CN113308704B - Electrooxidation preparation method of naproxen intermediate - Google Patents
Electrooxidation preparation method of naproxen intermediate Download PDFInfo
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Abstract
The invention relates to 6-methoxy-2-naphthyl ethanone shown in formula IThe electrooxidation preparation method of acid ester is characterized in that the preparation reaction is as follows:
Description
Technical Field
The invention relates to a preparation method of a compound, in particular to a novel electrooxidation preparation method of a key intermediate of naproxen, namely 6-methoxy-2-naphthyl acetate.
Background
Larionov et al [ chem.Sci.,2020,11,9101.]Selecting 2-bromo-6-methoxynaphthalene to react with Mg to generate Grignard reagent, then reacting with chloroethanedioic acid monoethyl ester to prepare 6-methoxy-2-naphthaleneacetic acid ethyl ester, and then reacting with BMe3And P (OMe)3And finally, hydrolyzing under the action of LiOH to prepare the non-steroidal anti-inflammatory drug naproxen.
The preparation method of 6-methoxy-2-naphthyl acetate is less reported, and the preparation method is summarized as follows:
kazuhiko et al [ Tetrahedron: Asymmetry,2005,16, 3807-.
The preparation and reaction of the Grignard reagent of 2-bromo-6-methoxynaphthalene are required to be carried out under absolute anhydrous and anaerobic conditions, and ultralow temperature (-78 ℃) is required for reaction; the industrial production is difficult.
Kozlowski et al [ org.Lett.2012,14, 760-); j.org.chem.2013,78, 717. 722 ] selecting 2-bromo-6-methoxynaphthalene to prepare 6-methoxy-2-naphthoic acid ethyl ester through an intermediate, namely 2- (6-methoxynaphthyl) -2-nitroacetic acid ethyl ester under the action of TBAF, wherein the yield is 70%.
The reagent and the catalyst used for preparing the 2- (6-methoxy naphthyl) -2-ethyl nitroacetate are expensive and the reaction condition is harsh; the preparation of the ethyl 6-methoxy-2-naphthaleneacetate from the ethyl 2- (6-methoxynaphthyl) -2-nitroacetate adopts a fluorine compound, and laboratory experiments need to be carried out in a glove box.
Disclosure of Invention
The invention aims to provide a 6-methoxy-2-naphthyl acetate electrooxidation preparation method shown in a chemical structural formula I, which is characterized by comprising the following preparation reactions:
r is selected from: methyl, ethyl, C3-C4 straight chain alkyl or C3-C4 branched chain alkyl;
it is a further object of the present invention to provide 6-methoxy-2-naphthaleneacetic acid esters of the formula I preferably:
the electrooxidation preparation method is that an anode working electrode and a cathode are arranged in a non-diaphragm type electrolytic tank, and 6-methoxy-2-naphthylacetic ester, phthalimide derivatives, organic solvent, alkali and electrolyte are taken as electrolyte; electrolyzing for a certain time at a constant current at a certain temperature, and carrying out electrooxidation reaction to obtain the 6-methoxy-2-naphthyl acetate.
The anodic working electrode of the cell is selected from: carbon felt electrodes, platinum mesh electrodes or graphite electrodes; preferably: a carbon felt electrode; the anodic working electrode current density is selected from: 5mA/cm2～20mA/cm2(ii) a The cathode of the cell is selected from: platinum mesh or nickel foam; preferably: a platinum mesh.
The constant current is selected from: 10 mA-40 mA;
the electrolysis temperature is selected from: 15-65 ℃;
the electrolysis time is selected from: 4 h-10 h;
the organic solvent in the electrolyte is selected from: any one or more of acetonitrile, ethyl acetate, tetrahydrofuran or dioxane; preferably: and (3) acetonitrile.
The base is selected from: pyridine, 2, 6-lutidine or 4-dimethylaminopyridine; preferably: pyridine, 2, 6-lutidine.
The phthalimide derivative is selected from: n-hydroxyphthalimide, N-hydroxy-4-bromophthalimide, N-hydroxy-4-chlorophthalimide, N-hydroxy-4, 5-dichlorophthalimide or N-hydroxytetrachlorophthalimide; preferably: n-hydroxyphthalimide; the concentration of the phthalimide derivative is selected from: 0.01mol/L to 0.1 mol/L.
The electrolyte is selected from: n-Bu4NPF6、LiClO4Tetrabutylammonium perchlorate or tetrabutylammonium tetrafluoroborate; the electrolyte concentration is selected from: 0.02 mol/L-0.1 mol/L; preferably: tetrabutylammonium perchlorate.
Preferably, the concentration of 6-methoxy-2-naphthaleneacetic acid ester in the electrolyte is selected from: 8g/L to 40 g/L.
Further preferably, the preparation method of the electrolyte comprises the following steps: dissolving 6-methoxy-2-naphthylacetic ester in an organic solvent and water to obtain an organic solution, and mixing the organic solution with the N-hydroxyphthalimide and the pyridine according to a molar ratio of 1:1 to obtain a mixed solution.
The second aspect of the present invention provides a novel process for the preparation of naproxen of formula II, characterized in that it is prepared by the following reaction:
r is selected from: methyl, ethyl, C3-C4 straight chain alkyl or C3-C4 branched chain alkyl.
The beneficial technical effects of the invention are as follows:
(1) no toxic or dangerous oxidant is needed in the oxidation reaction, and the 'electron' is a clean reaction reagent and is an important component for developing the 'green pharmaceutical industry'.
(2) During the electro-oxidation process, the conversion rate and selectivity can be controlled by changing the constant current density; thereby obtaining the intermediate with high purity and high yield.
(3) In industrial production, the process flow is simplified, the production cost is reduced, and the method is safe and environment-friendly and is suitable for large-scale popularization and application.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1
Electrooxidation preparation of methyl 6-methoxy-2-naphthaleneacetonate
The anode of the electrolytic cell is carbon felt (10X 2 mm)3) The cathode is a platinum mesh (10 multiplied by 2 mm)3) (ii) a Adding a magnetic stirrer into an electrolytic bath, adding 115mg (0.5mmol) of 6-methoxy-2-naphthylacetic acid methyl ester, 163m g (1.0mmol) of N-hydroxyphthalimide and 342mg (1mmol) of tetrabutylammonium perchlorate, adding 10mL of acetonitrile and 2mL of water for dissolving, adding 80mg (1mmol) of pyridine, electrolyzing at 20 ℃ under constant current of 10mA for 8h, carrying out rotary evaporation on the reaction solution, dissolving ethyl acetate, washing for three times, drying an organic layer by using anhydrous sodium sulfate, and carrying out rotary evaporation to obtain 110mg of 6-methoxy-2-naphthylacetic acid methyl ester; the yield is 90 percent;1HNMR(400MHz，CDCl3) δ: 8.51-7.19 (m, 6H, naphthalene ring), 4.05(s, 3H, OCH)3)，3.99(s，3H，COOCH3)。
Example 2
Electrooxidation preparation of 6-methoxy-2-ethyl naphthaleneacetate
The anode of the electrolytic cell is carbon felt (10X 2 mm)3) The cathode is a platinum net (10 function)10×2mm3) (ii) a Adding a magnetic stirrer into an electrolytic bath, adding 122mg (0.5mmol) of 6-methoxy-2-naphthyl acetic ether, 163mg (1.0mmol) of N-hydroxyphthalimide and 342mg (1mmol) of tetrabutylammonium perchlorate, adding 10mL of acetonitrile and 2mL of water for dissolving, adding 80mg (1mmol) of pyridine, electrolyzing at 50 ℃ under constant current of 10mA for 4h, carrying out rotary evaporation on the reaction solution, dissolving ethyl acetate, washing for three times, drying an organic layer by using anhydrous sodium sulfate, and carrying out rotary evaporation to obtain 117mg of 6-methoxy-2-naphthyl acetic acid ethyl ester; the yield is 91%;1H NMR(400MHz，CDCl3) δ: 8.51 to 7.18(m, 6H, naphthalene ring), 4.47(q, J ═ 7.2Hz, 2H, OCH)2)，4.05(s，3H，OCH3)，1.45(t，J＝7.2Hz，3H，CH3)。
Example 3
Electrooxidation preparation of methyl 6-methoxy-2-naphthaleneacetonate
The anode of the electrolytic cell is carbon felt (10X 2 mm)3) The cathode is a platinum mesh (10 multiplied by 2 mm)3) Adding a magnetic stirrer into the tank; 0.5mmol (0.122g) of methyl 6-methoxy-2-naphthaleneacetate, 1.0mmol (0.163g) of 0.15mmol of 2, 6-dimethylpyridine N-hydroxyphthalimide and 1mmol (0.342g) of tetrabutylammonium perchlorate are added into an electrolytic bath, 9.5mL of acetonitrile and 0.5mL of water are dissolved, 5mA electrolysis is carried out at a constant current under an oxygen atmosphere at 60 ℃, the reaction is stopped when the bath voltage reaches 3.0V, the reaction solution is dried by reduced pressure distillation, ethyl acetate is dissolved and washed for three times, and the organic layer is dried by anhydrous sodium sulfate to obtain 0.111g of methyl 6-methoxy-2-naphthaleneacetate; the yield is 86%;1H NMR(400MHz，CDCl3) δ: 8.51-7.18 (m, 6H, naphthalene ring), 4.05(s, 3H, OCH)3)，3.99(s，3H，COOCH3)。
Example 4
Electrooxidation preparation of 6-methoxy-2-ethyl naphthaleneacetate
The anode of the electrolytic cell is carbon felt (10X 2 mm)3) The cathode is a platinum mesh (10 multiplied by 2 mm)3) Adding a magnetic stirrer into the tank; 0.5mmol (0.129g) of 6-methoxy-2-naphthyl ethyl acetate, 1.0mmol (0.163g) of N-hydroxyphthalimide, 0.15mmol of 2, 6-dimethylpyridine and 1mmol (0.342g) of tetrabutylammonium perchlorate are added into an electrolytic bath, 9.5mL of acetonitrile and 0.5mL of water are dissolved, 5mA electrolysis is carried out at a constant current under an oxygen atmosphere at 60 ℃, the reaction is stopped when the bath voltage reaches 3.0V, the reaction solution is dried by reduced pressure distillation, ethyl acetate is dissolved and washed for three times, and an organic layer is dried by anhydrous sodium sulfate to obtain 0.117g of 6-methoxy-2-naphthyl ethyl acetate; the yield is 86%;1H NMR(400MHz，CDCl3) δ: 8.46 to 7.14(m, 6H, naphthalene ring), 4.49(q, J ═ 7.0Hz, 2H, COOCH2)，3.94(s，3H，OCH3)，1.45(t，J＝7.0Hz，3H，CH3)。
Example 5 (control experiment 1)
Preparation of 6-methoxy-2-ethyl naphthaleneacetonate
763 according to the document [ org.Lett.2012,14, 760-)]The preparation method comprises the following steps: in a glove box, 9.8mg (9.5. mu. mol) Pd was added to a dry microwave bottle2(dba)3·CHCl316.1mg t-BuXPhos (38. mu. mol) and 88.0mg (0.427mmol) caesium bicarbonate; 0.48mL of ethyl nitroacetate in toluene (0.38mmol,0.8M, oftouene) and an additional 1.42mL of toluene were then added, removed from the glove box, and 134.0mg (0.570mmol) of 2-bromo-6-methoxynaphthalene was added via syringe and stirred at 80 ℃ for 18 h. Cooling 1mL ethyl acetate to dilute, adjusting pH with 2mL 1M hydrochloric acid, extracting with ethyl acetate, and performing column chromatography to obtain 83.5mg ethyl 2- (6-methoxynaphthyl) -2-nitroacetate with yield of 76%.
According to the document [ J.org.chem.2013,78, 717-722-]The preparation method comprises the following steps: 0.3M ethyl 2- (6-methoxynaphthyl) -2-nitroacetate THF solution, 5 mol% tetrabutylammonium fluoride and 12.5 equivalents of KF were added. The reaction mixture was cooled to 0 ℃ and 2.5 equivalents of MeI were added. Heating the mixture to room temperatureAfter stirring for 16h, 1mL (5M) of dilute hydrochloric acid was added. Et for aqueous layer2O (3X 2mL), Na2SO4Drying, and vacuum concentrating to obtain 6-methoxy-2-ethyl naphthaleneacetic acid. By column chromatography (V)Ethyl acetate/VHexane (C)2: 98-5: 95) to obtain 6-methoxy-2-ethyl naphthaleneacetic acid with the yield of 70%.
Example 6
Preparation of naproxen (application of 6-methoxy-2-ethyl naphthaleneacetonate)
According to the literature [ chem.Sci.,2020,11,9101]The preparation method comprises the following steps: 51.6mg (0.2mmol) of ethyl 6-methoxy-2-naphthaleneacetonate, 30mg (0.24mmol) of P (OMe)3)，0.3mL Me3B and 1.7mL of tetrahydrofuran were mixed well and stirred at 50 ℃ for 16 h. Then, 2.0mL of methanol and 82mg (2mmol) of LiOH. H were added2O and 1.0mL of water, stirred at room temperature for 12 h. Adding 1M hydrochloric acid to adjust pH 1; extraction with ethyl acetate (3X 10mL), drying over anhydrous sodium sulfate, and column chromatography (V)Ethyl acetate/VHexane (C)30: 70) to yield 28mg naproxen in 60% yield.
Example 7
Preparation of naproxen (application of 6-methoxy-2-methyl naphthalene ketonate)
According to the literature [ chem.Sci.,2020,11,9101]The preparation method comprises the following steps: 48.8mg (0.2mmol) methyl 6-methoxy-2-naphthaleneacetonate, 30mg (0.24mmol) P (OMe)3)，0.3mL Me3B and 1.7mL of tetrahydrofuran were mixed well and stirred at 50 ℃ for 16 h. 2.0mL of methanol and 82mg (2mmol) of LiOH. H were added2O and 1.0mL of water, stirred at room temperature for 12 h. 1M hydrochloric acid was added to adjust the pH 1. Extraction with ethyl acetate (3X 10mL), drying over anhydrous sodium sulfate, and column chromatography (V)Ethyl acetate/VHexane (C)30: 70) to yield 28mg naproxen in 60% yield.
In the present specification, the invention has been described with reference to specific embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention. The description is thus to be regarded as illustrative instead of limiting.
Claims (9)
1. The electrooxidation preparation method of 6-methoxy-2-naphthyl acetate shown in formula I is characterized in that the preparation reaction is as follows:
r is selected from: methyl, ethyl, C3-C4 straight chain alkyl or C3-C4 branched chain alkyl;
the electrooxidation preparation method is that an anode working electrode and a cathode are arranged in a non-diaphragm type electrolytic tank, and 6-methoxy-2-naphthylacetic ester, phthalimide derivatives, organic solvent, alkali and electrolyte are taken as electrolyte; electrolyzing for a certain time at a constant current at a certain temperature, and carrying out electrooxidation reaction to obtain the 6-methoxy-2-naphthyl acetate (I).
2. The process for the electro-oxidative preparation of 6-methoxy-2-naphthaleneacetonate as claimed in claim 1, wherein the anodic working electrode of the cell is selected from the group consisting of: carbon felt electrodes, platinum mesh electrodes or graphite electrodes; the anodic working electrode current density is selected from: 5mA/cm2～20mA/cm2(ii) a The cathode of the electrolytic cell is selected from: platinum mesh or nickel foam.
3. The process for the electro-oxidative preparation of 6-methoxy-2-naphthaleneacetonate according to claim 1, wherein the constant current is selected from the group consisting of: 10 mA-40 mA; the electrolysis is carried out at a temperature selected from: 15-65 ℃; the electrolysis is carried out for a time selected from: 4 to 10 hours.
4. The electrooxidation production method of 6-methoxy-2-naphthaleneacetic acid ester according to claim 1, characterized in that the organic solvent in the electrolyte is selected from: any one or more of acetonitrile, ethyl acetate, tetrahydrofuran or dioxane.
5. The process for the electro-oxidative preparation of 6-methoxy-2-naphthaleneacetonate according to claim 1, characterized in that the base is selected from: pyridine, 2, 6-lutidine or 4-dimethylaminopyridine.
6. The process for the electro-oxidative preparation of 6-methoxy-2-naphthaleneacetonate according to claim 1, characterized in that the phthalimide derivative is selected from: n-hydroxyphthalimide, N-hydroxy-4-bromophthalimide, N-hydroxy-4-chlorophthalimide, N-hydroxy-4, 5-dichlorophthalimide or N-hydroxytetrachlorophthalimide; the concentration of the phthalimide derivative is selected from: 0.01mol/L to 0.1 mol/L.
7. The process for the electro-oxidative preparation of 6-methoxy-2-naphthaleneacetonate according to claim 1, characterized in that the electrolyte is selected from: n-Bu4NPF6、LiClO4Tetrabutylammonium perchlorate or tetrabutylammonium tetrafluoroborate; the electrolyte concentration is selected from: 0.02 mol/L-0.1 mol/L.
8. The process for the electro-oxidative preparation of 6-methoxy-2-naphthaleneacetonate according to claim 1, wherein the concentration of methyl phenylacetate in the electrolyte is selected from the group consisting of: 8 g/L-40 g/L; the preparation method of the electrolyte comprises the following steps: dissolving methyl phenylacetate in an organic solvent and water to obtain an organic solution, and mixing the organic solution with N-hydroxyphthalimide and pyridine in a molar ratio of 1:1:1 to obtain a mixed solution.
9. A method for preparing naproxen shown as a structural formula II is characterized in that 6-methoxy-2-naphthylacetic ester is selected to be subjected to electrooxidation by the preparation method of any one of claims 1 to 8 to prepare 6-methoxy-2-naphthylacetic ester, and the naproxen is prepared by two-step reaction, wherein the preparation reaction comprises the following steps:
r is selected from: methyl, ethyl, C3-C4 straight chain alkyl or C3-C4 branched chain alkyl.
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