over 5 steps). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine In acetic anhydride at 110℃; | 4.1.3. General procedure for the synthesis of 2a-2n General procedure: Cinnamaldehydes (10 mmol) and 2-phenylacetic acids(10 mmol) were dissolved in acetic anhydride (2.84 mL, 30 mmol),and then triethylamine (4.16 mL, 30 mmol) was added slowly. Themixture was stirred at 110 C overnight. After cooling to roomtemperature, ice-cold water was added and the mixture was acidifiedwith 12 N HCl. The precipitated crude product was collectedand was dissolved in 10% aq NaOH. After extracting with EtOAc, theaqueous layer was acidified with HCl to pH 6e7. The precipitatedcrude product was collected by filtration and washed with coldEtOAc to afford 2a-2n as a light yellow solid. 4.1.3.1. |
75% | With triethylamine In acetic anhydride at 110℃; | 4.1.3. General procedure for the synthesis of 2a-2n General procedure: Cinnamaldehydes (10 mmol) and 2-phenylacetic acids(10 mmol) were dissolved in acetic anhydride (2.84 mL, 30 mmol),and then triethylamine (4.16 mL, 30 mmol) was added slowly. Themixture was stirred at 110 C overnight. After cooling to roomtemperature, ice-cold water was added and the mixture was acidifiedwith 12 N HCl. The precipitated crude product was collectedand was dissolved in 10% aq NaOH. After extracting with EtOAc, theaqueous layer was acidified with HCl to pH 6e7. The precipitatedcrude product was collected by filtration and washed with coldEtOAc to afford 2a-2n as a light yellow solid. 4.1.3.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine In acetic anhydride at 110℃; | 4.1.3. General procedure for the synthesis of 2a-2n General procedure: Cinnamaldehydes (10 mmol) and 2-phenylacetic acids(10 mmol) were dissolved in acetic anhydride (2.84 mL, 30 mmol),and then triethylamine (4.16 mL, 30 mmol) was added slowly. Themixture was stirred at 110 C overnight. After cooling to roomtemperature, ice-cold water was added and the mixture was acidifiedwith 12 N HCl. The precipitated crude product was collectedand was dissolved in 10% aq NaOH. After extracting with EtOAc, theaqueous layer was acidified with HCl to pH 6e7. The precipitatedcrude product was collected by filtration and washed with coldEtOAc to afford 2a-2n as a light yellow solid. 4.1.3.1. |
67% | With triethylamine In acetic anhydride at 110℃; | 4.1.3. General procedure for the synthesis of 2a-2n General procedure: Cinnamaldehydes (10 mmol) and 2-phenylacetic acids(10 mmol) were dissolved in acetic anhydride (2.84 mL, 30 mmol),and then triethylamine (4.16 mL, 30 mmol) was added slowly. Themixture was stirred at 110 C overnight. After cooling to roomtemperature, ice-cold water was added and the mixture was acidifiedwith 12 N HCl. The precipitated crude product was collectedand was dissolved in 10% aq NaOH. After extracting with EtOAc, theaqueous layer was acidified with HCl to pH 6e7. The precipitatedcrude product was collected by filtration and washed with coldEtOAc to afford 2a-2n as a light yellow solid. 4.1.3.1. |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
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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 |
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