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Chemical Structure| 481-85-6 Chemical Structure| 481-85-6
Chemical Structure| 481-85-6

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Synonyms: Dihydrovitamin K3

4.5 *For Research Use Only! Not for Human Use. We Do Not Sell to Patients.

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Product Details of Menadiol

CAS No. :481-85-6
Formula : C11H10O2
M.W : 174.20
SMILES Code : OC1=C2C=CC=CC2=C(O)C=C1C
Synonyms :
Dihydrovitamin K3
English Name :2-Methylnaphthalene-1,4-diol
MDL No. :MFCD00655068
InChI Key :ZJTLZYDQJHKRMQ-UHFFFAOYSA-N
Pubchem ID :10209

Safety of Menadiol

Application In Synthesis of Menadiol

* 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.

  • Downstream synthetic route of [ 481-85-6 ]

[ 481-85-6 ] Synthesis Path-Downstream   1~13

  • 2
  • [ 481-85-6 ]
  • [ 58-27-5 ]
YieldReaction ConditionsOperation in experiment
100% With iodate form of Amberlyst A26 In dichloromethane at 20℃; for 2h; further reagent;
99% With sulfuric acid; sodium bromide In dichloromethane; water at 15℃; for 2.98h; Electrolysis; General procedurefor oxidation of 1,4-dihydroxybenzene General procedure: To a stirred solution of 1,4-dihydroxybenzene 1.1 g (10 mmol) in 25 ml of CH2Cl2 taken in a jacketed glass reactor (Fig. 1), a 12.5% aqueous NaBr solution (45 ml) acidified with H2SO4 (2.75 g) was added and the resulting biphasic solution was cooled to 15 °C. Two smooth platinum foil electrodes (3x2 cm2) were placed 1 cm apart in the upper aqueous phase and electrolysed galvanostatically at a current density of 30 mA/cm2 for 2.98 h (Fig. 2). The reaction was monitored by HPLC (Shimadzu). The voltage observed during electrolysis is 2.1 V. After completion of the reaction (2 F/mol), the lower organic phase containing the quinone or brominated product was isolated by simple phase separation. The aqueous portion was extracted once with 25 ml CH2Cl2. The combined organic phase was washed with brine (2x25 ml), dried with anhydrous Na2SO4 and concentrated in vacuo to isolate the solid product 1,4-benzoquinone (1.06 g,99% yield). The crude product was boiled with 20 ml of n-hexane and the resulting yellowish clear solution was transferred to a conical flask. On cooling to room temperature, separated yellow needles were filtered and then characterised by its melting point, HPLC, IR, and NMR spectra. The isolated yield of the product and current efficiency were determined.
96% With carbon dioxide; oxygen In water at 35 - 60℃; for 0.0833333h; Autoclave; 1 (1) Place 150g of 2-menahydroquinone and 0.015g of deionized water in an autoclave, replace with carbon dioxide twice, add carbon dioxide to a pressure of 7.6MPa in the autoclave, stir and heat the autoclave to 35°C, then add Oxygen controls the oxygen content in the autoclave to 4% (volume content, the same below), stir and mix uniformly. (2) Use a compressor to pump the mixture into the tubular reactor (the diameter of the reactor is 1cm, the length of the pipe is 0.5m, and the hot water is kept at 60), and the pressure in the reactor is controlled to 8.18.3MPa by adjusting the back pressure valve. Residence time 300s, cooling after the reaction, remove the pressure of carbon dioxide, remove oxygen and carbon dioxide to obtain 2-methyl-1,4-naphthoquinone, using a mixture of ethanol and water with a water content of 10% (volume content, the same below) Solvent crystallization (cooled to 10°C), suction filtered and dried to obtain 142.3g 2-methyl-1,4-naphthoquinone with a purity of 99.2% (GC internal standard purity, the same below), and a yield of 96%.
94% With pyridine; thionyl chloride In benzene for 2h; Heating;
91% With sodium periodate In dichloromethane at 20℃; for 1h; further solvents;
88% With oxygen; silica gel In dichloromethane at 25℃; for 1h; 3.3. General Procedure for P1/Silica-gel Combined Catalyst Catalyzed Aerobic Oxidation of Various Dihydroxy Arenes General procedure: In a two-neck 100 ml round bottomed flask connected tomolecular oxygen balloon (1.0 atm) and containing dihydroxyarene (0.1 mmol), P1 (100 mg, 0.1 mmol/g loading)and 250 mg silica-gel, a 3.0 mL of CH2Cl2 was injected and the reaction mixture was stirred at room temperature and followed by TLC until the starting material had completely converted to quinone. The quinone product was extracted with CH2Cl2 or ether and was obtained under reduced pressure.The further purification of most of the quinone product was not necessary. The P1/silica-gel combined catalyst was washed several times with ether or CH2Cl2 until it became completely clean and dried under vacuum to be ready for the next cycle.
88% With oxygen; silica gel In dichloromethane at 25℃; for 1h; 3.3. General Procedure for P1/Silica-gel Combined Catalyst Catalyzed Aerobic Oxidation of Various Dihydroxy Arenes General procedure: In a two-neck 100 ml round bottomed flask connected tomolecular oxygen balloon (1.0 atm) and containing dihydroxyarene (0.1 mmol), P1 (100 mg, 0.1 mmol/g loading)and 250 mg silica-gel, a 3.0 mL of CH2Cl2 was injected and the reaction mixture was stirred at room temperature and followed by TLC until the starting material had completely converted to quinone. The quinone product was extracted with CH2Cl2 or ether and was obtained under reduced pressure.The further purification of most of the quinone product was not necessary. The P1/silica-gel combined catalyst was washed several times with ether or CH2Cl2 until it became completely clean and dried under vacuum to be ready for the next cycle.
80% With zirconium phosphate; phthalocyanine[Fe(3+)]; oxygen In 1,4-dioxane; water at 20℃; for 1.16667h;
80% With oxygen In 1,4-dioxane; water at 20℃; for 6h;
75% With salcomine; oxygen In N,N-dimethyl-formamide for 6h; Ambient temperature;
With dihydrogen peroxide In acetic acid at 50℃;
In water at 30℃; Irradiation; influence of concentration, temperature and solvent;
With chromium(VI) oxide; acetic acid at 40℃; anschliessend kurzes Erhitzen;
With sodium hypobromide
With iron(III) chloride; acetic acid
With nitric acid
With oxygen In methanol; phosphate buffer at 37℃;
With air In aq. phosphate buffer
98 % With Trametes sp. laccase In water at 20℃; Enzymatic reaction;
With ethylenediaminetetraacetic acid; oxygen; methylene blue In aq. phosphate buffer 4. Materials and Methods General procedure: Oxygen uptake assays. Reactions (5 mL) contained 0.4 or 1 mM quinone, MB and EDTA in 10 mM PB pH 7.4 in a 15 mL glass vial. Dissolved oxygen was measured priorto light exposure and at the indicated time intervals using a Mettler-Toledo 605-ISM(Columbus, OH, USA) polarographic dissolved oxygen probe. Reactions were performed under ambient oxygen, and the surface of the solution was exposed to air. The maximum amount of DMF was 5% to minimize damage to the electrode components. Absorbance(100 μL or 1 mL portions) was measured prior to and immediately after lightexposure. For CoQ0, absorbance at 405 nm was used to calculate changes in concentration.Based on scans of known concentrations of CoQ0, we determined a molar absorptivity of 740 M-1 cm-1. For experiments with 1,2-NQ, we determined a molar absorptivity of2400 M-1 cm-1 at 415 nm.

References: [1]Harrison, Charles R.; Hodge, Philip [Journal of the Chemical Society. Perkin transactions I, 1982, p. 509 - 511].
[2]Shanmugam; Kulangiappar; Ramaprakash; Vasudevan; Senthil Kumar; Velayutham; Raju [Tetrahedron Letters, 2017, vol. 58, # 23, p. 2294 - 2297].
[3]Current Patent Assignee: ZHEJIANG NHU - CN112321404, 2021, A Location in patent: Paragraph 0030-0032.
[4]Shi; Katz; Yang; Liu [Journal of Organic Chemistry, 1995, vol. 60, # 5, p. 1285 - 1297].
[5]Gupta, Dharmendra N.; Hodge, Philip; Davies, J. Eric [Journal of the Chemical Society. Perkin transactions I, 1981, p. 2970 - 2973].
[6]Abu-Elfotoh, Abdel-Moneim [Letters in Organic Chemistry, 2022, vol. 19, # 3, p. 236 - 243].
[7]Abu-Elfotoh, Abdel-Moneim [Letters in Organic Chemistry, 2022, vol. 19, # 3, p. 236 - 243].
[8]Villemin, Didier; Hammadi, Mohamed; Hachemi, Messaoud [Synthetic Communications, 2002, vol. 32, # 10, p. 1501 - 1515].
[9]Hadjila, Dokari; Mohamed, Hammadi [Asian Journal of Chemistry, 2013, vol. 25, # 11, p. 6112 - 6116].
[10]Rao, A. V. Rama; Deshpande, V. H.; Ravichandran, K. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1985, vol. 24, p. 233 - 235].
[11]Yamaguchi, Satoru; Inoue, Masami; Enomoto, Saburo [Bulletin of the Chemical Society of Japan, 1986, vol. 59, # 9, p. 2881 - 2884].
[12]Marciniec, Barbara; Jaskula-Begol, Jolanta [Acta poloniae pharmaceutica, 1996, vol. 53, # 3, p. 187 - 191].
[13]Sah [Recueil des Travaux Chimiques des Pays-Bas, 1940, vol. 59, p. 1029,1034].
[14]Sagorewskii; Sykow [Zhurnal Prikladnoi Khimii, 1959, vol. 32, p. 2815; engl. Ausg. S. 2896].
[15]Fries; Lohmann [Chemische Berichte, 1921, vol. 54, p. 2917].
[16]Fries; Lohmann [Chemische Berichte, 1921, vol. 54, p. 2917].
[17]Roginsky, Vitaly; Barsukova, Tatyana [Journal of the Chemical Society. Perkin Transactions 2 (2001), 2000, # 7, p. 1575 - 1582].
[18]Mishima, Eikan; Ito, Junya; Wu, Zijun; Nakamura, Toshitaka; Wahida, Adam; Doll, Sebastian; Tonnus, Wulf; Nepachalovich, Palina; Eggenhofer, Elke; Aldrovandi, Maceler; Henkelmann, Bernhard; Yamada, Ken-ichi; Wanninger, Jonas; Zilka, Omkar; Sato, Emiko; Feederle, Regina; Hass, Daniela; Maida, Adriano; Mourão, André Santos Dias; Linkermann, Andreas; Geissler, Edward K.; Nakagawa, Kiyotaka; Abe, Takaaki; Fedorova, Maria; Proneth, Bettina; Pratt, Derek A.; Conrad, Marcus [Nature, 2022, vol. 608, # 7924, p. 778 - 783].
[19]Samsonowicz-Górski, Jan; Hrunyk, Anastasiia; Brodzka, Anna; Ostaszewski, Ryszard; Koszelewski, Dominik [Green Chemistry, 2023, vol. 25, # 16, p. 6306 - 6314].
[20]Landino, Lisa M.; Reed, Joseph A. [Molecules, 2025, vol. 30, # 6].
  • 3
  • [ 58-27-5 ]
  • [ 481-85-6 ]
YieldReaction ConditionsOperation in experiment
100% With sodium dithionite In diethyl ether; water
100% With sodium dithionite In diethyl ether; water at 20℃;
100% With sodium dithionite In diethyl ether; water
98% With sodium dithionite; water In water; ethyl acetate Inert atmosphere; 1 Example 1.Preparation of 2-Methyl-naphthalene-1,4-diol Example 1. Preparation of 2-Methyl-naphthalene-1,4-diol To a 400 ml solution of menadione (50 g, 0.29 mol) in EtOAc, was added a solution of sodium dithionite (120 g, 0.69 mol) in 100 ml water under nitrogen atmosphere. The reaction mixture was subjected to vigorous stirring. The discoloration of the organic layer indicated the completion of the reaction which was supported by TLC observation. Then 100 ml of 1M Sodium metabisulfite solution was added. The aqueous layer was separated and extracted with Ethyl acetate (2 x 50 ml). The combined organic layers were washed with saturated sodium chloride solution and finally dried over MgSO4 before evaporating the solvent in vacuum. A pale purple solid was recovered which was titurated with 300 ml of hexanes and the solid was filtered off to obtain 2-Methyl-naphthalene-1,4-diol (50 g, 98% yield) which was used for the next reaction without any purification.
98% With sodium dithionite; water In ethyl acetate Inert atmosphere; 1 Preparation of 2-Methyl-naphthalene-1,4-diol Example 1 Preparation of 2-Methyl-naphthalene-1,4-diol To a 400 ml solution of menadione (50 g, 0.29 mol) in EtOAc, was added a solution of sodium dithionite (120 g, 0.69 mol) in 100 ml water under nitrogen atmosphere. The reaction mixture was subjected to vigorous stirring. The discoloration of the organic layer indicated the completion of the reaction which was supported by TLC observation. Then 100 ml of 1M Sodium metabisulfite solution was added. The aqueous layer was separated and extracted with Ethyl acetate (2*50 ml). The combined organic layers were washed with saturated sodium chloride solution and finally dried over MgSO4 before evaporating the solvent in vacuum. A pale purple solid was recovered which was titurated with 300 ml of hexanes and the solid was filtered off to obtain 2-Methyl-naphthalene-1,4-diol (50 g, 98% yield) which was used for the next reaction without any purification.
98% With sodium dithionite In water; ethyl acetate Inert atmosphere; 1.1 Step 1 - 2-methylnaphthalene-1,4-diol (2) To a 250 mL solution of menadione (1) (20 g, 0.116 mol) in EtOAc was added a solution of sodium dithionite (61 g, 0.349 mol) in 250 mL water under nitrogen atmosphere. The reaction mixture was subjected to vigorous stirring. The discoloration of the organic layer indicated the completion of the reaction which was supported by TLC observation. The aqueous layer was separated and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated sodium chloride solution and finally dried over Na2SO4 before evaporating the solvent in vacuum. A pale purple solid was recovered which was triturated with 300 mL of hexanes and the solid was filtered off to obtain 2-Methyl- naphthalene-1,4-diol 2 (20 g, 98%) which was used in the next reaction without any purification.
98% With sodium dithionite In water; ethyl acetate at 20℃; for 1h; Step 1 ; Menadione Converted to 2-Methylnaphthalene-1,4-Diol (Menadiol - RLS2): To a solution of sodium hydrosulfite (15.2 g, .087 mol) in deionized water (40 mL) was added a solution of menadione (5 g, .029 mol) in EtOAc (60 mL) at room temperature. After being stirred at room temperature for 60 minutes, the reaction mixture was poured into a separatory funnel and extracted twice with EtOAc. The combined organic layers were dried with MgS0 and filtered. The filtrate was concentrated in vacuo, and the resulting light purple solid was confirmed with NMR and MS to be Menadiol (4.92 g, 0.028 mol, 98%) as a light purple solid
97% With sodium dithionite In water; ethyl acetate at 20℃; for 0.5h;
95% With isopropyl alcohol; zirconium(IV) oxide for 2h; Heating;
95% With sodium dithionite In water; ethyl acetate at 20℃; for 0.333333h; Inert atmosphere;
89% With hydrogen; C20H23IrN2O3(1+)*CF3O3S(1-) In methylbutane at 20℃; for 12h; 19 Example 19:2-Methyl-1,4-naphthoquinone 2-Methyl-1,4-naphthoquinone (172 mg, 1 mmol),cat 1 (2.7 mg, 0.005 mmol, 0.5 mol%), and tert-amyl alcohol (4 ml) were added sequentially to a 25 mL Kjeldahl tube.A balloon filled with hydrogen was connected to the branch.After reacting at room temperature for 12 hours, the solvent was removed by rotary evaporation.Then, the target compound was purified by column chromatography (developing solvent: petroleum ether/ethyl acetate) to obtain an 89% yield.
82.7% With formic acid; C36H36N2O2OsS; triethylamine In benzene-d6 at 36.84℃; for 0.5h; Inert atmosphere;
80% With sodium dithionite In water; ethyl acetate at 25℃; for 0.5h; Inert atmosphere;
80% With sodium tetrahydroborate In ethanol; water at 0 - 20℃; for 6h; Inert atmosphere;
77% With sodium dithionite In water for 0.5h; Inert atmosphere;
53% With zinc(II) chloride; zinc In ethanol for 1h; Heating;
42% With 5,6-O-isopropylidene-L-ascorbic acid In 1,2-dimethoxyethane for 80h; UV-irradiation;
With acetic acid; platinum Hydrogenation;
With diethyl ether; sulfuric acid; zinc
With hydrogenchloride; ethanol; tin(ll) chloride
With sodium dithionite; diethyl ether
With palladium-on-charcoal; acetic acid Hydrogenation;
With acetic acid; tin(ll) chloride
With bis(tetra-n-butylammonium) tetrakis(benzenethiolato-μ3-sulfidoiron); thiophenol In methanol; acetonitrile at 20℃; for 20h; Yield given;
With hydrogen In methanol
With Nafion membrane electrodes with Pt layer In 1,2-dichloro-ethane elctrochemical reduction;
With hydrogen In acetone at 20℃; for 24h;
With hydrogenchloride; tin(ll) chloride In ethanol at 20℃; for 1h;
With sodium dithionite In ethanol; water at 20℃; for 1h;
With NADH In N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid at 25℃; for 1h; Microbiological reaction; Enzymatic reaction;
With palladium 10% on activated carbon; hydrogen In tetrahydrofuran at 20℃; for 4.16667h; Inert atmosphere;
With acetic acid; zinc at 20℃; for 0.5h; 6.1 2-Methyl-1,4-naphthoquinone (5 g, 0.029 mole) was added to a reaction flask containing 50 ml of acetic acid under nitrogen. Zinc powder (8 g) was added to the flask and stirred under nitrogen for 30 minutes at room temperature. The mixture was filtered and residue was washed with 25 ml of chloroform. The filtrates were combined and 100 ml of water was added. The resulting mixture was extracted with three 25 ml portions of chloroform. The organic extracts were combined, washed with distilled water, and dried over magnesium sulfate. Evaporation of solvent resulted in an oily residue that was crystallized from diethyl ether. The solid was suction filtered, washed with hexane and air dried. The resulting solid product (4 g).was used directly in the next step. A nuclear magnetic resonance (NMR) spectrum showed the isolated product to have a structure consistent with 2-methyl-1,4-dihydroxynaphthalene.
With hydrogenchloride; tin(ll) chloride In methanol; water for 1h;
With sodium dithionite In water; ethyl acetate at 20℃; for 0.5h;
With NADH; [(η5-C5Me5)Ir(1,10-phenanthroline)(H2O)](PF6)2 In CD3OD; water at 24.84℃;
With sodium dithionite; water In diethyl ether; ethyl acetate at 20℃; for 3h;
With quinone oxidoreductase; tris hydrochloride; bovine serum albumin at 25℃; Enzymatic reaction;
Multi-step reaction with 2 steps 1: 4-cyanopyridine / pentane / 12 h / 50 °C / Inert atmosphere; Sealed tube 2: water / 0.17 h / 20 °C / Inert atmosphere
With sodium dithionite In water; ethyl acetate at 20℃; for 0.333333h; Inert atmosphere;
With sodium dithionite In diethyl ether; Petroleum ether for 4h; 1.1 Synthesis of 2-methyl-1,4-naphthalenediol: To a 500-ml round-bottomed flask, 120 g of anhydrous ether and 20 g of 2-methyl-1,4-naphthoquinone were added, and after stirring, 80 g of petroleum ether was added, the temperature was increased to reflux, and then 200 g of 25% sodium hydrosulfite solution , About 1 hour drop is completed, after the completion of dropping, heat reflux 3 hours;After the reaction, the reaction solution was cooled to below 25 ° C. Stirring was stopped. The aqueous layer was separated, washed twice with saturated brine, dehydrated with 10 g of anhydrous sodium sulfate and filtered. The filtrate was 2-methyl 1,4-naphthalene Diphenol solution.
With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate In dichloromethane at 25℃; for 0.5h; Inert atmosphere;
With sodium dithionite In diethyl ether
4.25 g With sodium dithionite In diethyl ether at 20℃; for 0.5h; Schlenk technique;
With sodium dithionite In water; ethyl acetate at 20℃; for 0.333333h; Inert atmosphere;
With hydrogen In tetrahydrofuran at 30℃; Flow reactor;
With sodium dithionite In water; ethyl acetate at 20℃; for 3h; Inert atmosphere; General procedure: In short, 1,4-Naphthoquinone 3 (5 mmol) was dissolved in EtOAc (15 mL) and anaqueous solution of sodium dithionite (2.61 g, 15 mmol, 15 mL) was added under nitrogenatmosphere at room temperature. After stirring for 3 h, the mixture was diluted with asaturated solution of ammonium chloride (15 mL) and extracted with EtOAc (3 25 mL).The combined organic layers were washed with water (50 mL) and brine (50 mL) anddried over magnesium sulfate. The solvent was removed in vacuo, and the crude 1,4-dihydroxynaphthalene 5 was directly used for the next step.
With sodium dithionite In ethanol; water at 20℃; Inert atmosphere; 4.1.1. General procedure for the preparation of compounds 22-23 General procedure: A mixture of naphthoquinone (14.7 mmol) and sodiumdithionite (5.0 g, 28.7 mmol) in Et2O/H2O (30/30 ml) was stirred atroom temperature under a nitrogen atmosphere overnight. Thereaction mixture was extracted by EtOAc (3 100 mL) quickly. Theorganic layers were combined, dried over anhydrous Na2SO4 andconcentrated to give a light pink solid (hydroquinone), which wasdirectly used in the next reaction without purification.
With sodium dithionite; water In ethyl acetate at 20℃; for 10h; Inert atmosphere; 1-3 Example 1 5g (29mmol) menadione was added to 50ml EA (ethyl acetate),Then add 6g (34.5mmol) sodium hydrosulfite (sodium hydrosulfite),Add 1.3 g (72.2 mmol) of purified water with a syringe under nitrogen protection,React overnight (about 10 hours) at room temperature.When the reaction solution completely turned into milky white turbidity,Under nitrogen protection, 5.2 g (36.6 mmol) of boron trifluoride ether was added dropwise,heated to 60 degrees Celsius,Slowly add 10.4g (35.8mmol) geranyl linalool dropwise,The temperature-controlled reaction was performed for 3 hours.Take the reaction solution and send it to liquid phase detection,The HPLC detection results are shown in Figure 2.Wherein the main impurity is unreacted menaquinone, which can be recovered by purification means.After the reaction is over,The reaction solution can be poured into water to flush,It was extracted twice with ethyl acetate, backwashed with saturated brine, dried over sodium sulfate, concentrated to dryness, added with silica gel and mixed with sample and purified by column, eluent ethyl acetate: petroleum ether=1:10, v/v. After purification, 4.5 g of product was obtained, the total yield was 35%, and the purity was 99%.
With D,L-dithiothreitol In water at 20℃; for 0.0833333h; Chemical reduction of menadione Menadione and menadiol (300 μM) were incubated with 1 mM DTT or 10 mM GSH in water at room temperature for 5 min, and then measured by absorbance spectrum ranging from 200 to 450 nm by using a Spectra Max M2e (Molecular Devices). Background control (in blank well) of absorbance values was subtracted from each individual absorbance value.
With D,L-dithiothreitol In water at 20℃; for 0.0833333h; Chemical reduction of menadione Menadione and menadiol (300 μM) were incubated with 1 mM DTT or 10 mM GSH in water at room temperature for 5 min, and then measured by absorbance spectrum ranging from 200 to 450 nm by using a Spectra Max M2e (Molecular Devices). Background control (in blank well) of absorbance values was subtracted from each individual absorbance value.

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[22]Sawa; Tsuji [Shionogi Kenkyusho Nenpo, 1956, # 6, p. 7,13][Chem.Abstr., 1957, p. 5026].
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[32]Current Patent Assignee: TRANSITIONS OPTICAL - EP994871, 2006, B1 Location in patent: Page/Page column 14.
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[39]Baj, Aneta; Wałejko, Piotr; Kutner, Andrzej; Kaczmarek, Lłukasz; Morzycki, Jacek W; Witkowski, Stanislław [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1026 - 1033].
[40]Current Patent Assignee: SHANDONG GUANGTONGBAO PHARMACEUTICALS - CN105399615, 2016, A Location in patent: Paragraph 0023; 0025.
[41]Xu, Xiao-Long; Li, Zhi [Angewandte Chemie - International Edition, 2017, vol. 56, # 28, p. 8196 - 8200][Angew. Chem., 2017, vol. 129, # 28, p. 8308 - 8312].
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[43]Koehn, Jordan T.; Magallanes, Estela S.; Peters, Benjamin J.; Beuning, Cheryle N.; Haase, Allison A.; Zhu, Michelle J.; Rithner, Christopher D.; Crick, Dean C.; Crans, Debbie C. [Journal of Organic Chemistry, 2018, vol. 83, # 1, p. 275 - 288].
[44]Smets, Robert J.; Torfs, Eveline; Lemière, Filip; Cos, Paul; Cappoen, Davie; Abbaspour Tehrani, Kourosch [Organic and Biomolecular Chemistry, 2019, vol. 17, # 11, p. 2923 - 2939].
[45]Miyamura, Hiroyuki; Tobita, Fumiya; Suzuki, Aya; Kobayashi, Shū [Angewandte Chemie - International Edition, 2019, vol. 58, # 27, p. 9220 - 9224][Angew. Chem., 2019, vol. 131, p. 9318 - 9322,5].
[46]Bauch, Marcel; Fudickar, Werner; Linker, Torsten [Molecules, 2021, vol. 26, # 4].
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[48]Current Patent Assignee: ANHUI PROVINCE AND PHARMACEUTICAL RES - CN114149314, 2022, A Location in patent: Paragraph 0011; 0025-0030.
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  • 4
  • [ 481-85-6 ]
  • [ 108-24-7 ]
  • [ 573-20-6 ]
YieldReaction ConditionsOperation in experiment
With sulfuric acid
With hydrogen at 80℃; for 24h;
With sulfuric acid at 20℃; for 2h; Inert atmosphere; Schlenk technique;
90.2 % With pyridine at 65 - 70℃; 1.2; 2; 3.2 (2) the above0.45 g (0.006 mol) of pyridine is added to the 2-methyl-1,4-naphthalenediol ethyl acetate solution,17.1 g (0.167 mol) of acetic anhydride was added dropwise at 65-70° C. and aged at the same temperature for 3 hours. The organic layer was washed with city water and 5% sodium bicarbonate water,The organic layer was concentrated, and a mixed solution of isopropanol (IPA) and city water was added to the residue. The resulting slurry was filtered and dried under reduced pressure to give 12.0 g of colorless crystalline powder of 1,4-diacetoxy-2-methylnaphthalene.(0.046 mol) was obtained.HPLC purity is 99.96 Area%,The yield from bisulfite trihydrate of 2-methylnaphthoquinone was 90.2%.
230 g With sulfuric acid In toluene at 50℃; 1 Example 1 Preparation of Menadiol (1) and Diacetylmenadiol (2) A solution of menadione 200 g (1 eq) in ethyl acetate (1700 ml), and a solution of sodium dithionite 333 g (1.65 eq) in water were added to a flask. It was vigorously stirred at 25° C. for 15 min. Stirring was stopped, phases were separated. Organic phase was rinsed with water and brine. It was concentrated in vacuo, with further azeotropic drying with toluene to obtain slightly violet precipitate of compound (1). The precipitate was directed to acylation without further purification.To the precipitate it was added toluene 700 ml, and acetic anhydride 400 ml (3.5 eq), and a catalytic amount of sulfuric acid. After 1 h at 50° C., the solution was cooled and excess anhydride was decomposed with water at 25° C. Phases were separated, rinsed with water and brine. Organic layer was concentrated in vacuo to obtain orange precipitate. After recrystallization from methanol 230 g of white precipitate was obtained. Yield after two steps 77%.1H NMR (500 MHz, CDCl3) δ 7.85-7.79; (m, 1H), 7.78-7.73; (m, 1H), 7.50; (dddd, 2H), 7.15; (s, 1H), 2.48; (s, 3H), 2.46; (s, 3H), 2.33; (s, 3H),13C NMR (126 MHz, CDCl3) δ 169.39, 168.86, 144.11, 142.13, 127.90, 127.08, 126.49, 126.16, 126.02, 121.46, 121.16, 120.71, 20.99, 20.58, 16.50.
230 g With sulfuric acid In toluene at 50℃; 1 Example 1 Preparation of Menadiol (1) and Diacetylmenadiol (2) A solution of menadione 200 g (1 eq) in ethyl acetate (1700 ml), and a solution of sodium dithionite 333 g (1.65 eq) in water were added to a flask. It was vigorously stirred at 25° C. for 15 min. Stirring was stopped, phases were separated. Organic phase was rinsed with water and brine. It was concentrated in vacuo, with further azeotropic drying with toluene to obtain slightly violet precipitate of compound (1). The precipitate was directed to acylation without further purification.To the precipitate it was added toluene 700 ml, and acetic anhydride 400 ml (3.5 eq), and a catalytic amount of sulfuric acid. After 1 h at 50° C., the solution was cooled and excess anhydride was decomposed with water at 25° C. Phases were separated, rinsed with water and brine. Organic layer was concentrated in vacuo to obtain orange precipitate. After recrystallization from methanol 230 g of white precipitate was obtained. Yield after two steps 77%.1H NMR (500 MHz, CDCl3) δ 7.85-7.79; (m, 1H), 7.78-7.73; (m, 1H), 7.50; (dddd, 2H), 7.15; (s, 1H), 2.48; (s, 3H), 2.46; (s, 3H), 2.33; (s, 3H),13C NMR (126 MHz, CDCl3) δ 169.39, 168.86, 144.11, 142.13, 127.90, 127.08, 126.49, 126.16, 126.02, 121.46, 121.16, 120.71, 20.99, 20.58, 16.50.

  • 5
  • [ 481-85-6 ]
  • [ 106-95-6 ]
  • [ 690229-66-4 ]
YieldReaction ConditionsOperation in experiment
82% With 18-crown-6 ether; potassium carbonate In acetone at 20℃; for 24h; 8 Diallyl-menadiol (12) K2C03( 61.8 g, 446.9 mM), l8-Crown-6 ether (0.1 g) and allyl bromide (11.7 mL, 132.2 mM) were added to the solution of menadiol (9.73 g, 55.9 mM) in acetone (195 mL). The suspension was stirred for 24 h at RT. K2C03was filtered off and the filtrate was concentrated under the reduced pressure. The residue was dissolved in DCM (300 mL), and washed with water (150 mL). The organic phase was concentrated and purified by column chromatography (hexane/ethyl acetate 95:5- > 90:10) to obtain an oily product M2 (11.45 g, 82%).JH NMR (CDCl3, 500 MHz) d 8.25 (d, J = 5 Hz, 1H), 8.01 (d, J = 5 Hz, 1H), 7.51-7.48 (m, 1H), 7.44-7.40 (m, 1H), 6.62 (s, 1H), 6.23-6.14 (m, 2H, -CH=CR2), 5.53-5.48 (m, 2H, -CH=C), 5.34-5.29 (m, 2H, -CH=G%), 4.68-4.67 (m, 2H, -0-C//2-CH=CH2), 4.45-4.44 (m, 2H, -0-Ctf2-CH=CH2), 2.43 (s, 3H, C).13C NMR (CDCls, 125 MHz) 6 150.4, 145.9, 134.2, 133.4, 128.9, 126.4, 125.8, 125.3, 124.5, 122.3, 121.5, 117.3, 117.2. 108.1, 74.5, 69.1, 16.5.HR-MS (ESI) calc, for Ci7Hl802(M+H)+: 254.1307. Found: 254.1312.
With sodium dithionite; potassium carbonate; acetone
  • 6
  • [ 481-85-6 ]
  • [ 77-78-1 ]
  • [ 53772-19-3 ]
YieldReaction ConditionsOperation in experiment
98% With sodium methylate In methanol; isopropyl alcohol at 63℃; for 0.5h;
87% With potassium carbonate In acetone for 2h; Reflux; 1.2 Step 2 - 1,4-dimethoxy-2-methylnaphthalene (3) To a 250 mL solution of 2-methyl-naphthalene-1,4-diol (2) (20 g, 0.115 mol) in acetone was sequentially added K2CO3 (72 g, 0.575 mol) and dimethylsulfate (79 g, 0.575 mol). The resulting orange colored reaction mixture was refluxed for 2 h at which time TLC indicated the completion of the reaction. The reaction mixture was filtered and the filtrate was treated with 1N NaOH solution. The organic layer was separated and washed with brine before drying over Na2SO4. Solvent was removed under reduced pressure to provide crude 1,4-dimethoxy-2-methylnaphthalene (3). The residue was purified by column (0214) chromatography on silica gel (eluent: PE) to give 1,4-dimethoxy-2-methylnaphthalene (3) (20 g, 87%) as a yellow oil.1H NMR (400 MHz, CDCl3): d 8.15 (d, 1H), 8.03 (d, 1H), 7.50 (m, 1H), 7.49 (m, 1H), 6.61 (s, 1H), 3.97 (s, 3H), 3.87 (s, 3H), 2.46 (s, 3H).
85% With potassium carbonate In acetone for 6h; Reflux; 2 Example 2.Synthesis of 1,4-Dimethoxy-2-methyl-naphthalene Example 2. Synthesis of 1,4-Dimethoxy-2-methyl-naphthalene To a 50 ml solution of 2-Methyl-naphthalene-1,4-diol (3.8 g, 0.022 mol) in acetone was sequentially added K2CO3 (15.20 g, 0.11 mol) and dimethylsulfate (10.43 ml, 0.110 mol). The resulting orange colored reaction mixture was refluxed for 6h at which time TLC indicated the completion of the reaction. The reaction mixture was the filtered and the filtrate was treated with 1N NaOH solution to adjust the pH to 5 or 6. The organic layer was separated and washed with brine before drying over Na2SO4. Solvent was removed under reduced pressure to provide a thick oil (3.7 g, 85%) which eventually solidified at lower temperature. 1H NMR(400 MHz, CDCl3):8.17-8.19 (d, 1H, J = 8.24 Hz), 8.00-8.02 (d, 1H, J = 8.24 Hz), 7.50-7.41 (t, 1H, J = 8.24 Hz), 6.59 (s, 1 H), 3.85 (s, 3H), 2.44 (s, 3H), 1.42 (s, 3H).
85% With potassium carbonate In acetone for 6h; Reflux; 2 Synthesis of 1,4-Dimethoxy-2-methyl-naphthalene Example 2 Synthesis of 1,4-Dimethoxy-2-methyl-naphthalene To a 50 ml solution of 2-Methyl-naphthalene-1,4-diol (3.8 g, 0.022 mol) in acetone was sequentially added K2CO3 (15.20 g, 0.11 mol) and dimethylsulfate (10.43 ml, 0.110 mol). The resulting orange colored reaction mixture was refluxed for 6 h at which time TLC indicated the completion of the reaction. The reaction mixture was the filtered and the filtrate was treated with 1N NaOH solution to adjust the pH to 5 or 6. The organic layer was separated and washed with brine before drying over Na2SO4. Solvent was removed under reduced pressure to provide a thick oil (3.7 g, 85%) which eventually solidified at lower temperature. 1H NMR (400 MHz, CDCl3): 8.17-8.19 (d, 1H, J=8.24 Hz), 8.00-8.02 (d, 1H, J=8.24 Hz), 7.50-7.41 (t, 1H, J=8.24 Hz), 6.59 (s, 1H), 3.85 (s, 3H), 2.44 (s, 3H), 1.42 (s, 3H).
77% With sodium methylate In methanol; isopropyl alcohol at 60 - 65℃; for 1h; Inert atmosphere;
76% With potassium hydroxide In tetrahydrofuran; water Flow reactor;
With sodium hydroxide
With potassium hydroxide
With potassium hydroxide
With potassium carbonate In acetone at 20℃; for 2.5h;
5.0 g With potassium carbonate In acetone for 4h; Heating;
With sodium hydroxide In methanol
1.49 g Stage #1: 2-methyl-1,4-naphthohydroquinone With sodium hydride In tetrahydrofuran at 0℃; Inert atmosphere; Stage #2: dimethyl sulfate In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
12.6 g With potassium carbonate In acetone for 4h; Reflux;
9.35 g With potassium carbonate In acetone for 6h; Reflux;
With potassium carbonate In acetone for 6h; Heating;
With potassium hydroxide In methanol; acetone at 60℃; Inert atmosphere;

References: [1]Ito, Tatsuya; Ikemoto, Tomomi; Yamano, Toru; Mizuno, Yukio; Tomimatsu, Kiminori [Tetrahedron Asymmetry, 2003, vol. 14, # 22, p. 3525 - 3531].
[2]Current Patent Assignee: PTC THERAPEUTICS - WO2020/252414, 2020, A1 Location in patent: Paragraph 00126.
[3]Current Patent Assignee: MEHTA DILIP S - EP2868658, 2015, A1 Location in patent: Paragraph 0053-0054.
[4]Current Patent Assignee: MEHTA DILIP S - US2015/126763, 2015, A1 Location in patent: Paragraph 0149-0150.
[5]Patel, Jignesh J.; Laars, Marju; Gan, Wei; Board, Johnathan; Kitching, Matthew O.; Snieckus, Victor [Angewandte Chemie - International Edition, 2018, vol. 57, # 30, p. 9425 - 9429][Angew. Chem., 2018, vol. 130, # 30, p. 9569 - 9573,5].
[6]Miyamura, Hiroyuki; Tobita, Fumiya; Suzuki, Aya; Kobayashi, Shū [Angewandte Chemie - International Edition, 2019, vol. 58, # 27, p. 9220 - 9224][Angew. Chem., 2019, vol. 131, p. 9318 - 9322,5].
[7]Smith; Wawzonek; Miller [Journal of Organic Chemistry, 1941, vol. 6, p. 229,232] Ansbacher; Fernholz; Dolliver [Journal of the American Chemical Society, 1940, vol. 62, p. 155,156] Giral [Anales de la Real Sociedad Espanola de Fisica y Quimica, 1933, vol. 31, p. 861,878].
[8]Smith; Wawzonek; Miller [Journal of Organic Chemistry, 1941, vol. 6, p. 229,232] Ansbacher; Fernholz; Dolliver [Journal of the American Chemical Society, 1940, vol. 62, p. 155,156] Giral [Anales de la Real Sociedad Espanola de Fisica y Quimica, 1933, vol. 31, p. 861,878].
[9]Smith; Wawzonek; Miller [Journal of Organic Chemistry, 1941, vol. 6, p. 229,232] Ansbacher; Fernholz; Dolliver [Journal of the American Chemical Society, 1940, vol. 62, p. 155,156] Giral [Anales de la Real Sociedad Espanola de Fisica y Quimica, 1933, vol. 31, p. 861,878].
[10]Tomatsu, Ayumi; Takemura, Syunji; Hashimoto, Kimiko; Nakata, Masaya [Synlett, 1999, # 9, p. 1474 - 1476].
[11]Van Tuyen, Nguyen; Kesteleyn, Bart; De Kimpe, Norbert [Tetrahedron, 2002, vol. 58, # 1, p. 121 - 127].
[12]Jung, Young-Sik; Joe, Bo-Young; Cho, Sung Ju; Konishi, Yasuo [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 4, p. 1125 - 1129].
[13]Location in patent: experimental part Nyland II, Rodney L.; Luo, Meihua; Kelley, Mark R.; Borch, Richard F. [Journal of Medicinal Chemistry, 2010, vol. 53, # 3, p. 1200 - 1210].
[14]Location in patent: experimental part Cui, Xing-Ri; Saito, Ryota; Kubo, Takatsugu; Kon, Daijiro; Hirano, Yuich; Saito, Setsuo [Chemical and Pharmaceutical Bulletin, 2011, vol. 59, # 3, p. 302 - 314].
[15]Baj, Aneta; Wałejko, Piotr; Kutner, Andrzej; Kaczmarek, Łukasz; Morzycki, Jacek W.; Witkowski, Stanisław [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1026 - 1033] Baj, Aneta; Wałejko, Piotr; Kutner, Andrzej; Kaczmarek, Lłukasz; Morzycki, Jacek W; Witkowski, Stanislław [Organic Process Research and Development, 2016, vol. 20, # 6, p. 1026 - 1033].
[16]Smets, Robert J.; Torfs, Eveline; Lemière, Filip; Cos, Paul; Cappoen, Davie; Abbaspour Tehrani, Kourosch [Organic and Biomolecular Chemistry, 2019, vol. 17, # 11, p. 2923 - 2939].
[17]Cichocki, Bogdan Adam; Khobragade, Vrushali; Donzel, Maxime; Cotos, Leandro; Blandin, Stephanie; Schaeffer-Reiss, Christine; Cianférani, Sarah; Strub, Jean-Marc; Elhabiri, Mourad; Davioud-Charvet, Elisabeth [Journal of the American Chemical Society, 2021, vol. 1, # 5, p. 669 - 689].
  • 7
  • [ 481-85-6 ]
  • [ 13190-97-1 ]
  • [ 523-39-7 ]
YieldReaction ConditionsOperation in experiment
(i) ZnCl2, BF3-Et2O, (ii) Ag2O; Multistep reaction;
  • 8
  • [ 481-85-6 ]
  • [ 74-88-4 ]
  • [ 53772-19-3 ]
YieldReaction ConditionsOperation in experiment
85% With potassium carbonate In acetone at 40℃; for 12h; Inert atmosphere;
74% Stage #1: 2-methyl-1,4-naphthohydroquinone With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 0.0333333h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 90℃; for 0.5h; Step 2; Methylation of 2-Methylnaphthalene-1,4-Diol to 1,4-Dimethoxy-2- Methyl naphthalene (Methyl Protected Menadiol - RLS3): To a solution of Menadiol (.5 g, 2.87 mmol) in DMF (10 mL) heated to 90SC was added potassium carbonate (2.56 g, 18.5 mmol). After being stirred at 90SC for 2 minutes, methyl iodide (1 .4 mL, 11 .5 mmol) was added to the Menadiol solution. Heat was maintained at 90SC for 30 minutes and confirmed absence of starting material with TLC. The mixture was added to a separatory funnel with 1M HCI and then extracted with EtOAc. The combined organic layers were dried with MgS04 and filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica gel (eluted with EtOAc/Hexane = 1 :20) to afford Methyl Protected Menadiol (429 mg, 2.1 mmol, 74%) as a red oil. The product was confirmed on NMR and MS and carried forward.
1.18 g With sodium hydride In N,N-dimethyl-formamide; mineral oil at -10℃; for 2h;
  • 9
  • [ 924-50-5 ]
  • [ 481-85-6 ]
  • [ 1631958-79-6 ]
YieldReaction ConditionsOperation in experiment
35% With methanesulfonic acid at 70℃; for 2h; 4.1 Synthesis of 6-hydroxy-4,4,5-trimethyl-3,4-dihydro-2H-benzo[h]chromen-2-one Example 4 Synthesis of 4-(nitrooxy)butyl 3-methyl-3-(3-methyl-l,4-dioxo-l,4- dihydronaphthalen-2-yl)butanoate (Compound 4) Methanesulfonic acid (30 mL) was heated at 70°C. In parallel, 2- methylnaphthalene-l,4-diol (4.75 g, 25.0 mmol) and methyl 3-methylbut-2-enoate (2.85 g, 25.0 mmol, 1 eq) were added quickly and the reaction was heated for 2 h at this temperature. The reaction was then poured in water and, after cooling, was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed successively with water, saturated NaHC03, water and brine, dried (Na2S04), filtered and evaporated. The residue was purified flash chromatography (Biotage System, 2 SNAP Cartridge silica 100 g, eluent: n-hexane/ethyl acetate 90/10 to n-hexane/ethyl acetate 70/30 during 10 CV) affording the title compound as a pale yellowish solid (2.26 g, Yield: 35%). 1H NMR (300 MHz, CDC13) δ 7.90 (d, J = 8.3, 2H), 7.45 (d, J = 8.0, 2H), 3.88 - 3.67 (m, 2H), 2.45 (s, 3H), 1.56 (s, 6H).
35% With methanesulfonic acid at 70℃; for 2h; 4.1 Synthesis of 6-hydroxy-4,4,5-trimethyl-3,4-dihydro-2H-benzo[h]chromen-2-one Example 4 Synthesis of 4-(nitrooxy)butyl 3-methyl-3-(3-methyl-l,4-dioxo-l,4- dihydronaphthalen-2-yl)butanoate (Compound 4) Methanesulfonic acid (30 mL) was heated at 70°C. In parallel, 2- methylnaphthalene-l,4-diol (4.75 g, 25.0 mmol) and methyl 3-methylbut-2-enoate (2.85 g, 25.0 mmol, 1 eq) were added quickly and the reaction was heated for 2 h at this temperature. The reaction was then poured in water and, after cooling, was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed successively with water, saturated NaHC03, water and brine, dried (Na2S04), filtered and evaporated. The residue was purified flash chromatography (Biotage System, 2 SNAP Cartridge silica 100 g, eluent: n-hexane/ethyl acetate 90/10 to n-hexane/ethyl acetate 70/30 during 10 CV) affording the title compound as a pale yellowish solid (2.26 g, Yield: 35%). 1H NMR (300 MHz, CDC13) δ 7.90 (d, J = 8.3, 2H), 7.45 (d, J = 8.0, 2H), 3.88 - 3.67 (m, 2H), 2.45 (s, 3H), 1.56 (s, 6H).
20% With methanesulfonic acid at 85℃; for 4h; Inert atmosphere; 4.1.2. General procedure for the preparation of compounds 24-25 General procedure: Hydroquinone (22-23, 14.7 mmol) was mixed with 3,3-dimethylacrylic acid methyl ester (1.9 g, 16.2 mmol) and methanesulfonic acid (50 mL). The mixture was stirred at 85° Cunder nitrogen for 4 h and then cooled to room temperature. To themixture was added 100 g of ice with stirring. The reaction mixturewas extracted with EtOAc (3 x 100 mL). The combined organic layerwas washed with saturated NaHCO3 (3 x 100 mL) and water(3 x 100 mL) and dried over Na2SO4. After filtration and evaporation,the crude product (24-25) was obtained which was purifiedthrough column chromatography over silica gel. 4.1.2.1. 6-hydroxy-4,4,5-trimethyl-3,4-dihydro-2H-benzo[h]chromen-2-one (24). Following the above procedure, the crude productwas purified by column chromatography (eluent: Petroleum ether/EtOAc 25:1) to afford 24 as a white solid (753.5 mg, 20%). m.p.167.0-168.0 °C. 1H NMR (300 MHz, DMSO) ν 10.22 (s, 1H), 9.09 (d,J= 9.7 Hz, 1H), 8.28 (d, J =9.9 Hz, 1H), 7.61-7.53 (m, 2H), 3.39-3.28(m, 2H), 2.62 (s, 3H), 1.52 (s, 6H).
  • 10
  • [ 481-85-6 ]
  • [ 2124-57-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 11 steps 1.1: potassium carbonate / acetone / 6 h / Reflux 2.1: titanium tetrachloride / dichloromethane / 2.17 h / -45 - 0 °C / Inert atmosphere 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.5 h / 0 °C 3.2: 2.25 h / 0 °C 3.3: 0.67 h / Reflux 4.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere 4.2: 14 h / Inert atmosphere 5.1: diisobutylaluminium hydride / tetrahydrofuran / 6 h / Inert atmosphere 6.1: dipyridinium dichromate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 7.1: iodine / chloroform / 6 h / 20 °C 8.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 8.2: 12 h / Inert atmosphere 9.1: Dess-Martin periodane; water / dichloromethane; acetonitrile / 20 °C 10.1: hydrazine; potassium hydroxide / diethylene glycol / 4 h / 60 - 215 °C / Inert atmosphere; Reflux 11.1: ammonium cerium (IV) nitrate / water; acetonitrile / 4.08 h / 20 °C
Multi-step reaction with 11 steps 1.1: potassium carbonate / acetone / 6 h / Reflux 2.1: titanium tetrachloride / dichloromethane / 2.17 h / -45 - 0 °C / Inert atmosphere 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.5 h / 0 °C 3.2: 2.25 h / 0 °C 3.3: 0.67 h / Reflux 4.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere 4.2: 14 h / Inert atmosphere 5.1: diisobutylaluminium hydride / tetrahydrofuran / 6 h / Inert atmosphere 6.1: dipyridinium dichromate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 7.1: iodine / chloroform / 6 h / 20 °C 8.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 8.2: 12 h / Inert atmosphere 9.1: Dess-Martin periodane; water / dichloromethane; acetonitrile / 20 °C 10.1: hydrazine; potassium hydroxide / diethylene glycol / 4 h / 60 - 215 °C / Inert atmosphere; Reflux 11.1: ammonium cerium (IV) nitrate / acetonitrile / 4.08 h / 20 °C
Multi-step reaction with 5 steps 1: potassium carbonate / acetone / 6 h / Reflux 2: tin(IV) chloride / 1,2-dichloro-ethane / 20 - 80 °C 3: potassium <i>tert</i>-butylate / tetrahydrofuran; N,N-dimethyl-formamide / -20 °C 4: (1,2-bis(diphenylphosphanyl)ethane)dichloridopalladium(II); lithium triethylborohydride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 5: ammonium cerium (IV) nitrate / water; acetonitrile / 0.75 h / 0 °C
Multi-step reaction with 5 steps 1: potassium carbonate / acetone / 6 h / Reflux 2: tin(IV) chloride / 1,2-dichloro-ethane / 5 h / 80 °C 3: potassium <i>tert</i>-butylate / tetrahydrofuran; N,N-dimethyl-formamide / 1 h / -20 °C 4: (1,2-bis(diphenylphosphanyl)ethane)dichloridopalladium(II); lithium triethylborohydride / tetrahydrofuran / 4 h / 0 °C / Inert atmosphere 5: ammonium cerium (IV) nitrate / water; acetonitrile; dichloromethane / 0.75 h / 0 °C
Multi-step reaction with 5 steps 1: potassium carbonate; 18-crown-6 ether / acetone / 24 h / 20 °C 2: indium(III) chloride; sodium carbonate / dichloromethane / 6 h / 0 - 20 °C 3: sodium hexamethyldisilazane / tetrahydrofuran; N,N-dimethyl-formamide / 2 h / -20 °C / Inert atmosphere 4: disodium hydrogenphosphate; sodium amalgam / tetrahydrofuran / 2 h / 20 °C / Inert atmosphere 5: ammonium cerium (IV) nitrate / water; dichloromethane; acetonitrile / 1 h / 0 °C
Multi-step reaction with 5 steps 1: potassium carbonate; 18-crown-6 ether / acetone / 24 h / 20 °C 2: indium(III) chloride; sodium carbonate / dichloromethane / 6 h / 0 - 20 °C 3: sodium hexamethyldisilazane / tetrahydrofuran; N,N-dimethyl-formamide / 2 h / -20 °C / Inert atmosphere 4: disodium hydrogenphosphate; sodium amalgam / tetrahydrofuran / 7 h / 20 °C / Inert atmosphere 5: ammonium cerium (IV) nitrate / water; dichloromethane; acetonitrile / 1 h / 0 °C
Multi-step reaction with 6 steps 1.1: triethylamine; tetrabutylammomium bromide; dmap / tetrahydrofuran / 20 °C 2.1: N-Bromosuccinimide / dichloromethane 3.1: magnesium / tetrahydrofuran / 1 h / 5 - 10 °C 3.2: 2 h 4.1: tetrabutylammomium bromide; 18-crown-6 ether / tetrahydrofuran; N,N-dimethyl-formamide / 5 min / -5 - 0 °C / Inert atmosphere 4.2: 2.5 h / -5 - 0 °C / Inert atmosphere 5.1: bis(diphenylphosphino)propanepalladium(II) dichloride; lithium triethylborohydride / tetrahydrofuran / -5 - 20 °C 6.1: chromium(VI) oxide; periodic acid / acetonitrile / -5 - 0 °C

  • 11
  • [ 481-85-6 ]
  • [ 46492-08-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: potassium carbonate / acetone / 6 h / Heating 2: bromine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 3: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / ethyl acetate / Inert atmosphere 4: sodium hydride / dimethyl sulfoxide 5: palladium diacetate; dicyclohexyl(1,1-dimethylethyl)phosphonium tetrafluoroborate; caesium carbonate / N,N-dimethyl-formamide / 22.5 h / 130 °C / Inert atmosphere
Multi-step reaction with 6 steps 1: potassium carbonate / acetone / 6 h / Heating 2: bromine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 3: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / ethyl acetate / Inert atmosphere 4: sodium hydride / dimethyl sulfoxide 5: palladium diacetate; dicyclohexyl(1,1-dimethylethyl)phosphonium tetrafluoroborate; caesium carbonate / N,N-dimethyl-formamide / 22.5 h / 130 °C / Inert atmosphere 6: ammonium cerium (IV) nitrate / water; acetonitrile / 1 h / 0 °C
Multi-step reaction with 7 steps 1: potassium carbonate / acetone / 6 h / Heating 2: bromine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 3: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / ethyl acetate / Inert atmosphere 4: sodium hydride / dimethyl sulfoxide 5: potassium carbonate / N,N-dimethyl-formamide / 16 h / 130 °C / Inert atmosphere 6: sodium hydroxide / water; methanol / 8 h / Reflux 7: ammonium cerium (IV) nitrate / water; acetonitrile / 1 h / 0 °C
Multi-step reaction with 7 steps 1: potassium carbonate / acetone / 6 h / Heating 2: bromine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 3: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / ethyl acetate / Inert atmosphere 4: sodium hydride / dimethyl sulfoxide 5: palladium diacetate; dicyclohexyl(1,1-dimethylethyl)phosphonium tetrafluoroborate; caesium carbonate / N,N-dimethyl-formamide / 16.5 h / 130 °C / Inert atmosphere 6: sodium hydroxide / water; methanol / 8 h / Reflux 7: ammonium cerium (IV) nitrate / water; acetonitrile / 1 h / 0 °C

  • 12
  • [ 481-85-6 ]
  • [ 1256836-63-1 ]
  • [ 2568482-66-4 ]
YieldReaction ConditionsOperation in experiment
43% With toluene-4-sulfonic acid In tetrahydrofuran at 80℃; for 16h; Inert atmosphere; 145 Example 145 - 2-((5-methoxy-4-(trifluoromethyl)pyridin-2-yl)methyl)-3- methylnaphthalene-1,4-dione To the mixture of 5-methoxy-4-(trifluoromethyl)picolinaldehyde (50)(prepared as described in Scheme 15, compound 45)(0.30 g, 1.7 mmol, 1.0 eq) in tetrahydrofuran (5 mL) was added 2-methylnaphthalene-1,4-diol (0.35 g, 1.7 mmol, 1.0 eq) and p-toluenesulfonic acid (0.33 g, 1.7 mmol, 1.0 eq). The mixture was degassed with nitrogen three times, warmed to 80 oC and stirred for 16 h. LCMS analysis of the reaction mixture showed full conversion to the desired product. The reaction mixture was concentrated under reduced pressure. The residue was triturated with ethanol (2 mL). The precipitated solid was filtered. The filter cake was dried under reduced pressure to afford 2-((5-methoxy-4-(trifluoromethyl)pyridin-2- yl)methyl)-3-methylnaphthalene-1,4-dione (Example 145)(269.1 mg, 43%) as yellow solid. 1H NMR (CDCl3, 400 MHz): d 8.27 (s, 1H), 8.07 (t, J = 8.0 Hz, 2H), 7.72- 7.65 (m, 2H), 7.42 (s, 1H), 4.17 (s, 2H), 3.93 (s, 3H), 2.27 (s, 3H). MS (m/z) for C19H14F3NO3: found 362.3 (M+H).
  • 13
  • [ 481-85-6 ]
  • [ 1113-21-9 ]
  • [ 863-61-6 ]
YieldReaction ConditionsOperation in experiment
4.5 g With boron trifluoride diethyl ether complex In ethyl acetate at 20 - 60℃; for 3h; Inert atmosphere; 1-3 Example 1 5g (29mmol) menadione was added to 50ml EA (ethyl acetate),Then add 6g (34.5mmol) sodium hydrosulfite (sodium hydrosulfite),Add 1.3 g (72.2 mmol) of purified water with a syringe under nitrogen protection,React overnight (about 10 hours) at room temperature.When the reaction solution completely turned into milky white turbidity,Under nitrogen protection, 5.2 g (36.6 mmol) of boron trifluoride diethyl ether was added dropwise,heated to 60 degrees Celsius,Slowly add 10.4g (35.8mmol) geranyllinalool dropwise,The temperature-controlled reaction was performed for 3 hours.Take the reaction solution and send it to liquid phase detection,The HPLC detection results are shown in Figure 2.Wherein the main impurity is unreacted menaquinone, which can be recovered by purification means.After the reaction is over,The reaction solution can be poured into water to flush,It was extracted twice with ethyl acetate, backwashed with saturated brine, dried over sodium sulfate, concentrated to dryness, added with silica gel and mixed with sample and purified by column, eluent ethyl acetate: petroleum ether=1:10, v/v. After purification, 4.5 g of product was obtained, the total yield was 35%, and the purity was 99%.
 

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