Purification method of cannabinoid compounds

Abstract

The application discloses a cannabinoid purification method, and the cannabinoid is more economical and has better purification effect.

Description

Technical Field

[0001] The present application relates to the field of compound purification, and in particular to a method for purifying cannabinoid compounds. Background Art

[0002] Cannabinoid compounds have great application value in pharmaceuticals. For example, they have medical effects or potential for indications such as epilepsy associated with Lennox-Gastaut syndrome, epilepsy associated with tuberous sclerosis, autism, post-traumatic stress disorder, inflammatory heart disease, traumatic brain injury, and colon cancer.

[0003] Cannabinoids obtained through synthesis and extraction contain a variety of impurities, and chromatography is typically used to separate and purify cannabinoid compounds. However, in industrial applications, chromatography not only requires the use of large amounts of solvents, but also struggles to achieve the desired purification results, significantly limiting the scale and efficiency of the separation method. Furthermore, most cannabinoid compounds are unstable and prone to rearrangement and oxidation at room temperature, making their separation and storage difficult, particularly for the most widely used cannabidiol (CBD) and tetrahydrocannabinol (THC).

[0004] There is an urgent need for cost-effective and large-scale purification methods for cannabinoid compounds. Summary of the Invention

[0005] The purpose of this application is to provide a method for purifying cannabinoid compounds, which has the characteristics of better purification effect and suitability for industrial production compared with existing purification methods.

[0006] One or more embodiments of the present application provide a method for purifying a cannabinoid compound, a stereoisomer thereof, or a deuterated substance or salt thereof, comprising:

[0007]

[0008] in

[0009] for:

[0010]

[0011] for:

[0012]

[0013] in:

[0014] is a single bond or a double bond;

[0015] R0 is C 1-6 Alkyl or C 1-6 hydroxyalkyl;

[0016] R is H or C 1-12 alkyl;

[0017] R1is H or -COOH;

[0018] R2is H, -COOH or C1-6alkyl;

[0019] R3and R 3′ are each independently OH or C 1-6 alkoxy, and R3and R 3′ are each independently C 1-6 alkyl;

[0020] R4is OH, C 1-6 alkoxy, -COOH or -OCOC 1-6 alkyl;

[0021] G is a silicon-based protecting group;

[0022] R 3a and R 3b are each independently -OG or C 1-6 alkoxy, and R 3a and R 3b are each independently C 1-8 alkyl;

[0023] n is 1 or 2.

[0024] In one or more embodiments, triethylchlorosilane is added in the first step.

[0025] In one or more embodiments, tetra-n-butylammonium fluoride is added in the second step.

[0026] In one or more embodiments,

[0027] is:

[0028] is:

[0029] wherein:

[0030] is a single or double bond;

[0031] R0is methyl or -CH2OH;

[0032] R is H or C 1-8 alkyl;

[0033] R1is H or -COOH;

[0034] R2is H;

[0035] R3 and R 3′ are each independently OH or -OCH3, and R3 and R 3′ At least one of them is OH;

[0036] G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;

[0037] R 3a and R 3b are each independently -OG or -OCH3, and R 3a and R 3b At least one of them is -OG;

[0038] n is 1 or 2.

[0039] In one or more embodiments,

[0040]

[0041] in:

[0042] G is triethylsilyl or tert-butyldimethylsilyl.

[0043] In one or more embodiments, the C 1-6 The alkyl group is methyl, the C 1-6 Hydroxyalkyl is -CH2OH.

[0044] In one or more embodiments, the C 1-12 The alkyl group is pentyl.

[0045] In one or more embodiments, the pentyl group is n-pentyl group.

[0046] In one or more embodiments, the C 1-6 Alkoxy is -OCH3.

[0047] In one or more embodiments, the silicon-protecting group is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

[0048] In one or more embodiments, n is 2.

[0049] One or more embodiments of the present application provide a compound having the following structure:

[0050]

[0051] in

[0052] is a single bond or a double bond;

[0053] R0 is C 1-6 Alkyl or C 1-6 hydroxyalkyl;

[0054] R is H or C 1-12 alkyl;

[0055] R1 is H or -COOH;

[0056] R2 is H, -COOH or C 1-6 alkyl;

[0057] R3 and R 3′ Each independently is OH or C1-6 Alkoxy, and R3 and R 3′ The least one is C 1-6 alkoxy;

[0058] R4 is OH, C 1-6 Alkoxy, -COOH or -OCOC 1-6 alkyl;

[0059] G is a silicon-based protecting group;

[0060] R 3a and R 3b Each independently is -OG or C 1-6 Alkoxy, and R 3a and R 3b At least one of them is -OG.

[0061] In one or more embodiments, the C 1-6 The alkyl group is methyl, the C 1-6 Hydroxyalkyl is -CH2OH, the C 1-12 The alkyl group is pentyl, the C 1-6 The alkoxy group is -OCH3, and the silicon protecting group is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

[0062] In one or more embodiments:

[0063] is a single bond or a double bond;

[0064] R0 is methyl or -CH2OH;

[0065] R is H or C 1-8 alkyl;

[0066] R1 is H or -COOH;

[0067] R2 is H;

[0068] R3 and R 3′are each independently OH or -OCH3, and R3 and R 3′ At least one of them is OH;

[0069] G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl;

[0070] R 3a and R 3b are each independently -OG or -OCH3, and R 3a and R 3b At least one of them is -OG.

[0071] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0072] The carbon, hydrogen or oxygen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen or oxygen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O.

[0073] "Alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms), for example, an alkyl group of 1 to 8 carbon atoms, an alkyl group of 1 to 6 carbon atoms, or an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; when an alkyl group is substituted, it may be optionally further substituted with one or more substituents.

[0074] "Hydroxyalkyl" refers to an alkyl group substituted with at least one hydroxyl group. The definition of the alkyl group is the same as that of the "alkyl" group described above.

[0075] "Alkoxy" refers to a group in which at least one carbon atom in an alkyl group is replaced by an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy. The definition of "alkyl" is the same as that of "alkyl" described above.

[0076] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0077] "Optional" or "optionally" or "selectively" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclyl group is substituted with an alkyl group and instances where the heterocyclyl group is not substituted with an alkyl group.

[0078] The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as limiting the present invention. For those skilled in the art, without departing from the principles of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention. DETAILED DESCRIPTION

[0079] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0080] Example 1

[0081] (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (Compound 1)

[0082] (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphe-nyl]-2,6-diol

[0083]

[0084] first step:

[0085] (((1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl)bis(oxy))bis(tert-butyldimethylsilane)(1b)

[0086] (((1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-bip-henyl]-2,6-diyl)bis(oxy))bis(tert-butyldimethylsilane)

[0087] (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 1a (crude compound 1) (0.1 g) and imidazole (87 mg, 1.28 mmol) mixed with impurities were dissolved in dichloromethane (0.7 ml). Tert-butyldimethylsilyl chloride (TBDMSCl) (116 mg, 0.76 mmol) was added at 0°C and the mixture was reacted at 40°C for 3 hours. The reaction was stopped when it was complete, as monitored by TLC. The solvent was dried and separated and purified by silica gel column chromatography (dichloromethane / n-hexane (v / v) = 1 / 19) to give the title compound (((1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl)bis(oxy))bis(tert-butyldimethylsilane) 1b (146 mg, 84% yield, light yellow oil).

[0088] 1 H NMR(300MHz,Chloroform-d)δ6.19(s,2H),5.22(t,1H),4.45-4.52(m,2H),3.89–3.94(m,1H),3.02(td,1H),2.39–2.44(m ,2H),1.94–2.14(m,2H),1.66–1.78(m,2H),1.44-1.61(m,8H),1.24-1.34(m,6H),0.84-1.05(s,21H),0.15-0.23(m,12H).

[0089] LC-MS m / z(ESI)=543.45[M+1].

[0090] Step 2

[0091] (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (Compound 1)

[0092] (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphe-nyl]-2,6-diol

[0093] (((1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]- 2,6-diyl)bis(oxy))bis(tert-butyldimethylsilane) 1b (146 mg, 0.27 mmol) was dissolved in dichloromethane (1 ml), tetra-n-butylammonium fluoride in tetrahydrofuran (0.54 ml, 0.54 mmol) was added at 0 °C, and the reaction was allowed to proceed at 0 °C for 30 minutes. The reaction was monitored by TLC and stopped when the reaction was complete. The solvent was evaporated and purified by silica gel column chromatography (ethyl acetate / n-hexane (v / v) = 2 / 8) to give the title compound (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (compound 1) (80 mg, 95% yield, purity >99%, white solid).

[0094] 1 H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 2H), 5.99 (s, 2H), 5.06 (s, 1H), 4.38 - 4.47 (m, 2H), 3.80 (d, 1H), 2.96 - 3.04 (m, 1H), 2.25 - 2.30 (m, 2H), 1.86 - 2.07 (m, 2H), 1.42 - 1.64 (m, 10H), 1.20 - 1.28 (m, 4H), 0.83 (t, 3H).

[0095] LC-MS m / z (ESI) = 315.47 [M+1].

[0096] Example 2

[0097] (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphe-nyl]-2,6-diol

[0098] (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphe-nyl]-2,6-diol

[0099]

[0100] first step

[0101] (((1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl)bis(oxy))bis(triethylsilane)(1c)

[0102] (((1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-bip-henyl]-2,6-diyl)bis(oxy))bis(triethylsilane)

[0103] (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 1a (crude compound 1) (0.26 g) and imidazole (0.17 g, 2.5 mmol) were dissolved in dichloromethane (1.8 ml). Triethylsilyl chloride (TESCl) (320 mg, 2.1 mmol) was added at 0°C and the mixture was reacted at 40°C for 3 hours. The reaction was stopped when it was complete, as monitored by TLC. The solvent was dried and separated and purified by silica gel column chromatography (dichloromethane / n-hexane (v / v) = 1 / 19) to give the title compound (((1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl)bis(oxy))bis(triethylsilane) 1c (433 mg, 99% yield, light yellow oil).

[0104] 1 H NMR(300MHz,Chloroform-d)δ6.16(s,2H),5.19(s,1H),4.45–4.49(m,2H),3.85–3.89(m,1H),2.91-2. 99(m,1H),2.42(t,2H),1.94–2.14(m,2H),1.48-1.79(m,12H),1.18-1.35(m,4H),0.69-0.99(m,33H).

[0105] LC-MS m / z(ESI)=543.45[M+1].

[0106] Step 2:

[0107] (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (Compound 1)

[0108] (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphe-nyl]-2,6-diol

[0109] Dissolve (((1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diyl)bis(oxy))bis(triethylsilane) 1c (433 mg, 0.8 mmol) in anhydrous tetrahydrofuran (4 ml). Add a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1.8 ml, 1.8 mmol) at 0°C and allow to react at 0°C for 30 minutes. Stop the reaction when the reaction is complete, as monitored by TLC. The solvent was dried and separated and purified by silica gel column chromatography (ethyl acetate / n-hexane (v / v) = 2 / 8) to give the title compound (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol (Compound 1) (250 mg, 99% yield, purity >99%, white solid).

[0110] 1 H NMR(300 MHz, DMSO-d6)δ8.61(s,2H),5.99(s,2H),5.06(s,1H),4.38–4.47(m,2H),3.80(d,1H),2.96-3.04 (m,1H),2.25–2.30(m,2H),1.86–2.07(m,2H),1.42–1.64(m,10H),1.20–1.28(m,4H),0.83(t,3H).

[0111] LC-MS m / z(ESI)=315.47[M+1].

Claims

1. A method for purifying a cannabinoid compound, a stereoisomer thereof, or a salt thereof, comprising: in for: for: in: is a single bond or a double bond; R0 is methyl or -CH2OH; R is H or C 1-8 alkyl; R1 is H or -COOH; R2 is H; R3 and R3′ are each independently OH or —OCH3, and at least one of R3 and R3′ is OH; G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl; R 3a and R 3b are each independently -OG or -OCH3, and R 3a and R 3b At least one of them is -OG; n is 1 or 2.

2. The purification method according to claim 1, wherein in: G is triethylsilyl or tert-butyldimethylsilyl.

3. The purification method according to claim 1, wherein the C 1-8 The alkyl group is pentyl. The purification method according to claim 3 , wherein the pentyl group is an n-pentyl group. The purification method according to claim 1 , wherein n is 2.

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