A process for the preparation of 5,6-dimethoxy-1-indanone

Abstract

The application discloses a preparation method of 5,6-dimethoxy-1-indanone and belongs to the technical field of medical intermediates. The preparation method comprises the following steps: 5-indanol is used as raw material, and under the action of an oxidant and a tetrabutylammonium iodide catalyst, intermediate A and intermediate B mixture are generated; then, complex reaction with borate ester is carried out, and intermediate B is separated out through distillation; then, reduction reaction is carried out, and 5,6-indandiol is generated; then, methyl etherification reaction is carried out through dimethyl sulfate; finally, CrO3 and Ac2O oxidation system are used to oxidize, and 5,6-dimethoxy-1-indanone is generated. The application adopts borate ester to separate isomers, and the operation is simple, which provides a new idea for synthesizing the compounds.

Description

Technical Field

[0001] This invention relates to a method for preparing 5,6-dimethoxy-1-indanone, belonging to the field of pharmaceutical intermediates technology. Background Technology

[0002] Dimethoxy-1-indanone (CAS: 2107-69-9) is the main raw material for the synthesis of donepezil hydrochloride, an anti-Alzheimer's drug. It can also be used as an important pharmaceutical intermediate or raw material in the synthesis of other drugs, demonstrating its wide range of applications. Donepezil hydrochloride is a brain metabolism improver and nootropic agent, suitable for mild to moderate Alzheimer's disease. Clinical trials have shown that donepezil, as a reversible acetylcholinesterase inhibitor, has demonstrated clinical safety and efficacy.

[0003]

[0004] Based on a literature search of existing technologies, the main synthesis routes for this product are summarized as follows: 5,6-Dimethoxy-1-indanone (CAS: 2107-69-9) is the main raw material for the synthesis of donepezil hydrochloride, an anti-Alzheimer's drug. It can also be used as an important pharmaceutical intermediate or raw material in the synthesis of other drugs, demonstrating its wide range of applications. Donepezil hydrochloride is a brain metabolism improver and nootropic agent, suitable for mild to moderate Alzheimer's disease. Clinical trials have shown that donepezil, as a reversible acetylcholinesterase inhibitor, has demonstrated clinical safety and efficacy.

[0005] A. The literature [ACS Medicinal Chemistry Letters, 2016, 7, 470; Molecules, 2014, 19, 5599; Green Chemistry, 2021, 23, 1995; Bulletin of the Chemical Society of Japan, 1995, 68, 2379; Journal of Medicinal Chemistry, 2001, 44, 4716] reported the use of 3-(3,4-dimethoxyphenyl)propionic acid or 3-(3,4-dimethoxyphenyl)propionyl chloride as raw materials, and Friedel-Crafts cyclization reaction to generate 5,6-dimethoxy-1-indanone.

[0006] B. The literature [Journal of the American Chemical Society, 2003, 125, 4804] reports the use of 2-iodo-4,5-dimethoxybenzaldehyde as a raw material, reacting it with carbon monoxide under high temperature and pressure conditions, in the presence of a palladium catalyst, to obtain 5,6-dimethoxy-1-indanone.

[0007] C. Literature [Chemical Communications, 2011, 47, 6635; Green Chemistry, 2021, 23, 1036] reports the cyclization reaction of 4,5-dimethoxy-2-vinylbenzaldehyde under catalytic conditions to obtain 5,6-dimethoxy-1-indanone.

[0008] The existing methods mentioned above have drawbacks such as excessive waste, difficulty in obtaining raw materials, or involvement of highly toxic substances. In order to expand the applications of 5,6-dimethoxy-1-indanone, it is necessary to research and develop new synthetic processes that provide routes that are simple to operate, have readily available raw materials, are low in cost, and have high yields to meet future market demands. Summary of the Invention

[0009] To overcome the aforementioned technical deficiencies, the present invention aims to provide a method for preparing 5,6-dimethoxy-1-indanone. To achieve this objective, the present invention uses 5-indanol as a raw material, and under the action of an oxidant and a tetrabutylammonium iodide catalyst, generates a mixture of intermediates A and B; subsequently, it undergoes a complexation reaction with a borate ester, and intermediate B is separated by distillation; then, a reduction reaction is carried out to generate 5,6-indandiol; then, a methyl etherification reaction is performed using dimethyl sulfate; finally, oxidation is carried out using a CrO3 and Ac2O oxidation system to generate 5,6-dimethoxy-1-indanone.

[0010] The synthetic route is shown below:

[0011] The method for preparing 5,6-dimethoxy-1-indanone according to the present invention includes the following steps: Step 1: Mix 5-indanol, oxidant and tetrabutylammonium iodide in a polar aprotic solvent, react under low temperature conditions, add ether solvent by vacuum distillation and slurry, filter to obtain intermediate A and intermediate B in ether solvent solution; The second step involves mixing the ether solvent solutions of intermediates A and B with borate esters, performing a complexation reaction under reflux conditions, and then separating intermediate B by vacuum distillation. The third step involves mixing intermediate B with a polar aprotic solvent, adding sodium dithionite to react and generate intermediate C; or mixing intermediate B with palladium on carbon in ethanol and catalytically hydrogenating to generate intermediate C. Step 4: Mix intermediate C, dimethyl sulfate and inorganic base in acetone and react under reflux to generate intermediate D; Step 5: Mix intermediate D and acetic anhydride, and add chromium trioxide in batches under heating to produce 5,6-dimethoxy-1-indanone.

[0012] Under further preferred conditions, in step A, the oxidant is iodobenzoic acid (IBX); the polar aprotic solvent is selected from sulfolane, DMF or DMSO; the ether solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or cyclopentylmethyl ether; and the low temperature condition is -10 to 10°C.

[0013] Under further preferred conditions, in the first step, the molar ratio of 5-indanol, oxidant and tetrabutylammonium iodide is 1:1.1-1.3:0.05-0.15.

[0014] Under further preferred conditions, in the second step, the borate ester is selected from trimethyl borate or triisopropyl borate.

[0015] Under further preferred conditions, in the second step, the molar ratio of intermediate B to borate ester is 1:1-1.5.

[0016] Under further preferred conditions, in the third step, the polar aprotic solvent is selected from sulfolane, DMF or DMSO; the molar ratio of intermediate B to sodium dithionite is 1:2.5-3.5; and the weight ratio of intermediate B to palladium on carbon is 1:0.01-0.05.

[0017] Under further preferred conditions, in the fourth step, the inorganic base is selected from sodium hydroxide or potassium hydroxide.

[0018] Under further optimized conditions, in the fourth step, the molar ratio of intermediate C, dimethyl sulfate, and inorganic base is 1:2.2-2.5:2-2.2.

[0019] Under further optimized conditions, in the fifth step, the heating condition is 60-90℃; when the reaction temperature exceeds 110℃, two carbonyl byproducts (1,3-dicarbonyl) are easily generated, which are difficult to separate and purify.

[0020] Under further preferred conditions, in the fifth step, the molar ratio of intermediate D to chromium trioxide is 1:1.5-2.5. Beneficial effects of the invention

[0021] A. In this invention, 5-indanol is used as the raw material, iodobenzoic acid is used as the oxidant and tetrabutylammonium iodide is used as the catalyst, resulting in high oxidation yield, good selectivity and reasonable route design.

[0022] B. In this invention, borate esters are used to separate isomers. The operation is simple and the separation effect is good, which provides a reference for similar reactions.

[0023] C. In this invention, the oxidation system of acetic anhydride and CrO3 is used, which can avoid over-oxidation, has good selectivity, simple steps, less waste, and good economic benefits. Attached Figure Description

[0024] Figure 1 The 1H NMR spectrum of 5,6-dimethoxy-1-indanone was obtained in Example 6. Specific Implementation

[0025] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the present invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the present invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should also be covered within the protection scope of the present invention. Therefore, the protection scope of the present invention should be determined by the scope of the claims. Example 1

[0026]

[0027] Under nitrogen protection, 5-indanol (13.4 g, 0.1 mol) and tetrabutylammonium iodide (3.7 g, 0.01 mol) were mixed in 300 mL of LMF, cooled to 0 °C, and IBX (33.6 g, 0.12 mol) was added in portions. The reaction was continued for 1.5 hours, then heated to room temperature, and the solvent was removed by vacuum distillation. The residue was added to 150 mL of THF and slurried. After filtration, THF solutions of intermediates A and B were obtained. HPLC monitoring showed that the conversion rate of the starting material 5-indanol was 87% (the reaction solution was concentrated, dissolved in CDCl3, and filtered). 1 Quantitative analysis using external standard HNMR (molar ratio of intermediate A to intermediate B: 1:6.2) Comparative Example 1

[0028]

[0029] Under nitrogen protection, 5-indanol (13.4 g, 0.1 mol) was mixed in 300 mL of LMF, cooled to 0 °C, and IBX (33.6 g, 0.12 mol) was added in portions. The reaction was continued for 1.5 hours, then heated to room temperature. The solvent was removed by vacuum distillation, and the residue was added to 150 mL of THF and slurried. After filtration, THF solutions of intermediates A and B were obtained. HPLC monitoring showed that the conversion rate of the starting material 5-indanol was 70% (the reaction solution was concentrated, dissolved in CDCl3, and filtered). 1 Quantitative analysis using external standard HNMR (molar ratio of intermediate A to intermediate B: 1:4.5) Example 2

[0030]

[0031] Under nitrogen protection, 150 mL of THF solution of intermediate A and intermediate B was mixed with trimethyl borate (10.4 g, 0.1 mol), and the mixture was heated to reflux for 3 hours to undergo complexation. The intermediate B complex was separated by vacuum distillation. 30 mL of THF and 30 mL of water were added to the distillate and stirred for 30 min. The mixture was separated into layers, the organic layer was dried, and concentrated to obtain 10.5 g of intermediate B, with a yield of 95% and an HPLC purity of 99.6%. 1 HNMR(400MHz, CDCl3): 6.33(s, 2H), 2.24(t, 4H), 1.62(t, 2H)ppm. Example 3

[0032]

[0033] Under nitrogen protection, intermediate B (14.8 g, 0.1 mol) was mixed in 300 mL of LDMF, and Na2S2O4 (52.2 g, 0.3 mol) was added. The mixture was reacted at room temperature for 3 hours, and then 50 mL of water and 300 mL of ethyl acetate were added. The mixture was separated into layers, and the organic layer was concentrated. The crude product was purified by column chromatography using hexane / ethyl acetate as the eluent to give 12.5 g of intermediate C, with a yield of 83% and an HPLC purity of 99.4%. 1 H NMR (400 MHz, DMSO- d 6): 8.48(s, 2H), 6.58(s, 2H), 2.69(t, 4H), 1.93(t, 2H). Example 4

[0034]

[0035] Under nitrogen protection, intermediate B (14.8 g, 0.1 mol) was mixed in 150 mL of ethanol in an autoclave. 5% wet palladium on carbon (0.44 g after dehydration) was added, and the mixture was sealed. Nitrogen was purged three times, and H2 was introduced at room temperature while maintaining a pressure of 0.1 MPa for 3 hours. The reaction solution was then removed, filtered, concentrated, and the crude product was purified by column chromatography using hexane / ethyl acetate as the eluent to obtain 12.8 g of intermediate C, with a yield of 85% and an HPLC purity of 99.5%. Example 5

[0036]

[0037] Under nitrogen protection, intermediate C (15 g, 0.1 mol), 100 mL of acetone, and 21 g of sodium hydroxide aqueous solution (40%) were mixed and stirred at room temperature for 1 hour. Then, dimethyl sulfate (29 g, 0.23 mol) was added, and the mixture was heated to reflux and reacted for 5 hours. The mixture was then cooled to room temperature, 60 mL of water was added, and then 120 mL of ethyl acetate was added for extraction twice. The organic layer was concentrated, and the crude product was purified by column chromatography using petroleum ether / ethyl acetate = 20 / 1 as the eluent to obtain intermediate D, 16.6 g, yield 93%, HPLC purity 99.2%. 1 HNMR (400MHz, DMSO- d 6): 6.79 (s, 2 H), 3.87 (s, 6 H), 2.89-2.85 (t, 4 H), 2.10-2.04 (m, 2 H). Example 6

[0038]

[0039] Under nitrogen protection, intermediate D (17.8 g, 0.1 mol) and 220 mL of acetic anhydride were mixed and heated to 80 °C. CrO3 (20 g, 0.2 mol) was added in eight batches, and the reaction was continued for 6 hours. After cooling to room temperature, most of the acetic anhydride was concentrated. The residue was poured into 200 mL of water and extracted twice with 100 mL of ethyl acetate. The organic layer was washed twice with 50 mL of saturated sodium carbonate aqueous solution. The organic layer was concentrated, and the crude product was purified by column chromatography using petroleum ether / ethyl acetate = 6 / 1 as the eluent, yielding 15.1 g of 5,6-dimethoxy-1-indanone, with a yield of 78% and an HPLC purity of 99.1%. 1 HNMR (400MHz, CDCl3): 7.21 (s, 1H), 6.92 (s,1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.10-3.07 (m, 2H), 2.72-2.68 (m, 2H).

[0040] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing 5,6-dimethoxy-1-indanone, characterized in that, Includes the following steps: ； Step 1: Mix 5-indanol, oxidant and tetrabutylammonium iodide in a polar aprotic solvent, react under low temperature conditions, add ether solvent by vacuum distillation and slurry, filter to obtain intermediate A and intermediate B in ether solvent solution; The second step involves mixing the ether solvent solutions of intermediates A and B with borate esters, performing a complexation reaction under reflux conditions, and then separating intermediate B by vacuum distillation. The third step involves mixing intermediate B with a polar aprotic solvent, adding sodium dithionite to react and generate intermediate C; or mixing intermediate B with palladium on carbon in ethanol and catalytically hydrogenating to generate intermediate C. Step 4: Mix intermediate C, dimethyl sulfate and inorganic base in acetone and react under reflux to generate intermediate D; Step 5: Mix intermediate D and acetic anhydride, and add chromium trioxide in batches under heating to produce 5,6-dimethoxy-1-indanone.

2. The method for preparing 5,6-dimethoxy-1-indanone according to claim 1, characterized in that: In step A, the oxidant is iodobenzoic acid; the polar aprotic solvent is selected from sulfolane, DMF or DMSO; the ether solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or cyclopentylmethyl ether; and the low temperature condition is -10 to 10°C.

3. The method for preparing 5,6-dimethoxy-1-indanone according to claim 1, characterized in that: In the first step, the molar ratio of 5-indanol, oxidant and tetrabutylammonium iodide is 1:1.1-1.3:0.05-0.

15.

4. The method for preparing 5,6-dimethoxy-1-indanone according to claim 1, characterized in that: In the second step, the borate ester is selected from trimethyl borate or triisopropyl borate.

5. The method for preparing 5,6-dimethoxy-1-indanone according to claim 1, characterized in that: In the second step, the molar ratio of intermediate B to borate ester is 1:1-1.

5.

6. The method for preparing 5,6-dimethoxy-1-indanone according to claim 1, characterized in that: In the third step, the polar aprotic solvent is selected from sulfolane, DMF or DMSO; the molar ratio of intermediate B to sodium dithionite is 1:2.5-3.5; and the weight ratio of intermediate B to palladium on carbon is 1:0.01-0.

05.

7. The method for preparing 5,6-dimethoxy-1-indanone according to claim 1, characterized in that: In the fourth step, the inorganic base is selected from sodium hydroxide or potassium hydroxide.

8. The method for preparing 5,6-dimethoxy-1-indanone according to claim 1, characterized in that: In the fourth step, the molar ratio of intermediate C, dimethyl sulfate, and inorganic base is 1:2.2-2.5:2-2.

2.

9. The method for preparing 5,6-dimethoxy-1-indanone according to claim 1, characterized in that: In the fifth step, the heating conditions are 60-90℃.

10. The method for preparing 5,6-dimethoxy-1-indanone according to claim 1, characterized in that: In the fifth step, the molar ratio of intermediate D to chromium trioxide is 1:1.5-2.5.

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