A method for continuously preparing cannabidiol intermediates by green photooxidation

Abstract

A new method for synthesizing cannabidiol, (-)-Cannabidiol (CBD, formula I), is provided to solve the defects in the prior art. The method is characterized in that the production process comprises the following steps: using (R)-(+)-Limonene (compound I-a) as a starting material, carrying out an oxidation reaction with a photocatalyst under light and then carrying out a reduction reaction, purifying to obtain a pure key intermediate formula I-e, the reaction formula is as follows: #imgabs0# This reaction and purification are simple; the technical route adopted by the present invention is simple and easy, the raw material source is wide, the conditions are mild, the production cost is low, the yield is high, and it is environmentally friendly, providing a more effective synthesis method for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a novel method for synthesizing cannabidiol (Formula I). ​​The technology adopted by the present invention has the advantages of simple and easy route, mild conditions, low production cost, etc. Background Art

[0002] (-)-Cannabidiol (CBD, Formula I) is a natural extract of the main non-psychoactive component of the cannabis plant, with a variety of pharmacological effects, including anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. Although cannabidiol has a low affinity for cannabinoid CB1 and CB2 receptors, it is an effective GPR55 antagonist. In June 2018, Epidiolex, an oral cannabidiol solution, was approved by the US FDA for the treatment of patients aged 2 years and above with rare forms of epilepsy: Lennox–Gastaut syndrome or Dravet syndrome. The drug was developed and manufactured by GW Pharmaceuticals in the UK.

[0003] Chemical name of cannabidiol:

[0004] 2-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol. The empirical formula is C 21 H 30 O 2 The molecular weight is 314.46 g / mol. The chemical structure is as follows:

[0005]

[0006] The preparation method of cannabidiol is reported a lot in literature and patents. Conventional methods for producing cannabidiol include natural extraction (such as agricultural hemp or hemp plants), or chemical synthesis, or biological extraction. Extraction from plants usually contains harmful substances such as heavy metals and toxin mud absorbed by plants from plants. The current chemical synthesis method uses a large amount of chemical reagents and column chromatography purification, with cumbersome steps, low yield and possible harmful impurities. Although biological production is more environmentally friendly, it is difficult to mass produce, and the steps are relatively cumbersome, thereby suppressing its sales ability. In patents US20170349518A1 and CN106810426A, compound Ie is used as an intermediate to obtain CBD through a series of reactions.

[0007] There are many publicly reported methods for synthesizing intermediate Ie, among which Shane M. Wilkinson et al. (Tetrahedron Letters 2013, 54, 52–54.) reported a synthesis method (Scheme 1), using (+)-limonene (Ia) as the starting material, firstly oxidized with meta-chloroperbenzoic acid to obtain epoxide (Ib) with a yield of 62%, then reacted in a 40% dimethylamine aqueous solution at 80°C for 18 hours to obtain intermediate Ic with a yield of 88%, then oxidized with hydrogen peroxide to quantitatively obtain Id, and finally obtained intermediate Ie with a yield of 74% under strong heat and high vacuum (180°C, 1 mm Hg). The total yield of the four-step reaction of this synthesis method is only about 40%, and peroxides such as meta-chloroperbenzoic acid and hydrogen peroxide are used in the synthesis, which has a high safety risk. The last step requires high temperature and high vacuum, which places high demands on production equipment and has extremely high operating costs.

[0008]

[0009] Longwu Qi et al. reported a synthetic method (Scheme 2) in (Journal of Medicinal Chemistry, 2005, 48, 7389-7399), with (+)-limonene epoxide (Ib) as starting raw material, in the presence of diphenyl diselenide and sodium borohydride, intermediate II-a was obtained, then oxidized with hydrogen peroxide to obtain intermediate II-b, and finally refluxed at high temperature to obtain Ie, with a three-step reaction total yield of 54%. In the synthesis step, diphenyl diselenide, sodium borohydride, and hydrogen peroxide with higher risk levels were also used, and high-temperature operation was also used in the last step, and the comprehensive process cost was higher.

[0010]

[0011] The present invention relates to the preparation of cannabidiol intermediate compound Ie using a simple synthetic route, thereby producing cannabidiol intermediate compound Ie in high yield, high stereospecificity, or both. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] [ Figure 1 ] Figure 1 The crude product of the cannabidiol intermediate compound Ie prepared by the method of the present invention is purified to obtain a pure product of formula Ie. 1 H-NMR spectrum. Summary of the invention

[0013] The present invention provides a method for preparing a cannabidiol intermediate (4R)-1-methyl-4-(2-(1-propylene))-2-cyclohexene-2-ol (Formula Ie). The method is simple and easy to operate, has mild conditions, does not require column separation and purification, greatly reduces production costs, and is convenient for industrial production.

[0014] In order to achieve the purpose of the present invention, the present invention provides the following technical solutions:

[0015] First, the present invention provides a method for synthesizing a cannabidiol intermediate of formula Ie, which is prepared from (R)-(+)-limonene (formula Ia) as a starting material, oxidized by introducing oxygen into a solvent under light, and then subjected to a reduction reaction to be purified. The reaction formula is as follows:

[0016]

[0017] The solvent is one or a combination of methanol, ethanol, isopropanol, acetonitrile, acetone, methyl acetate, ethyl acetate, methyl formate, ethyl formate, isopropyl acetate, tetrahydrofuran, dioxane, chlorobenzene, toluene, n-hexane, cyclohexane, n-heptane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, formic acid, acetic acid and water.

[0018] The catalyst is VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-j, VI-k, VI-l, VI-m, VI-n, VI-o, VI-p. The structural formula is as follows:

[0019]

[0020] The light source is a low-pressure mercury lamp, a medium-pressure mercury lamp, a high-pressure mercury lamp, a sodium lamp, a halogen tungsten lamp, a metal halide lamp, a light emitting diode (LED), and an array of light emitting diodes in different shapes (LED Array).

[0021] The light source power is 0.05W-10KW.

[0022] The wavelength of the light source is 200nm-800nm.

[0023] The oxygen purity is 0.1-100%. The reducing agent is sodium sulfite, sodium bisulfite, sulfurous acid, sulfur dioxide, phosphorous acid, phosphite, lithium borohydride, sodium borohydride, potassium borohydride, lithium aluminum tetrahydride, methanol, ethanol, isopropanol, formic acid, methyl formate, ethyl formate, ammonium formate, sodium formate, potassium formate.

[0024] The purification method is chromatography, countercurrent extraction, simple distillation, or a combination thereof.

[0025] On the other hand, the present invention also provides a method for synthesizing a cannabidiol intermediate of formula Ie, comprising the following steps: 1) mixing (R)-(+)-limonene (formula Ia), a solvent, and a catalyst, and stirring to dissolve; 2) using a horizontal flow pump to pump the reaction solution into a photochemical reactor, while introducing oxygen and continuously irradiating with a light source; 3) after the reaction solution is decompressed and concentrated, it is reduced with a reducing agent and purified to obtain formula Ie.

[0026] The solvent in step 1) is one or a combination of methanol, ethanol, isopropanol, acetonitrile, acetone, methyl acetate, ethyl acetate, methyl formate, ethyl formate, isopropyl acetate, tetrahydrofuran, dioxane, chlorobenzene, toluene, n-hexane, cyclohexane, n-heptane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, formic acid, acetic acid and water.

[0027] Step 1) The catalyst is VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-j, VI-k, VI-l, VI-m, VI-n, VI-o, VI-p. The structural formula is as follows:

[0028]

[0029]

[0030] Step 2) The light source is a low-pressure mercury lamp, a medium-pressure mercury lamp, a high-pressure mercury lamp, a sodium lamp, a halogen tungsten lamp, a metal halide lamp, a light emitting diode (LED), and arrays of different shapes composed of light emitting diodes (LED Array).

[0031] Step 2) The light source power is 0.05W to 10KW.

[0032] Step 2) The wavelength of the light source is 200nm to 800nm.

[0033] Step 2) The oxygen purity is 0.1-100%. The reducing agent is sodium sulfite, sodium bisulfite, sulfurous acid, sulfur dioxide, phosphorous acid, phosphite, lithium borohydride, sodium borohydride, potassium borohydride, lithium aluminum tetrahydride, methanol, ethanol, isopropanol, formic acid, methyl formate, ethyl formate, ammonium formate, sodium formate, potassium formate.

[0034] Step 3) The reducing agent is sodium sulfite, sodium bisulfite, sulfurous acid, sulfur dioxide, phosphorous acid, phosphite, lithium borohydride, sodium borohydride, potassium borohydride, lithium aluminum tetrahydride, methanol, ethanol, isopropanol, formic acid, methyl formate, ethyl formate, ammonium formate, sodium formate, potassium formate.

[0035] Step 3) The purification method is chromatography, countercurrent extraction, simple distillation, or a combination thereof.

[0036] The reaction of the invention is short, and the intermediate can be obtained in one step. The reagents used are green and environmentally friendly, and the cost is relatively low. The yield can reach 64% to 82%, which provides a more effective synthesis method for industrial production. DETAILED DESCRIPTION

[0037] The present invention is further defined in the following examples. It should be understood that these examples, while indicating preferred embodiments of the present invention, are given by way of illustration only and do not limit the present invention as claimed.

[0038] Embodiment 1:

[0039] Add (R)-(+)-limonene (6.80 g, 49.92 mmol, 1.0 eq), acetonitrile (180 mL, 26.5 V), and catalyst (126 mg, 0.12 mmol) to a 250 mL glass single-mouth bottle, and stir to dissolve. Use a horizontal flow pump to pump the reaction solution into the photochemical reactor, while continuously passing oxygen, and continuously irradiate with a halogen tungsten lamp (250 W) for 18 hours. Take samples for central control, and the raw material residue is 6.9% (GC, area%). The reaction solution is concentrated to 100 mL under reduced pressure, and sodium sulfite (12.58 g, 2.0 eq, 15%) aqueous solution is slowly added under ice water cooling, stirring while adding. After the addition is completed, a large amount of solid precipitates. Remove the ice water bath, continue stirring at room temperature for 2 hours, then heat to reflux, and continue stirring for 2 hours. Cool to 40-50°C and concentrate under reduced pressure to remove acetonitrile. Add water (150 mL) to dissolve the solid, add ether (3×100 mL) to extract, and combine the organic phases. The organic phase is washed with water (100 mL) and sodium bicarbonate solution (100 mL, 10%) in turn. After washing, the organic phase is dried by adding anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure until no liquid flows out to obtain a light yellow oily liquid (4.89 g, crude yield 64%). Gas chromatography analysis of the crude product: Ie (26.5%).

[0040] Embodiment 2:

[0041] Add (R)-(+)-limonene (6.80 g, 49.92 mmol, 1.0 eq), acetonitrile (200 mL, 29.4 V), and catalyst (126 mg, 0.12 mmol) to a 250 mL glass single-mouth bottle, and stir to dissolve. Use a horizontal flow pump to pump the reaction solution into the photochemical reactor, while continuously passing oxygen, and continuously irradiate with a halogen tungsten lamp (500 W) for 20 hours. Take samples for central control, and the raw material residue is 4.2% (GC, area%). The reaction solution is concentrated to 100 mL under reduced pressure, and sodium sulfite (12.58 g, 2.0 eq, 15%) aqueous solution is slowly added under ice water cooling, stirring while adding. After the addition is completed, a large amount of solid precipitates. Remove the ice water bath, continue stirring at room temperature for 2 hours, then heat to reflux, and continue stirring for 2 hours. Cool to 40-50°C and concentrate under reduced pressure to remove acetonitrile. Add water (150 mL) to dissolve the solid, add ether (3×100 mL) to extract, and combine the organic phases. The organic phase is washed with water (100 mL) and sodium bicarbonate solution (100 mL, 10%) in turn. After washing, the organic phase is dried by adding anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure until no liquid flows out to obtain a light yellow oily liquid (5.4 g, crude yield 71%). Gas chromatography analysis of the crude product: Ie (27.9%).

[0042] Embodiment 3:

[0043] Add (R)-(+)-limonene (3.40 g, 24.96 mmol, 1.0 eq), acetonitrile (700 mL, 205 V), and catalyst (63 mg, 0.06 mmol) to a 1000 mL glass single-mouth bottle, and stir to dissolve. Use a horizontal flow pump to pump the reaction solution into the photochemical reactor, while continuously passing oxygen, and irradiate with a halogen tungsten lamp (500 W) for 36 hours. Take samples for central control, and the raw material residue is 8.2% (GC, area%). The reaction solution is concentrated to 100 mL under reduced pressure, and sodium sulfite (12.58 g, 2.0 eq, 15%) aqueous solution is slowly added under ice water cooling, stirring while adding. After the addition is completed, a large amount of solid precipitates. Remove the ice water bath, continue stirring at room temperature for 2 hours, then heat to reflux, and continue stirring for 2 hours. Cool to 40-50°C and concentrate under reduced pressure to remove acetonitrile. Add water (150 mL) to dissolve the solid, add ether (3×100 mL) to extract, and combine the organic phases. The organic phase is washed with water (100 mL) and sodium bicarbonate solution (100 mL, 10%) in turn. After washing, the organic phase is dried by adding anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure until no liquid flows out to obtain a light yellow oily liquid (2.7 g, crude yield 71%). Gas chromatography analysis of the crude product: Ie (39.1%).

[0044] Embodiment 4:

[0045] Add (R)-(+)-limonene (6.80 g, 49.92 mmol, 1.0 eq), methanol (700 mL, 102.5 V), and catalyst (126 mg, 0.12 mmol) to a 1000 mL glass single-mouth bottle, and stir to dissolve. Use a horizontal flow pump to pump the reaction solution into the photochemical reactor, while continuously passing oxygen, and irradiate with a sodium lamp (600 W) for 10 hours. Take samples for central control, and the raw material residue is 5% (GC, area%). The reaction solution is concentrated to 100 mL under reduced pressure, and sodium sulfite (12.58 g, 2.0 eq, 15%) aqueous solution is slowly added under ice water cooling, stirring while adding. After the addition is completed, a large amount of solid precipitates. Remove the ice water bath, continue stirring at room temperature for 2 hours, then heat to reflux, and continue stirring for 2 hours. Cool to 40-50°C and concentrate under reduced pressure to remove acetonitrile. Add water (150 mL) to dissolve the solid, add ether (3×100 mL) to extract, and combine the organic phases. The organic phase is washed with water (100 mL) and sodium bicarbonate solution (100 mL, 10%) in turn. After washing, the organic phase is dried by adding anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure until no liquid flows out to obtain a light yellow oily liquid (6.27 g, crude yield 82.5%). Gas chromatography analysis of the crude product: Ie (40.8%).

[0046] Embodiment 5:

[0047] Add (R)-(+)-limonene (6.80 g, 49.92 mmol, 1.0 eq), acetonitrile (700 mL, 102.5 V), and catalyst (126 mg, 0.12 mmol) to a 1000 mL glass single-mouth bottle, and stir to dissolve. Use a horizontal flow pump to pump the reaction solution into the photochemical reactor, while continuously passing oxygen, and continuously irradiate with a sodium lamp (600 W) for 2.5 hours. Take samples for central control, and the raw material residue is 3% (GC, area%). The reaction solution is concentrated to 100 mL under reduced pressure, and sodium sulfite (12.58 g, 2.0 eq, 15%) aqueous solution is slowly added under ice water cooling, stirring while adding. After the addition is completed, a large amount of solid precipitates. Remove the ice water bath, continue stirring at room temperature for 2 hours, then heat to reflux, and continue stirring for 2 hours. Cool to 40-50°C and concentrate under reduced pressure to remove acetonitrile. Add water (150 mL) to dissolve the solid, add ether (3×100 mL) to extract, and combine the organic phases. The organic phase is washed with water (100 mL) and sodium bicarbonate solution (100 mL, 10%) in turn. After washing, the organic phase is dried by adding anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure until no liquid flows out to obtain a light yellow oily liquid (5.48 g, crude yield 72.1%). Gas chromatography analysis of the crude product: Ie (40.7%).

[0048] Embodiment 6:

[0049] Add (R)-(+)-limonene (6.80 g, 49.92 mmol, 1.0 eq), acetonitrile (700 mL, 102.5 V), and catalyst (126 mg, 0.12 mmol) to a 1000 mL glass single-mouth bottle, and stir to dissolve. Use a horizontal flow pump to pump the reaction solution into the photochemical reactor, while continuously passing air, and irradiate with a sodium lamp (600 W) for 5 hours. Take samples for central control, and the raw material residue is 3% (GC, area%). The reaction solution is concentrated to 100 mL under reduced pressure, and sodium sulfite (12.58 g, 2.0 eq, 15%) aqueous solution is slowly added under ice water cooling, stirring while adding. After the addition is completed, a large amount of solid precipitates. Remove the ice water bath, continue stirring at room temperature for 2 hours, then heat to reflux, and continue stirring for 2 hours. Cool to 40-50°C and concentrate under reduced pressure to remove acetonitrile. Add water (150 mL) to dissolve the solid, add ether (3×100 mL) to extract, and combine the organic phases. The organic phase is washed with water (100 mL) and sodium bicarbonate solution (100 mL, 10%) in turn. After washing, the organic phase is dried by adding anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure until no liquid flows out to obtain a light yellow oily liquid (5.2 g, crude yield 68.4%). Gas chromatography analysis of the crude product: Ie (22.5%).

[0050] Embodiment 7:

[0051] Add (R)-(+)-limonene (6.80 g, 49.92 mmol, 1.0 eq), acetonitrile (700 mL, 102.5 V), and catalyst (126 mg, 0.12 mmol) to a 1000 mL glass single-mouth bottle, and stir to dissolve. Use a horizontal flow pump to pump the reaction solution into the photochemical reactor, while continuously passing air, and irradiate with a metal halide lamp (600 W) for 5 hours. Take samples for central control, and the raw material residue is 5.4% (GC, area%). The reaction solution is concentrated to 100 mL under reduced pressure, and sodium sulfite (12.58 g, 2.0 eq, 15%) aqueous solution is slowly added under ice water cooling, stirring while adding. After the addition is completed, a large amount of solid precipitates. Remove the ice water bath, continue stirring at room temperature for 2 hours, then heat to reflux, and continue stirring for 2 hours. Cool to 40-50°C and concentrate under reduced pressure to remove acetonitrile. Add water (150 mL) to dissolve the solid, add ether (3×100 mL) to extract, and combine the organic phases. The organic phase is washed with water (100 mL) and sodium bicarbonate solution (100 mL, 10%) in turn. After washing, the organic phase is dried by adding anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure until no liquid flows out to obtain a light yellow oily liquid (5.1 g, crude yield 67.1%). Gas chromatography analysis of the crude product: Ie (24.8%).

Claims

1. A method for synthesizing a cannabidiol intermediate of formula Ie, characterized in that: (R)-(+)-limonene (Formula Ia) is used as a starting material, and a photocatalyst is oxidized by introducing oxygen into a solvent under light, and then reduced and purified. The reaction formula is as follows: The catalyst is VI-d, and the structural formula is as follows:

2. A method for synthesizing a cannabidiol intermediate of formula Ie, characterized in that: The following steps are involved: 1) (R)-(+)-limonene (Formula Ia), a solvent and a catalyst are mixed and stirred to dissolve; 2) The reaction solution is pumped into a photochemical reactor using a horizontal flow pump, oxygen is introduced at the same time, and a light source is continuously irradiated; 3) After the reaction solution is reduced in pressure and concentrated, it is reduced with a reducing agent and purified to obtain Formula Ie, wherein the catalyst is VI-d, and the structural formula is as follows:

3. The preparation method according to claim 1 or 2, wherein the solvent is one or a combination of methanol, ethanol, isopropanol, acetonitrile, acetone, methyl acetate, ethyl acetate, methyl formate, ethyl formate, isopropyl acetate, tetrahydrofuran, dioxane, chlorobenzene, toluene, n-hexane, cyclohexane, n-heptane, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

4. The preparation method according to claim 1 or 2, wherein the light source is a sodium lamp or a halogen tungsten lamp.

5. The preparation method according to claim 1 or 2, wherein the light source power is 0.05W to 10KW.

6. The preparation method according to claim 1 or 2, wherein the wavelength of the light source is 200nm to 800nm.

7. The preparation method according to claim 1 or 2, wherein the oxygen purity is 0.1 to 100%.

8. The preparation method according to claim 1 or 2, wherein the reducing agent is sodium sulfite, sodium bisulfite, sulfurous acid, sulfur dioxide, phosphorous acid, phosphite, lithium borohydride, sodium borohydride, potassium borohydride, lithium aluminum tetrahydride, ammonium formate, sodium formate or potassium formate.

9. The preparation method according to claim 1 or 2, wherein the purification method is chromatography, countercurrent extraction, simple distillation rectification, or a combination thereof.

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