Preparation method of cannabidiol compound

Abstract

The invention discloses a preparation method of a cannabidiol compound, the method synthesizes the cannabidiol compound from a resorcinol derivative and menthyl-2, 8-diene-1-ol under the catalysis of a condensing agent, and the method has the advantages of simple operation, high alkylation reaction site selectivity and the like, and is suitable for being developed into a large-scale production process.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of chemical synthesis of cannabidiol, and relates to a method for preparing a cannabidiol compound. BACKGROUND

[0002] Cannabidiol (CBD) is a non-psychoactive cannabinoid isolated from the plant cannabis sativa, which is popular in the fields of beverages, food, prescription drugs, non-prescription supplements and cosmetics, and its market size is rapidly expanding.

[0003] CBD has biological activity on various receptors such as endocannabinoid receptors (CB1R, CB2R, GPR55, etc.), serotonin receptors (5-HT 1A R), transient receptor potential ion channels (TRPV1, TRPA1, TRPV4 and TRPM8, etc.), calcium ion channels and sodium ion channels, etc. In behavioral studies, it shows neuroprotection, anti-tumor, anti-mental illness, anti-inflammatory and other effects, and has good safety and tolerance.

[0004] CBD has multiple synthesis routes reported. As shown in reaction formula (1), the earliest synthesis uses 3,5-dihydroxy pentylbenzene (olivetol) and trans-menthyl-2,8-dien-1-ol (formula II) as starting materials, and is synthesized under acid catalysis (Petrzilka et al., Helvetica Chimica Acta, Vol 50, Issue 2, p.719-723; Petrzilka et al., Helvetica Chimica Acta, Vol 52, Issue 4, p.1102-1134; Baek et al., Tetrahedron Letters, Vol 26, Issue 8, 1985, p.1083-1086). However, the reaction condition has problems such as poor selectivity and excessive alkylation, and by-products such as formula IV compound and formula V compound are generated in the reaction, which increases the difficulty of purification and reduces the yield of the target product CBD.

[0005]

[0006] Note: (-)-CBD in the synthesis route is CBD in the text

[0007] Reaction formula (1)

[0008] US2017008869A1 reported a route shown in reaction formula (2), wherein 3,5-dihydroxy pentyl benzene (olivetol) was first halogenated, then reacted with trans-menthyl-2,8-diene-1-ol, and finally removed halogen, but the halogenation reaction would produce isomers, and the final dehalogenation reaction would cause impurities.

[0009]

[0010] US2007093665A1 reported a route shown in reaction formula (3), wherein the olivetate was first alkylated with trans-menthyl-2,8-diene-1-ol under acid catalysis, and then saponified to decarboxylate to generate (-)-CBD, and the yield of the two steps was 57%.

[0011]

[0012] The existing synthesis methods all have certain deficiencies, such as poor reaction regioselectivity, complicated steps, difficult product separation and purification process, and low yield. Therefore, it is of great significance to develop a synthesis method with high reaction selectivity, simple operation and high yield for industrial production. SUMMARY

[0013] The present application intends to overcome the deficiencies of the prior art, and provides a method for preparing CBD compounds with mild reaction conditions, simple process, and suitable for industrial production.

[0014] The present application provides a method for preparing a compound of formula I, comprising: reacting a compound of formula II with a compound of formula III in the presence of a condensing agent M to generate a compound of formula I,

[0015]

[0016] wherein,

[0017] R is hydrogen or C1-C6 alkoxycarbonyl, preferably hydrogen, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;

[0018] The condensing agent M is one or more selected from the group consisting of Fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH), Cyanuric chloride ((NCCl)3), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), Pentafluorophenyl diphenylphosphinate (FDPP), 1,1'-carbonyldi-imidazole (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), N,N'-dicyclohexylcarbodiimide (DCC) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT); preferably one or more selected from the group consisting of Fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH), Cyanuric chloride ((NCCl)3), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP) and (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU).

[0019] In the process of the present application, the molar ratio of the catalyst M to the compound of formula III can be 0.01:1 to 1:1, preferably 0.1:1 to 1:1, for example 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, etc., but is not limited thereto.

[0020] In the process of the present application, the compound of formula II and the compound of formula III can be reacted in a solvent, which can be one or a mixture of two or more selected from the group consisting of alkanes, arenes, halogenated hydrocarbons, esters, ethers, polar aprotic solvents.

[0021] Preferably, the alkane can be a straight chain or branched chain or cyclic alkane of C5-C 20 including but not limited to n-pentane, n-hexane, n-heptane, cyclohexane, etc.

[0022] Preferably, the aromatic hydrocarbon can be a substituted benzene compound including but not limited to toluene, xylene, chlorobenzene, etc.

[0023] Preferably, the halogenated hydrocarbon includes but is not limited to dichloromethane, 1,2 dichloroethane, chloroform, etc.

[0024] Preferably, the ester solvent includes but is not limited to methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, etc.

[0025] Preferably, the ether solvent includes but is not limited to tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, methyl tert-butyl ether and anisole.

[0026] Preferably, the polar aprotic solvent includes but is not limited to acetonitrile, acetone, N,N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide.

[0027] More preferably, the solvent is one selected from the group consisting of n-heptane, n-hexane, toluene, xylene, chlorobenzene, dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, or a mixture of two or more thereof.

[0028] In the method of the present application, the molar ratio of the compound of formula II to the compound of formula III can be 1:1 to 1.5:1; preferably 1:1 to 1.2:1, such as 1.01:1, 1.02:1, 1.05:1, 1.10:1, 1.15:1, 1.18:1, 1.19:1, etc., but is not limited thereto.

[0029] In the method of the present application, the reaction temperature can be -15°C to 40°C; preferably -10°C to 25°C, such as -5, 0, 5, 10, 15, 20°C, etc., but is not limited thereto.

[0030] In the method of the present application, the reaction time can be 15 minutes to 24 hours; preferably 1 hour to 12 hours, such as 2, 3, 4, 5, 6, 7, 8, 9 hours, etc., but is not limited thereto.

[0031] The present application has been described in detail above, but the above-described embodiments are merely illustrative in nature and are not intended to limit the present application. Furthermore, the present text is not limited by any theory described in the foregoing prior art or summary of the invention or in the following examples.

[0032] Unless otherwise expressly stated, ranges of values included within the application file are inclusive of any sub-ranges within the range and any values within the minimum and maximum units of the given range. Unless otherwise expressly stated, values within the application file are approximations that are reasonably accurate, plus or minus the standard deviation of the measurement and the range of values that would be expected within the precision of the measurement, and the precision of the values presented. Except in connection with the work examples provided at the end of the detailed description, all numerical values in the application file, including the claims, are to be construed in a manner similar to that of a patent application filed in the United States, 35 U.S.C. § 1 12, 1 13, and 1 15, and to 37 C.F.R. §§ 1.72(b) and 1.53(c), unless expressly indicated otherwise. All measurements, values, ratings, positions, materials, directions, and other specifications that are set forth in this application file are assumed to be modified by the term "approximately" or "about" unless expressly stated otherwise. "Approximately" means that the stated value is allowed to be slightly inaccurate (some close to exact; about or reasonably close to the value; approximate). If the inaccuracy provided by "approximately" is not understood in this ordinary sense in the art, then "approximately" as used herein means at least the variations that can be produced by ordinary methods of measuring and using these parameters. For example, "approximately" can include variations of less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1 %, or less than or equal to 0.5%.

[0033] Advantages

[0034] The method for preparing cannabidiol provided by the present application has the advantages of simple operation, high selectivity of alkylation reaction site, etc. by reacting m-diphenol or its derivative with menthyl-2,8-dien-1-ol (Formula II) in the presence of a condensing agent, and is suitable for development as a large-scale production process. DETAILED DESCRIPTION

[0035] The following examples are intended to be illustrative only and should not be construed as limiting the embodiments of the present application to the particular details herein. Other variations having approximately the same effect are considered obvious to those skilled in the art in light of the disclosure herein.

[0036] Unless otherwise indicated, the starting materials and reagents are commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.

[0037] Abbreviations:

[0038] Cannabidiol: CBD

[0039] Olivetol: 3,5-dihydroxyphenylpentan-ol

[0040] Tetramethylfluoroformamidinium hexafluorophosphate: TFFH

[0041] 2-Chloro-1,3-dimethylimidazolium hexafluorophosphate: CIP

[0042] Tricyanochloroimidazole: (NCCl)3

[0043] (2-Hydroxyimino-cyanoacetic acid ethyl ester)-N,N-dimethyl-morpholinyl urea hexafluorophosphate: COMU

[0044] Dichloromethane: DCM

[0045] Example 1

[0046]

[0047] olivetol (119 mg, 0.66 mmol) and (NCCl)3(121.7 mg, 0.66 mmol) were placed in a reaction flask, replaced with nitrogen, 2 mL DCM was added, and the temperature was lowered to 0 °C. The compound II (105.3 mg, 0.69 mmol) was slowly added dropwise to the reaction system, and the reaction was monitored by TLC. After the reaction was completed, it was quenched with saturated NaCl and purified by column chromatography to obtain (-)-CBD with a yield of 41%. 1 H NMR (400 MHz, DMSO-d6): δ 8.64 (br, 2H), 6.01 (s, 2H), 5.09 (s, 1H), 4.49 (m, 1H), 4.41 (m, 1H), 3.84-3.82 (m, 1H), 3.03 (td, J = 8.4, 2.4 Hz, 1H), 2.30 (t, J = 6.4 Hz, 2H), 2.11-2.07 (m, 1H), 1.94-1.90 (m, 1H), 1.70-1.67 (m, 1H), 1.65-1.61 (m, 1H), 1.60 (s, 3H), 1.59 (s, 3H), 1.50-1.44 (m, 2H), 1.32-1.23 (m, 4H), 0.86 (t, J = 5.6 Hz, 3H).

[0048] Example 2

[0049]

[0050] olivetol (338 mg, 1.88 mmol) and COMU (804.6 mg, 1.88 mmol) were placed in a reaction flask, replaced with nitrogen, 5 mL DCM was added, and the temperature was lowered to 0 °C. The compound II (300 mg, 1.97 mmol) was slowly added dropwise to the reaction system, and the reaction was monitored by TLC. After the reaction was completed, it was quenched with saturated NaCl and purified by column chromatography to obtain (-)-CBD with a yield of 73%. The product was characterized by H NMR. 1 H NMR was the same as Example 1.

[0051] Example 3

[0052]

[0053] olivetol (104 mg, 0.58 mmol) and CIP (161.0 mg, 0.58 mmol) were placed in a reaction flask, replaced with nitrogen, 2 mL DCM was added, cooled to 0 °C, stirred at this temperature for 20 min, a solution of compound II (92.2 mg, 0.61 mmol) in DCM was slowly added dropwise to the reaction system, after TLC monitoring of the end of the reaction, saturated NaCl was quenched, column chromatography gave (-)-CBD, the yield was 64%. The product was characterized by H NMR. 1 H NMR was the same as example 1.

[0054] Example 4

[0055]

[0056] olivetol (110 mg, 0.61 mmol) and TFFH (161.1 mg, 0.61 mmol) were placed in a reaction flask, replaced with nitrogen, 2 mL DCM was added, cooled to 0 °C, stirred at this temperature for 20 min, a solution of compound II (97.3 mg, 0.64 mmol) in DCM was slowly added dropwise to the reaction system, after TLC monitoring of the end of the reaction, saturated NaCl was quenched, column chromatography gave (-)-CBD, the yield was 47%. The product was characterized by H NMR. 1 H NMR was the same as example 1.

[0057] Example 5

[0058]

[0059] VI (238.0 mg, 1.0 mmol) and (NCCl)3 (184.6 mg, 1.0 mmol) were placed in a reaction flask, replaced with nitrogen, 3 mL DCM was added, cooled to 0 °C, stirred at this temperature for 20 min, a solution of compound II (159.6 mg, 1.1 mmol) in DCM was slowly added dropwise to the reaction system, after TLC monitoring of the end of the reaction, saturated NaCl was quenched, column chromatography gave VII, the yield was 47%. 1HNMR (400 MHz, CDCL3): δ 11.97 (s, 1H), 6.48 (s, 1H), 6.21 (s, 1H), 5.55 (s, 1H), 4.52 (s, 1H), 4.39 (s, 1H), 4.10 (d, J = 9.0 Hz, 1H), 3.89 (s, 3H), 2.87 - 2.80 (m, 1H), 2.77 - 2.70 (m, 1H), 2.40 (t, J = 8.2 Hz, 1H), 2.25 - 2.19 (m, 1H), 2.09 (d, J = 14.4 Hz, 1H), 1.82 - 1.78 (m, 5H), 1.71 (s, 3H), 1.52 - 1.49 (m, 2H), 1.33 - 1.30 (m, 4H), 0.89 (d, J = 5.3 Hz, 3H).

[0060] Example 6

[0061]

[0062] VIII (252.1 mg, 1.0 mmol) and COMU (428 mg, 1.0 mmol) were placed in a reaction bottle, replaced with nitrogen, 3 mL of DCM was added, cooled to 0°C, stirred at this temperature for 20 min, a solution of compound II (167.2 mg, 1.1 mmol) in DCM was slowly added dropwise to the reaction system, TLC monitored the end of the reaction, quenched with saturated NaCl, column chromatography to give IX, the yield was 68%. 1 H NMR (400 MHz, CDCL3): δ 12.07 (s, 1H), 6.46 (s, 1H), 6.21 (s, 1H), 5.55 (s, 1H), 4.52 (t, J = 1.8 Hz, 1H), 4.40 - 4.35 (m, 3H), 4.10 (d, J = 9.3 Hz, 1H), 2.90 - 2.82 (m, 1H), 2.79 - 2.72 (m, 1H), 2.40 (d, J = 8.7 Hz, 1H), 2.25 - 2.18 (m, 1H), 2.09 (d, J = 17.6 Hz, 1H), 1.82 - 1.78 (m, 5H), 1.70 (s, 3H), 1.54 - 1.51 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.34 - 1.30 (m, 4H), 0.89 (t, J = 3.4 Hz, 3H).

[0063] Comparative Example 1

[0064]

[0065] olivetol (108.0 mg, 0.6 mmol) and BF3OEt2(7 μL, 0.06 mmol) were placed in a reaction flask, replaced with nitrogen, 2 mL DCM was added, and the temperature was lowered to 0 °C. The mixture was stirred at this temperature for 20 min, and a solution of compound II (159.6 mg, 0.63 mmol) in DCM was slowly added dropwise. After the reaction was completed as monitored by TLC, it was quenched with saturated NaCl and purified by column chromatography to give (-)-CBD in 37% yield. The product was characterized by1H NMR. 1 H NMR was the same as in Example 1.

[0066] The above examples are only to illustrate the technical concepts and characteristics of the present application, and the purpose is to enable those skilled in the art to understand the content of the present application and to implement it, and cannot limit the protection scope of the present application. Any equivalent changes or modifications made in accordance with the spirit and essence of the present application should be covered within the protection scope of the present application.

Claims

1. A process for preparing a compound of formula I, comprising: reacting a compound of formula II with a compound of formula III in the presence of a condensing agent M to form a compound of formula I, wherein, R is hydrogen or C1-C6 alkoxycarbonyl; the condensing agent M is one or more selected from the group consisting of tetramethylfluoro urea hexafluorophosphate, cyanuric chloride, 2-chloro-1,3-dimethylimidazolium hexafluorophosphate, (2-hydroximino-cyanoacetic acid ethyl ester)-N,N-dimethyl-morpholinyl urea hexafluorophosphate, pentafluorophenyl diphenyl phosphate, N,N'-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, N,N'-dicyclohexyl carbodiimide and 2-chloro-4,6-dimethoxy-1,3,5-triazine.

2. The method according to claim 1, wherein, R is hydrogen, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl; and / or the condensing agent M is one or more selected from the group consisting of tetramethylfluoro urea hexafluorophosphate, cyanuric chloride, 2-chloro-1,3-dimethylimidazolium hexafluorophosphate and (2-hydroximino-cyanoacetic acid ethyl ester)-N,N-dimethyl-morpholinyl urea hexafluorophosphate.

3. The method according to claim 1 or 2, wherein, the molar ratio of the catalyst M to the compound of formula III is 0.01:1 to 1:1; and / or the molar ratio of the compound of formula II to the compound of formula III is 1:1 to 1.5:

1.

4. The method according to claim 3, wherein, the molar ratio of the catalyst M to the compound of formula III is 0.1:1 to 1:1, and / or the molar ratio of the compound of formula II to the compound of formula III is 1:1 to 1.2:

1.

5. The method of claim 1 or 2, wherein, the compound of formula II and the compound of formula III are reacted in a solvent selected from one or more of alkanes, arenes, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, or a mixture of two or more thereof.

6. The method according to claim 5, wherein, said alkane is a C5-C 20 linear or branched or cyclic alkane; the arene is a substituted benzene compound; the halogenated hydrocarbon is selected from dichloromethane, 1,2 dichloroethane, chloroform; the ester solvent is selected from methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate; the ether solvent is selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, cyclopentyl methyl ether, methyl tert-butyl ether and anisole; the polar aprotic solvent is selected from acetonitrile, acetone, N,N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide.

7. The method according to claim 5, wherein, the alkane is selected from n-pentane, n-hexane, n-heptane, cyclohexane; the arene is selected from toluene, xylene, chlorobenzene.

8. The method of claim 5, wherein, the solvent is selected from one or more of n-heptane, n-hexane, toluene, xylene, chlorobenzene, dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, or a mixture of two or more thereof.

9. The method according to claim 1 or 2, wherein, the reaction temperature is -15°C to 40°C; and / or the reaction time is 15 minutes to 24 hours.

10. The method according to claim 9, wherein, the reaction temperature is -10°C to 25°C; and / or the reaction time is 1 hour to 12 hours.

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