METHOD FOR PURIFYING CANNABINOID COMPOUNDS

Abstract

Disclosed is a method for purifying cannabinoid compounds that enables cannabinoid compounds to be obtained more economically and with a better purification effect.

Claims

1. A method for purifying cannabinoid compounds, stereoisomers, deuterated products or salts thereof, comprising:
A-(OH).sub.nA-(OG).sub.nA-(OH).sub.n wherein, A-(OH).sub.n is: ##STR00009## A-(OG).sub.n is: ##STR00010## wherein, is a single bond or a double bond; R.sub.0 is C.sub.1-6 alkyl or C.sub.1-6 hydroxyalkyl; R is H or C.sub.1-12 alkyl; R.sub.1 is H or COOH; R.sub.2 is H, COOH or C.sub.1-6 alkyl; R.sub.3 and R.sub.3 are each independently OH or C.sub.1-6 alkoxy, and at least one of R.sub.3 and R.sub.3 is C.sub.1-6 alkoxy; R.sub.4 is OH, C.sub.1-6 alkoxy, COOH or OCOC.sub.1-6 alkyl; G is a silyl protecting group; R.sub.3a and R.sub.3b are each independently OG or C.sub.1-6 alkoxy, and at least one of R.sub.3a and R.sub.3b is OG; n is 1 or 2.

2. The method for purifying cannabinoid compounds according to claim 1, wherein A-(OH).sub.n is: ##STR00011## A-(OG).sub.n is: ##STR00012## wherein: is a single bond or a double bond; R.sub.0 is methyl or CH.sub.2OH; R is H or C.sub.1-8 alkyl; R.sub.1 is H or COOH; R.sub.2 is H; R.sub.3 and R.sub.3 are each independently OH or OCH.sub.3, and at least one of R.sub.3 and R.sub.3 is OH; G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl; R.sub.3a and R.sub.3b are each independently OG or OCH.sub.3, and at least one of R.sub.3a and R.sub.3b is OG; n is 1 or 2.

3. The method for purifying cannabinoid compounds according to claim 1, wherein ##STR00013## wherein: G is triethylsilyl or tert-butyldimethylsilyl.

4. The method for purifying cannabinoid compounds according to claim 1, wherein the C.sub.1-6 alkyl is methyl, and the C.sub.1-6 hydroxyalkyl is CH.sub.2OH.

5. The method for purifying cannabinoid compounds according to claim 1, wherein the C.sub.1-12 alkyl is pentyl, preferably, the pentyl is n-pentyl.

6. The method for purifying cannabinoid compounds according to claim 1, wherein the C.sub.1-6 alkoxy is OCH.sub.3.

7. The method for purifying cannabinoid compounds according to claim 1, wherein the silyl protecting group is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

8. The method for purifying cannabinoid compounds according to claim 1, wherein n is 2.

9. A compound having the following structure: ##STR00014## wherein: is a single bond or a double bond; R.sub.0 is C.sub.1-6 alkyl or C.sub.1-6 hydroxyalkyl; R is H or C.sub.1-12 alkyl; R.sub.1 is H or COOH; R.sub.2 is H, COOH or C.sub.1-6 alkyl; R.sub.3 and R.sub.3 are each independently OH or C.sub.1-6 alkoxy, and at least one of R.sub.3 and R.sub.3 is C.sub.1-6 alkoxy; R.sub.4 is OH, C.sub.1-6 alkoxy, COOH or OCOC.sub.1-6 alkyl; G is a silyl protecting group; R.sub.3a and R.sub.3b are each independently OG or C.sub.1-6 alkoxy, and at least one of R.sub.3a and R.sub.3b is OG; preferably, the C.sub.1-6 alkyl is methyl, the C.sub.1-6 hydroxyalkyl is CH.sub.2OH, the C.sub.1-12 alkyl is pentyl, and the C.sub.1-6 alkoxy is OCH.sub.3, the silyl protecting group is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

10. The compound according to claim 9, wherein is a single bond or a double bond; R.sub.0 is methyl or CH.sub.2OH; R is H or C.sub.1-8 alkyl; R.sub.1 is H or COOH; R.sub.2 is H; R.sub.3 and R.sub.3 are each independently OH or OCH.sub.3, and at least one of R.sub.3 and R.sub.3 is OH; G is trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl; R.sub.3a and R.sub.3b are each independently OG or OCH.sub.3, and at least one of R.sub.3a and R.sub.3b is OG.

Description

DETAILED DESCRIPTION

[0075] The following examples illustrate the technical schemes of the present application in detail, but the protection scope of the present application includes but is not limited thereto.

Example 1

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

[0076] ##STR00007##

[0077] Step 1:

(((1R,2R)-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)

[0078] (1R,2R)-5-methyl-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-2,6-diol 1a mixed with impurities (crude product of Compound 1) (0.1 g) and imidazole (87 mg, 1.28 mmol) were dissolved in dichloromethane (0.7 ml), and tert-butyldimethylsilyl chloride (TBDMSCl) (116 mg, 0.76 mmol) was added at 0 C., which was reacted at 40 C. for 3 hours. TLC detected that the reaction was completed, and then the reaction was stopped. The solvent was removed by rotary evaporation, and separated and purified by silica gel column chromatography (dichloromethane/n-hexane (v/v)=1/19) to obtain the title compound (((1R,2R)-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) 1 b (146 mg, 84% yield, pale yellow oil).

[0079] .sup.1H NMR (300 MHz, Chloroform-d) 6.19 (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).

[0080] LC-MS m/z (ESI)=543.45 [M+1].

[0081] Step 2:

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

[0082] (((1R,2R)-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), tetrahydrofuran solution of tetra-n-butylammonium fluoride (0.54 ml, 0.54 mmol) was added at 0 C., and which was reacted at 0 C. for 30 minutes. TLC detected that the reaction was completed, and then the reaction was stopped. The solvent was removed by rotary evaporation, and separated and purified by silica gel column chromatography (ethyl acetate/n-hexane (v/v)=2/8) to obtain the title compound (1R,2R)-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, >99% purity, white solid).

[0083] .sup.1H NMR (300 MHz, DMSO-d6) 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).

[0084] LC-MS m/z (ESI)=315.47 [M+1].

Example 2

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

[0085] ##STR00008##

[0086] Step 1

(((1R,2R)-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)

[0087] (1R,2R)-5-methyl-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-2,6-diol 1a mixed with impurities (crude product of Compound 1) (0.26 g) and imidazole (0.17 g, 2.5 mmol) were dissolved in dichloromethane (1.8 ml), and triethylchlorosilane (TESCl) (320 mg, 2.1 mmol) was added at 0 C., which was reacted at 40 C. for 3 hours. TLC detected that the reaction was completed, and then the reaction was stopped. The solvent was removed by rotary evaporation, and separated and purified by silica gel column chromatography (dichloromethane/n-hexane (v/v)=1/19) to obtain the title compound (((1R,2R)-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, pale yellow oil).

[0088] .sup.1H NMR (300 MHz, Chloroform-d) 6.16 (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).

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

[0090] Step 2:

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

[0091] (((1R,2R)-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) was dissolved in anhydrous tetrahydrofuran (4 ml), tetrahydrofuran solution of tetra-n-butylammonium fluoride (1.8 ml, 1.8 mmol) was added at 0 C., and which was reacted at 0 C. for 30 minutes. TLC detected that the reaction was completed, and then the reaction was stopped. The solvent was removed by rotary evaporation, and separated and purified by silica gel column chromatography (ethyl acetate/n-hexane (v/v)=2/8) to obtain the title compound (1R,2R)-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, >99% purity, white solid).

[0092] .sup.1H NMR (300 MHz, DMSO-d6) 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).

[0093] LC-MS m/z (ESI)=315.47 [M+1].