* 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.
Reference：
[1] Bulletin de la Societe Scientifique de Bretagne, 1956, vol. 31, p. Sonderheft S.9,41
4
[ 578-39-2 ]
[ 57556-31-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
With thionyl chloride In methanol; water; ethyl acetate
Example 12 Synthesis of 4-(2',3'-dihydrophytyloxy)-2-methylbenzyl alcohol To methanol (10 ml) was added dropwise thionyl chloride (1.92 ml, 26.3 mmol) at 0° C., 4-hydroxy-2-methylbenzoic acid (2.00 g, 13.1 mmol) was added, and the mixture was stirred at 60° C. overnight. After completion of the reaction, the solvent was evaporated, and the residue was dissolved in ethyl acetate (20 ml). The mixture was washed twice with 5percent aqueous sodium hydrogen carbonate solution (10 ml), once with 1N hydrochloric acid (10 ml), and once with water (10 ml), and the solvent was evaporated to give methyl 4-hydroxy-2-methylbenzoate (2.24 g, yield 100percent). 1H-NMR (300 MHz): δ 2.57 (3H, s, C2-Me), 3.86 (3H, s, -COOMe), 5.68 (1H, s, br, -OH), 6.66-6.72 (2H, m, C3, 5-H), 7.89 (1H, dd, J=2.4, 6.9 Hz, C6-H).
Reference：
[1] Patent: US2012/59149, 2012, A1,
[2] Bulletin de la Societe Scientifique de Bretagne, 1956, vol. 31, p. Sonderheft S.9,41
5
[ 67-56-1 ]
[ 578-39-2 ]
[ 57556-31-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 0 - 60℃;
To methanol (10 ml) was added dropwise thionyl chloride (1.92 ml, 26.3 mmol) at 0°C, 4-hydroxy-2-methylbenzoic acid (2.00 g, 13.1 mmol) was added, and the mixture was stirred at 60°C overnight. After completion of the reaction, the solvent was evaporated, and the residue was dissolved in ethyl acetate (20 ml). The mixture was washed twice with 5percent aqueous sodium hydrogen carbonate solution (10 ml), once with 1N hydrochloric acid (10 ml), and once with water (10 ml), and the solvent was evaporated to give methyl 4-hydroxy-2-methylbenzoate (2.24 g, yield 100percent). 1H-NMR(300MHz):δ2.57(3H,s,C2-Me),3.86(3H,s,-COOMe), 5.68(1H,s,br,-OH), 6.66-6.72(2H,m,C3,5-H), 7.89(1H,dd,J=2.4,6.9Hz,C6-H).
100%
at 0 - 60℃;
To methanol (10 ml) was added dropwise thionyl chloride (1.92 ml, 26.3 mmol) at 0°C, 4-hydroxy-2-methylbenzoicacid (2.00 g, 13.1 mmol) was added, and the mixture was stirred at 60°C overnight. After completion of thereaction, the solvent was evaporated, and the residue was dissolved in ethyl acetate (20 ml). The mixture was washedtwice with 5percent aqueous sodium hydrogen carbonate solution (10 ml), once with 1 mol/l hydrochloric acid (10 ml), andonce with water (10 ml), and the solvent was evaporated to give methyl 4-hydroxy-2-methylbenzoate (2.24 g, yield 100percent).
100%
at 60℃;
To methanol (10 ml) was added dropwise thionyl chloride (1.92 ml, 26.3 mmol) at 0° C., 4-hydroxy-2-methylbenzoic acid (2.00 g, 13.1 mmol) was added, and the mixture was stirred at 60° C. overnight. After completion of the reaction, the solvent was evaporated, and the residue was dissolved in ethyl acetate (20 ml). The mixture was washed twice with 5percent aqueous sodium hydrogen carbonate solution (10 ml), once with 1 mol/l hydrochloric acid (10 ml), and once with water (10 ml), and the solvent was evaporated to give methyl 4-hydroxy-2-methylbenzoate (2.24 g, yield 100percent).
95%
Heating / reflux
a) 4-Hydroxy-2-methyl-benzoic acid methyl ester4-Hydroxy-2-methyl-benzoic acid (4.8 g, 32.0 mmol) was dissolved in MeOH <n="52"/>(40 mL) and catalytic quantity of sulfuric acid (1 mL) was added. The mixture was refluxed overnight, after which the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated NaHCO3 to basic pH. The organic phase was dried and evaporated under reduced pressure, and the product (5.0 g, yield 95?/o) was used without further purification.C9H10O31H-NMR (dmso-d6): 2.43 (3H, s); 3.72 (3H, s); 6.62-6.64 (2H, m); 7.71-7.73 (IH, m); 10.10 (IH, s).
95%
Reflux
a) 4 -Hydroxy- 2 -methyl- benzoic acid methyl ester; [0182] 4-Hydroxy-2-methyl-benzoic acid (4.8 g, 32.0 mmol) was dissolved in MeOH (40 mL) and catalytic quantity of sulfuric acid (1 mL) was added. The mixture was refluxed overnight, after which the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated NaHCO3 to basic pH. The organic phase was dried and evaporated under reduced pressure, and the product (5.0 g, yield 95percent) was used without further purification.C9H10O31H-NMR (dmso-de): 2.43 (3H, s); 3.72 (3H, s); 6.62-6.64 (2H, m); 7.71-7.73 (1H, m); 10.10 (1H, s).
95%
Heating / reflux
4-Hydroxy-2-methyl-benzoic acid methyl ester (1.0 g, 6.0 mmol, 1.0 eq) was dissolved in acetone (14 mL), NaI (0.45 g, 3.0 mmol, 0.5 eq) and K2CO3 (1.66 g, 12.0 mmol, 2.0 eq) were added ad the mixture was stirred at room temperature for 20 min. (Bromomethyl)cyclopropane (0.53 mL, 5.4 mmol, 0.9 eq) was added, and the mixture was refluxed for 2 days. The solvent was concentrated under reduced pressure, NaOH 10percent was added, and the crude was extracted with DCM and dried. 0.42 g of title product (yield 32percent) were recovered and used without further purification. C13H16O31H-NMR (CDCl3): 0.23-0.34 (2H, m); 0.52-0.64 (2H, m); 1.15-1.24 (IH, m); 2.52 (3H, s); 3.75 (2H, d, J=7.2 Hz); 3.77 (3H, s); 6.64-6.66 (IH, m); 7.83-7.85 (2H, m).
4-Hvdroxy-2-methyl-benzoic acid: BBr3 (20 mmol, 5g, 10 eq.) was added to a solution of 4-methoxy-2-methyl benzoic acid (2 mmol, 0.332g) in DCM (20 ml) and the mixture was stirred under argon until HPLC indicated no starting material remained. HCI (0.1 M, 20 ml) was added and the mixture was filtered. The aqueous layer was evaporated then dissolved in methanol. The solvent was evaporated. The EPO <DP n="95"/>dissolution/evaporation protocol was repeated a further 3 times and gave the pure product as a yellow solid (0.24g, 80percent).
80%
Stage #1: With boron tribromide In dichloromethane Stage #2: With hydrogenchloride; water In dichloromethane
4.4 4-Hvdroxy-2-methyl-benzoic acid; BBr3 (20 mmol, 5 g, 10 eq.) was added to a solution of 4-methoxy-2-methyl benzoic acid (2 mmol, 0.332 g) in DCM (20 ml) and the mixture was stirred under argon until HPLC indicated no starting material remained. HCI (0.1 M, 20 ml) was added and the mixture was filtered. The aqueous layer was evaporated then dissolved in methanol. The solvent was evaporated. The dissolution/evaporation protocol was repeated a further 3 times and gave the pure product as a yellow solid (0.24 g, 80percent).
Reference：
[1] European Journal of Organic Chemistry, 2008, # 5, p. 816 - 825
[2] Patent: WO2006/64286, 2006, A1, . Location in patent: Page/Page column 93-94
[3] Patent: WO2007/144379, 2007, A1, . Location in patent: Page/Page column 39
[4] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1987, vol. 26, p. 679 - 682
[5] Patent: WO2006/79099, 2006, A2, . Location in patent: Page/Page column 68; 69
9
[ 41877-16-1 ]
[ 578-39-2 ]
Yield
Reaction Conditions
Operation in experiment
82.2%
Stage #1: With pyridine In ethyl acetate at 20 - 70℃; for 1 h; Stage #2: With sodium hydroxide In water for 1 h; Heating / reflux
B. 2-Methyl-4-hydroxybenzoic Acid 76.8 g of the compound obtained in the preceding stage are introduced into 310 ml of ethyl acetate and then 70.8 ml of pyridine are added. The temperature gradually rises from 20° C. to 50° C. The reaction medium is then heated at 70° C. for 1 hour and is then allowed to return to ambient temperature. The reaction mixture is filtered and then the isolated solid is taken up in 710 ml of 10percent aqueous sodium hydroxide. The mixture is brought to reflux for 1 hour and is then allowed to return to ambient temperature. The aqueous phase is washed with diethyl ether, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extracts are subsequently washed with water and a saturated sodium chloride solution. [lacuna] Purification is then carried out by recrystallization from water. In this way, 41.94 g of the desired compound are obtained. Yield: 82.2percent M.p.: 178-182° C.
4-Hvdroxy-2-methyl-benzoic acid: BBr3 (20 mmol, 5g, 10 eq.) was added to a solution of 4-methoxy-2-methyl benzoic acid (2 mmol, 0.332g) in DCM (20 ml) and the mixture was stirred under argon until HPLC indicated no starting material remained. HCI (0.1 M, 20 ml) was added and the mixture was filtered. The aqueous layer was evaporated then dissolved in methanol. The solvent was evaporated. The EPO <DP n="95"/>dissolution/evaporation protocol was repeated a further 3 times and gave the pure product as a yellow solid (0.24g, 80percent).
80%
4.4 4-Hvdroxy-2-methyl-benzoic acid; BBr3 (20 mmol, 5 g, 10 eq.) was added to a solution of 4-methoxy-2-methyl benzoic acid (2 mmol, 0.332 g) in DCM (20 ml) and the mixture was stirred under argon until HPLC indicated no starting material remained. HCI (0.1 M, 20 ml) was added and the mixture was filtered. The aqueous layer was evaporated then dissolved in methanol. The solvent was evaporated. The dissolution/evaporation protocol was repeated a further 3 times and gave the pure product as a yellow solid (0.24 g, 80percent).
With boron tribromide; In dichloromethane; at -78 - 20℃; for 24.5h;
4-Hydroxy-2-methylbenzoic acid (2). To a 250 mL flame dry 3 -neck round bottom flask was added 4-methoxy-2-methyl benzoic acid (1) (5.0 g, 30.08 mmol) and CH2Cl2 (80 mL). The reaction was cooled to -78 0C and treated with neat BBr3 (5.7 mL, 60.17 mmol) dropwise via an addition funnel. The reaction was stirred for 30 min at -78 0C. The solution temperature was increased to -15 0C and stirred for 4 h (- 15 to -10 0C). The cooling bath was removed. The reaction was stirred for 20 h at rt. The solution was cooled to 0 0C and quenched with ether (15 mL) and water (15 mL) (caution: water caused violent reaction; added water dropwise). The biphasic mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography (300 g SiO2, 70:30 hexanes-acetone, Rf = 0.31) to afford the title compound .
With sodium hydroxide; chlorine; sodium thiosulfate; In methanol; for 0.75h;Heating / reflux;
A mixture of 7 g (46 mmol) of the compound obtained in the preceding stage, 125 ml of methanol, 3.68 g (2 equivalents) of sodium hydroxide and 15.87 g (2.3 equivalents) of sodium iodide is brought to reflux. Still at reflux, 115 ml of a sodium hypochlorite solution comprising approximately 4percent of active chlorine are added over approxiamtely 30 minutes. Reflux is continued for 15 minutes and then the mixture is allowed to return to ambient temperature. 92 ml of 10percent sodium thiosulphate are added, followed by 20.7 ml of concentrated hydrochloric acid. Extraction is carried out with diisopropyl ether and then washing is carried out with water to neutral pH. In this way, 13.34 g of the desired compound are obtained in the crude form. Yield: quantitative
72%
To a solution of 4-hydroxy-2-methyl-benzoic acid (7.00 g, 46.0 mmol) in methanol (125 mL) is added sodium hydroxide (3.68 g, 92.0 mmol) and sodium iodide (15.86 g, 105.8 mmol) and the mixture is heated to reflux. While at reflux, a sodium hypochlorite solution containing approximately 4percent of active chlorine (115 mL, 1.69 mol) is added dropwise over 30 min. Reflux is continued for 30 min and the mixture is allowed to cool to rt. A solution of 10percent sodium thiosulfate (92 mL) is added, followed by the addition of concentrated hydrochloric acid (21 mL). The mixture is extracted with ethyl acetate and the combined organic phases are washed with water until neutral pH is obtained. The organic phase is dried over Na2SO4 and the solvent is removed in vacuo. The crude material is purified via silica gel chromatography using a gradient elution of 0-30percent ethyl acetate/hexanes to afford the desired product as an off-white solid (9.23 g, 72percent).
With ammonium hydroxide; iodine; potassium iodide; In water; at 5 - 20℃; for 2h;
4-Hydroxy-2-methylbenzoic acid (0201-25) (1.0 g, 6.6 mmol, 1.0 eq.)Add 10 (ml) water,Then aqueous ammonia (1 ml) was added.After cooling in an ice bath,Potassium iodide (3.26 g, 19.8 mmol, 3.0 equiv) was slowly added dropwise andIodine (1.66 g, 6.6 mmol, 1.0 eq)Aqueous solution (20 ml),Control temperature is below 5 degrees.The final mixture was stirred at room temperature for 2 hours.After the reaction is completed, add a saturated solution of sodium bisulfite (10 mMl) Quench, add 50 ml water and stir overnight. Concentrated hydrochloric acid to adjust the PH value to 3-4, precipitation of a solid, filtered, washed with water, the solid was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, filtered,Concentration under reduced pressure afforded the compound 4-hydroxy-5-iodo-2-methylbenzoic acid (1.8 g, crude).
B. 2-Methyl-4-hydroxybenzoic Acid 76.8 g of the compound obtained in the preceding stage are introduced into 310 ml of ethyl acetate and then 70.8 ml of pyridine are added. The temperature gradually rises from 20° C. to 50° C. The reaction medium is then heated at 70° C. for 1 hour and is then allowed to return to ambient temperature. The reaction mixture is filtered and then the isolated solid is taken up in 710 ml of 10percent aqueous sodium hydroxide. The mixture is brought to reflux for 1 hour and is then allowed to return to ambient temperature. The aqueous phase is washed with diethyl ether, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The extracts are subsequently washed with water and a saturated sodium chloride solution. [lacuna] Purification is then carried out by recrystallization from water. In this way, 41.94 g of the desired compound are obtained. Yield: 82.2percent M.p.: 178-182° C.
With 1,2-dichloro-ethane; In hexane; ethyl acetate; N,N-dimethyl-formamide;
Part D Preparation of Benzamide, N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-4-hydroxy-2-methyl To a solution of 175 mg of <strong>[578-39-2]4-hydroxy-2-methylbenzoic acid</strong> in 2 mL of anhydrous N,N-dimethylformamide at 0° C., was added 200 mg of N-hydroxybenzotriazole and then 220 mg of EDC. After 20 minutes of activation, 450 mg of 2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine was added. After stirring at room temperature for 16 hours, ethyl acetate was added, wshed with 5percent citric acid, sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated to afford crude product. This was chromatographed on silica gel using 50percent ethyl acetate/hexane to afford 102 mg of the desired benzamide, N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-4-hydroxy-2-methyl.
With 1,2-dichloro-ethane; In hexane; ethyl acetate; N,N-dimethyl-formamide;
Part D Preparation of Benzamide, N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-4-hydroxy-2-methyl To a solution of 175 mg of <strong>[578-39-2]4-hydroxy-2-methylbenzoic acid</strong> in 2 mL of anhydrous N,N-dimethylformamide at 0° C., was added 200 mg of N-hydroxybenzotriazole and then 220 mg of EDC. After 20 minutes of activation, 450 mg of 2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine was added. After stirring at room temperature for 16 hours, ethyl acetate was added, washed with 5percent citric acid, sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated to afford crude product. This was chromatographed on silica gel using 50percent ethyl acetate/hexane to afford 102 mg of the desired benzamide, N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-4-hydroxy-2-methyl.
methyl 2-methyl-4-trimethylsilyloxybenzoate[ No CAS ]
[ 578-39-2 ]
Yield
Reaction Conditions
Operation in experiment
With LiOH; In methanol; water;
Part C Preparation of 4-Hydroxy-2-methylbenzoic acid A 100 mL round bottom flask equipped with magnetic stir bar was charged with 5.7 g methyl 2-methyl-4-trimethylsilyloxybenzoate and 2.0 g LiOH in 40 mL methanol and 10 mL water. After 2 hours at reflux the reaction was poured into 10 mL concentrated HCl and then 100 g ice. Extraction with ethyl acetate followed by concentration in vacuo gave a crude solid (70:30) product:starting material. Flash Chromatography using 50--50 ethyl acetate/hexanes as an eluent gave 1.15 g 2-methyl-4-hydroxybenzoic acid, m/e=193(M+H).
With LiOH; In methanol; water;
Part C Preparation of 4-Hydroxy-2-methylbenzoic acid A 100 mL round bottom flask equipped with magnetic stir bar was charged with 5.7 g methyl 2-methyl-4-trimethylsilyloxybenzoate and 2.0 g LiOH in 40 mL methanol and 10 mL water. After 2 hours at reflux the reaction was poured into 10 mL concentrated HCl and then 100 g ice. Extraction with ethyl acetate followed by concentration in vacuo gave a crude solid (70:30) product:starting material. Flash Chromatography using 50-50 ethyl acetate/hexanes as an eluent gave 1.15 g 2-methyl-4-hydroxybenzoic acid, m/e=193(M+H).
(a) allyl 4-hydroxy-2-methylbenzoate In a manner analogous to Example 1(a), 5.34 g (32 mmoles) of 4-hydroxy-2-methyl benzoic acid treated at 100° C. for 12 hours with 50 ml of allyl alcohol and 1.5 ml of concentrated sulfuric acid, give 4 g (76percent yield) of the expected ester having a melting point of 76°-77° C.
3-methylcyclohexanone-4-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogen;sulfuric acid; In methanol; palladium-carbon catalyst;
EXAMPLE 6 Preparation of 3-methylcyclohexanone-4-carboxylic acid methyl ester: 2-Methyl-4-hydroxybenzoic acid was heated in methanol under the influence of sulfuric acid catalyst to convert it into its methyl ester. One mole of the methyl 2-methyl-4-hydroxybenzoate thus obtained was reacted with two moles of hydrogen in the presence of 5percent palladium-carbon catalyst. This reaction was carried out in isopropyl alcohol at a temperature of 150°-170° C. and a hydrogen pressure of 20-40 kg/cm2. After the reaction mixture was filtered to recover the catalyst therefom, the filtrate was distilled to obtain 3-methylcyclohexanone-4-carboxylic acid methyl ester as the distillate at 112°-120° C./5 mmHg.
Part A A mixture of 3.04 parts of <strong>[578-39-2]4-hydroxy-2-methylbenzoic acid</strong>, 8.57 parts of hexanoic anhydride, one drop of concentrated sulfuric acid and 3 parts by volume of benzene were refluxed for 15 minutes when the mixture was poured over ice and stirred for 10 minutes. The mixture was extracted three times with 100 parts by volume of chloroform. The combined extracts were dried over magnesium sulfate and the solvent evaporated to obtain 4-hexanoyloxy-2-methylbenzoic acid.
4-(ter?-Butyldimethylsilyloxy)-2-methylbenzoic acid (3). To a stirred solution of <strong>[578-39-2]4-hydroxy-2-methylbenzoic acid</strong> (2) (4.2 g, 27.60 mmol) in DMF (20 mL) was added ^-BDMSCl (10.2 g, 67.63 mmol) and stirred for 15 min. Dry J-Pr2NEt (14.0 mL, 80.05 mmol) was added dropwise via an addition funnel and stirred at rt for 20 h. The reaction was quenched with IM H3PO4 (7 mL) till the final pH was 3-4. The solution was extracted with hexanes (4 x 100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography (300 g SiO2, 90:9:1 hexanes- acetone- AcOH, Rf = 0.28) to afford the title compound.
To a solution of <strong>[578-39-2]4-hydroxy-2-methylbenzoic acid</strong> (4.20 g, 27.6 mmol) in lambda/,lambda/-dimethyl formamide (20.0 ml.) were added f-butyldimethylsilylchloride (10.2 g, 67.63 mmol) and diisopropylethylamine (14.4 ml_, 82.8 mmol), and the mixture was stirred overnight at rt. The reaction mixture was diluted with hexane and quenched with 1 M phosphoric acid until pH 4 was achieved. The organic layer was separated, washed with brine and the solvent was removed. The crude material was purified via silica gel chromatography to give 4.4 g of the title compound. 1H NMR (CDCI3) delta 7.98 (d, 1 H), 6.43 - 6.83 (m, 2 H), 2.58 (s, 3 H), 0.96 (s, 9 H), 0.21 (s, 6 H).
With N-ethyl-N,N-diisopropylamine; at 70℃; for 22h;
STEP 1 : A solution of <strong>[578-39-2]4-hydroxy-2-methylbenzoic acid</strong> (550 mg, 3.60 mmol), benzyl chloride (458 mg, 3.60 mmol) and N,N-diisopropylethylamine (465 mg, 3.6 mmol) was stirred at 70° C for 22 h. A solution of saturated sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/ethyl acetate) to afford phenylmethyl 4-hydroxy-2-methylbenzoate (687 mg, 79percent). 1H NMR (400 MHz, DMSO): 10.21-10.18 (br. s, I H), 7.84-7.77 (d, I H), 7.48-7.31 (m, 5H), 6.71-6.64 (br. s, 2H), 5.26 (s, 2H), 2.47 (s, 3H). MS (EI) for C15Hi4O3: 243 (MH+).
With borane-THF; In tetrahydrofuran; at 20 - 80℃;Inert atmosphere;
To a solution of 4-hydroxy-2-methyl benzoic acid (5 g, 32.9 mmol, Aldrich) in THF (60 ml) at ambient temperature under nitrogen was added dropwise 1.0M borane- tetrahydrofuran complex (70 ml, 70.0 mmol). The suspension was heated at 80 0C for 2 h. To the solution at ambient temperature was added methanol (40 ml) dropwise. The solution was heated to 80 0C for 30 min. The solvent was removed in vacuo and the residue dissolved in methanol (100 ml). The solvent was removed in vacuo to leave a white solid (4.63 g). The residue was further purified by SPE on aminopropyl (NH2) 70 g (prewashed with methanol) and eluted with methanol (three column volumes). The solvent was removed in vacuo to give impure 4- (hydroxymethyl)-3-methylphenol as an orange solid (4.25 g).
With sulfuric acid; In 1,4-dioxane; at 20℃; for 60h;Sealed tube;
[0156] A suspension of <strong>[578-39-2]4-hydroxy-2-methylbenzoic acid</strong> (5.0 g, 33 mmol) in dioxane (50 mL) in a 500 mL pressurebottle was cooled until the dioxane started to freeze, then sulfuric acid (conc., 1 mL) was added, followed by liquidisobutylene (100 mL, condensed in a graduated cylinder cooled in a dry ice bath). The pressure bottle was sealed andthe reaction was warmed to room temperature. After 2 hours, all the acid was in solution and the mixture was stirred for2.5 days. It was then recooled in a dry ice bath and slowly quenched into a large, stirred flask containing excess aq.sodium bicarbonate solution and diethyl ether and the mixture was stirred for 30 minutes. The ether layer was separatedand washed with another portion of aq. sodium bicarbonate solution. The aqueous layers were back extracted with asecond portion of ether and the ether layers were washed with brine, dried over sodium sulfate and evaporated in vacuo.The residue was purified by flash chromatography (5 to 25percent ethyl acetate in hexanes) to afford tert-butyl 4-tert-butoxy-2-methylbenzoate as the higher Rf band.Higher: 1H-NMR (400 MHz, CDCl3) delta ppm 7.79 (d, J= 8.3 Hz, 1H), 6.82 (dd, J= 2.5, 8.3 Hz, 1H), 6.81 (br s, 1H), 2.54(s, 3H), 1.58 (s, 9H), 1.38 (s, 9H).Lower: 1H-NMR (400 MHz, CDCl3) delta ppm 7.80 (d, J= 9.2 Hz, 1H), 6.66 (m, 2H), 5.46 (br s, 1H), 2.54 (s, 3H), 1.58 (s, 9H).
With sulfuric acid; In 1,4-dioxane; at 20℃; for 60h;High pressure; Cooling;
Step A: fert-Butyl 4-tert-Butoxy-2-methylbenzoate A suspension of <strong>[578-39-2]4-hydroxy-2-methylbenzoic acid</strong> (5.0 g, 33 mmol) in dioxane (50 mL) in a 500 mL pressure bottle was cooled until the dioxane started to freeze, then sulfuric acid (cone, 1 mL) was added, followed by liquid isobutylene (100 mL, condensed in a graduated cylinder cooled in a dry ice bath). The pressure bottle was sealed and the reaction was warmed to room temperature. After 2 hours, all the acid was in solution and the mixture was stirred for 2.5 days. It was then recooled in a dry ice bath and slowly quenched into a large, stirred flask containing excess aq. sodium bicarbonate solution and diethyl ether and the mixture was stirred for 30 minutes. The ether layer was separated and washed with another portion of aq. sodium bicarbonate solution. The aqueous layers were back extracted with a second portion of ether and the ether layers were washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (5 to 25percent ethyl acetate in hexanes) to afford tert- butyl 4-fert-butoxy-2-methylbenzoate as the higher Rf band. Higher: 1H-NMR (400 MHz, CDC13) delta ppm 7.79 (d, J= 8.3 Hz, 1H), 6.82 (dd, J= 2.5, 8.3 Hz, 1H), 6.81 (br s, 1H), 2.54 (s, 3H), 1.58 (s, 9H), 1.38 (s, 9H). Lower: 1H-NMR (400 MHz, CDC13) delta ppm 7.80 (d, J= 9.2 Hz, 1H), 6.66 (m, 2H), 5.46 (br s, 1H), 2.54 (s, 3H), 1.58 (s, 9H).
2-methyl-4-hydroxybenzoic acid (20.0 g, 0.13 mol), benzyl bromide (58.5 g, 0.34 mol) and potassium carbonate (46.9 g, 0.34 mol) were dissolved in acetone (500 mL). The reaction mixture was heated to 60° C. and refluxed overnight. After the reaction mixture was cooled to room temperature, anhydrous potassium carbonate was filtered off, and the filtrate was concentrated to give a pale yellow solid. The solid was further recrystallized to give benzenemethyl 4-benzyloxy-2-methyl-benzoate (34 g, a white solid, yield: 79percent). 1H NMR (400 MHz, CDCl3): delta 7.98 (d, J=8.7 Hz, 1H), 7.49-7.29 (m, 1014), 6.87-6.77 (m, 2H), 5.31 (s, 214), 5.10 (s, 2H), 2.61 (s, 3H).
6-[4-benzyloxy-2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-tribenzyloxy-6-benzyloxymethyltetrahydrothiopyran-2-yl)benzyl]-2,3-dihydrobenzo[b][1,4]dioxine[ No CAS ]
(2S,3R,4R,5S,6R)-2-(5-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-hydroxy-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-thiopyran-3,4,5-triol[ No CAS ]
(3R,4S,5S,6R)-3,4,5-tribenzyloxy-2-[2-benzyloxy-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl-4-methylphenyl]-6-benzyloxymethyltetrahydrothiopyran-2-ol[ No CAS ]
tetradecane-1,14-diyl bis(4-hydroxy-2-methylbenzoate)[ No CAS ]
14-(formyloxy)tetradecyl 4-hydroxy-2-methylbenzoate[ No CAS ]
14-bromotetradecyl 4-hydroxy-2-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6.6%; 6%; 7%
With sodium hydrogencarbonate; at 65℃; for 68h;Inert atmosphere;
General procedure: A Kimax tube was charged with an equimolar quantity of benzoic acid 33?37 (1.3mmol, 1 equiv.), sodium bicarbonate (1.3mmol, 1 equiv), and the dibromoalkane (1.3mmol, 1 equiv.) in anhydrous acetonitrile or DMF (10mL). The tube was flushed with argon, stopped, and the reaction mixture was stirred at 65°C or 90°C for the time indicated in each case. The solvent was evaporated under vacuum to give a crude solid residue. The different products were isolated by silica chromatography (5g SI prepacked column) using hexane/EtOAc (100/0?50/50) as eluent. The structure of the obtained isomer (i.e. the benzoate product and not the 4-alkyloxy-substituted benzoic acid isomer) was checked by 1H?13C HMBC and NOESY experiments.
Chemistry
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