FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Cannabidiol (1), having a purity greater than 99% by High-performance liquid chromatography (HPLC). The present invention further relates to a process for the purification of Cannabidiol (1) and process for the preparation of Ethyl olivetol (5).
BACKGROUND OF INVENTION
Cannabidiol is a phytocannabinoid indicated for the treatment of seizures associated with lennox-gastaut syndrome or dravet syndrome in patients 2 years of age and older. It is chemically known as 2-[(lR,6R)-3-Methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl]-5-pentyl-l,3-benzenediol marketed under the brand name Epidiolex.
The following journal describes the synthesis of Cannabidiol (1), the contents of which are hereby incorporated as reference in their entirety.
Journal of American Chemical society 96, 5860 (1974) discloses process for the preparation of Cannabidiol (1) by treating olivetol (4) with p-menthadienol (6) in the presence of weak acids. The process is not industrially viable due to the formation of unnatural isomer abn-cannabidiol (7). The abn-cannabidiol (7) obtained in this process may be converted to Cannabidiol (1) by treating with Boron trifluoride diethyl etherate by retro-Friedel-Crafts reaction, followed by recombination. However, this reagent further leads to cyclisation of Cannabidiol (1) to A-tetrahydro cannabinol (8) and iso-tetrahydro cannabinol (9).
Hence there is a need in the art to develop an industrially viable process for the preparation of Cannabidiol (1). The present inventors hereby reported an improved process for the preparation of Cannabidiol (1) with better yields and greater selectivity.

J/0H HC> r^H0 JL
U + y>CsH * Vx>c5Hl1 • LTX
J^ HO ^HO ==\ }-V^0H
HO
(4) (6) (1) (7)
X OH YTVTC5H11
Lil c5Hl1 + kVV
•V I J I OH
(8) (9)
Scheme -1
OBJECTIVE OF THE INVENTION
Accordingly, one objective of the present invention is to provide an improved process for the preparation of Cannabidiol (1).
Another objective of the present invention is to provide a process for the purification of Cannabidiol (1).
Another objective of the present invention is to provide a process for the preparation of Ethyl olivetol (5).
Yet, another objective of the present invention is to provide Cannabidiol (1) with purity greater than 99% by High-performance liquid chromatography (HPLC).
In yet, another objective of the present invention is to provide a process for limiting the impurities that are coupled with products of the respective stage.
SUMMARY OF THE INVENTION
Accordingly, in one embodiment the present invention provides an improved process for the preparation of Cannabidiol (1), with purity greater than 99% by (HPLC).

In another embodiment, the steps involved in the preparation of Cannabidiol (1) as shown in scheme-2 are as follows:
a) reacting 2,4-dihydroxy-6-pentylbenzoate (ethyl olivetol) (5) with (1S,4R)-l-methyl-4-(prop-l-en-2-yl) cyclohex-2-enol (4) to form ethyl 2,4-dihydroxy-3-((lR,6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-6-pentylbenzoate (3); and
b) hydrolysis of ethyl 2,4-dihydroxy-3-((lR,6R)-3-methyl-6-(prop-l-en-2-yl) cyclohex-2-enyl)-6-pentylbenzoate (3) followed by decarboxylation to obtain Cannabidiol (1).
In another embodiment the present invention provides process for the purification of Cannabidiol (1) comprising:
a) providing a solution of Cannabidiol (1) in a mixture of aprotic solvents;
b) stirring for 15-20 min and filtering;
c) adding pure cannabidiol;
d). adding aprotic solvent and cooling to suitable temperature;
e) stirring for 1-2 h and filtering; and
f) isolating pure Cannabidiol (1).
In another embodiment the present invention provides a process for the preparation of Ethyl olivetol (5) as shown in scheme-3 as follows:
i. reacting hexanal (10) with acetone in the presence of suitable base and pro tic
solvent to form (E)-non-3-en-2-one (12); ii. treating (E)-non-3-en-2-one (12) with diethyl malonate in a protic solvent and in the presence of suitable base to form ethyl 2-hydroxy-4-oxo-6-pentylcyclohex-2-enecarboxylate (13); and iii. reacting ethyl 2-hydroxy-4-oxo-6-pentylcyclohex-2-enecarboxylate (13) with bromine to form ethyl 2,4-dihydroxy-6-pentylbenzoate (Ethyl olivetol) (5).
In yet, another embodiment, Cannabidiol (1) obtained after purification is having impurities less than 1%, preferably less than 0.5%.

BRIEF DESCRIPTION OF DRAWINGS
Figure 1: illustrates the X-Ray powder diffraction pattern (XRPD) of Cannabidiol CO-DETAILED DESCRIPTION OF THE INVENTION
In one embodiment the present invention provides an improved process for the synthesis of Cannabidiol (1) with purity greater than 99% by HPLC as illustrated in scheme-2.
OH ~N?^ JL I
rA A LI YH fl OH
Jl + C J - VNrVCOOQHs - V\/L/COOH
H0 T^c5Hn /i stcna /-^ II stcpb I If T
COOC2H5 'OH S'Cpa HO^^^11" IHA^CSH,,
(5) (4) (3) L
(2)
step c
rS OH
HO C5HU
(1)
Scheme-2
Step a) proceeds with reacting 2,4-dihydroxy-6-pentylbenzoate (5) with (1S,4R)-1-methyl-4-(prop-l-en-2-yl)cyclohex-2-enol (4) in a suitable aprotic solvent and in the presence of suitable lewis acid to form ethyl 2,4-dihydroxy-3-((lR,6R)-3-methyl-6-(prop-l-en-2-yl) cyclohex-2-enyi)-6-pentylbenzoate (3).
The present inventors provided the compound ethyl 2,4-dihydroxy-3-((lR,6R)-3-methyl-6-(prop-l-en-2-yl) cyclohex-2-enyl)-6-pentylbenzoate (3) with yield 88% and purity 96% which is advantageous over prior art. The prior art methods suffered in terms of selectivity when olivetol (6) was treated with p-menthadienol (4) in the presence of weak acids. In the present invention the inventors have overcome the

problem by treating ethyl olivetol (5) with p-menthadienol (4) in the presence of suitable lewis acid.
Step b) proceeds with hydrolysis of ethyl 2,4-dihydroxy-3-((lR,6R)-3-methyl-6-(prop-l-en-2-yl) cyclohex-2-enyl)-6-pentylbenzoate (3) with suitable base in suitable protic solvent to form the intermediate 2,4-dihydroxy-3-((lS,6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-6-pentylbenzoic acid (2). The intermediate compound (2) undergoes decarboxylation at a suitable temperature to yield 2-[(lR,6R)-3-Methyl-6-(l-methylethenyl)-2cyclohexen-l-yl]-5-pentyl-l,3-benzenediol (Cannabidiol) (1).
The present inventors provided the compound Cannabidiol (1) with purity greater than 99%. In addition, the present invention reported the formation of impurity A-tetrahydro cannabinol (8) within the limit along with the desired compound Cannabidiol (1). Further the present invention also discloses purification method for the removal of impurities which is advantageous over the prior art.
In another embodiment the present invention provides process for the purification of Cannabidiol (1), comprising:
a) providing a solution of Cannabidiol (1) in a mixture of aprotic solvents;
b) stirring for 15-20 min and filtering;
c) adding pure cannabidiol;
d) adding aprotic solvent and cooling to suitable temperature;
e) stirring for 1-2 h and filtering; and
f) isolating pure Cannabidiol (1).
The said purification can be carried out at a temperature of -20 to 10 °C preferably at a temperature of-10 to 10 °C, more preferably at a temperature of-10 to 0 °C.
In another embodiment the present invention provides process for the preparation of ethyl olivetol (5) as illustrated in scheme3.

r i OH
O OH O ^L,COOEt
s.epi f^1* ^^W, stcpii /^
(10) (n) M)
11 u (12)
step iii
"
OH
Jv. ,COOEt ?H
„o«c„ fl
H° CsHu O^^C5Hn
(5) (14)
Scheme-3
Step i proceeds with reacting hexanal (10) with acetone in a suitable protic solvent in the presence of suitable base to form 4-hydroxynonan-2-one (11) which is converted into (E)-non-3-en-2-one (12) by treating with a suitable acid.
Step ii proceeds with reacting (E)-non-3-en-2-one (12) with diethyl malonate in a suitable protic solvent in the presence of suitable base to form ethyl 2-hydroxy-4-oxo-6-pentylcyclohex-2-enecarboxylate.
Step iii involves reacting ethyl 2-hydroxy-4-oxo-6-pentylcyclohex-2-enecarboxylate with bromine in suitable aprotic solvent to form ethyl 3-bromo-2-hydroxy-4-oxo-6-pentylcyclohex-2-enecarboxylate which is further converted to ethyl 2,4-dihydroxy-6-pentylbenzoate (Ethyl olivetol) (5).
The suitable lewis acid used in the present invention may be selected from the group comprising of boron trifluoride etherate, titanium tetrachloride, zinc chloride and the like preferably zinc chloride was used in the present invention.
The suitable bases used in the present invention may be selected from the group comprising of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide and the like preferably sodium hydroxide, sodium ethoxide were used in the present invention.

The suitable aprotic solvents used in the present invention may be selected from the group comprising of acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, n-hexane, dimethylformamide n-heptane and the like preferably ethyl acetate, dichloromethane, n-heptane, dimethylformamide were used in the present invention.
The suitable protic solvents used in the present invention may be selected from the group comprising of ethanol, methanol, isopropanol, water and the like preferably methanol, ethanol were used in the present invention.
Cannabidiol (1) obtained after purification is having purity greater than 99%, preferably 99.5 %.
In another embodiment Cannabidiol (1) obtained after purification is having total impurities less than 1%, preferably less than 0.5 % and more preferably less than 0.15%.
In another embodiment, Cannabidiol (1) obtained after purification is having impurity A-tetrahydro cannabinol (8) less than 0.15%, preferably less than 0.1%.
fl 0H
A-tetrahydro cannabinol (8)
In another embodiment, Cannabidiol (1) obtained after purification is having characteristic X-Ray powder diffraction is as shown in Figure-1 and characteristic values with (±0.2) 2 theta are as tabulated in Table-1.
Table-1
2-Theta ° I Relative Intensity %
5T5 63
831 8J

8/75 I 84
934 2L6
9^69 100
1014 553
1L7 26^6
12.49 213
12.94 22/7
1113 45
1169 163
15.09 316
16.09 6^6
16.54 9^6
16.98 164
1732 28
1X85 12~9
18^65 293
19^08 18/7
19.49 1A8
203 244
20.86 1L4
21.47 243
21.72 264
22.08 318
2Z6 184
2151 183
23.78 16^9
2437 9~8
2545 1L5
25.39 8^8
26.17 83

26\5 I 9^9
27.41 103
27.62 8
2Y21 7l
28^5 9£
29 733
30.38 14
31.08 69
33.09 52
33.95 69
The following examples further illustrate the present invention but should not be construed in any way as to limit its scope.
EXAMPLES
EXAMPLE 1
Preparation of ethyl 2,4-dihydroxy-3-((lR,6R)-3-methyl-6-(prop-l-en-2-yl)
cyclohex-2-enyl)-6-pentylbenzoate (3)
To a solution of 100 g of ethyl 2,4-dihydroxy-6-pentylbenzoate (5) in 1000 mL of dichloromethane, 32.95 g of zinc chloride, 6 mL of water were added at 25-30 °C. The reaction mixture was cooled to 0-5 °C and 60.3 g of (lS,4R)-l-methyl-4-(prop-l-en-2-yl)cyclohex-2-enol (4) was added slowly over a period of 4-5 h at 0-5 °C. The reaction mass was heated to 25-30 °C and allowed to stir for 18-20 h. After completion of the reaction, the reaction mass was filtered. The obtained filtrate was washed with sodium hydroxide, water. The organic layer was taken, and the solvent was removed under reduced pressure to afford ethyl 2,4-dihydroxy-3-((lR,6R)-3-methyl-6-(prop-l-en-2-yl) cyclohex-2-enyl)-6-pentylbenzoate (3).
Yield: 88 %; Purity: 96 %

EXAMPLE 2
Preparation of 2-[(lR,6R)-3-Methyl-6-(l-methyIethenyl)-2cyclohexen-l-yl]-5-
pentyl-l,3-benzenediol (1) (Cannabidiol)
To a solution of 100 g of ethyl 2,4-dihydroxy-3-((lR,6R)-3-methyl-6-(prop-l-en-2-yl) cyclohex-2-enyl)-6-pentylbenzoate (3) in 300 mL of methanol, 12.43 g of sodium hydroxide dissolved in 100 mL of water was added over a period of 10-20 min at 25-30 °C and allowed to stir for 10 min. 200 mL of n-heptane was added and stirred for 30-40 min at 25-30 °C. Separate organic and aqueous layer, the aqueous layer was taken and methanol was added at 25-30 °C. 29 g of sodium hydroxide dissolved in 200 mL of water was added over a period of 30-40 min at 25-30 °C. The reaction mixture was heated to 75-80 °C and stirred for 18-20 h at 75-80 °C. After completion of the reaction, the reaction mass was cooled to 25-30 °C and 150 g of citric acid dissolved in 1000 mL of water was added over a period of 30-40 min under nitrogen atmosphere, stirred for 20-30 min at 10-15 °C. 800 mL of hexane was added and stirred for 20-30 min at 10-15 °C. Separate the organic and aqueous layer, the organic layer was taken and washed with 10% aq. sodium bicarbonate solution. To the obtained organic layer 10 g of activated carbon, 20 g of silica gel were added and stirred for 20-30 min. The reaction mixture was filtered by using hexane. The solvent was removed under reduced pressure and n-heptane was added to the residue, stirred for 20-30 min at 25-30 °C. The reaction mixture was cooled to -10 to 0 °C and 100 mg of pure cannabidiol was added, stirred for 1-2 h at -10 to 0 °C. The reaction mixture was filtered and the obtained solid was washed with heptane and dried to afford crude 2-[(lR,6R)-3-Methyl-6-(l-methylethenyl)-2cyclohexen-l-yl]-5-pentyl-l,3-benzenediol (1).
Yield: 88%; Purity: 97 %

EXAMPLE 3
Purification of 2-[(lR,6R)-3-Methyl-6-(l-methylethenyl)-2cyclohexen-l-yI]-5-pentyI-l,3-benzenedioI (1) (Cannabidiol)
To 100 g of crude 2-[(lR,6R)-3-Methyl-6-(l-methylethenyl)-2cyclohexen-l-yl]-5-pentyl-l,3-benzenediol (1), 50 mL of ethyl acetate, 300 mL of n-heptane were added and stirred for 15-20 min at 25-30 °C. 10 g of cannabidiol was added and stirred for 30-40 min at 25-30 °C. The reaction mixture was filtered through hi-flow bed by using n-hexane. The solvent was removed under reduced pressure and n-heptane was added to the residue. The reaction mixture was cooled to -10 to 0 °C, stirred for 1-2 h. The reaction mixture was filtered and the obtained solid was washed with n-heptane and dried for 6-8 h to afford pure 2-[(lR,6R)-3-Methyl-6-(l-methylethenyl)-2cyclohexen-l-yl]-5-pentyl-l,3-benzenediol (1).
Yield: 90 %; Purity: 99.8 %
EXAMPLE 4
Preparation of (E)-non-3-en-2-one (12)
To a stirred solution of 2.5 g of sodium hydroxide in 252 mL of water, 115 g of acetone was added slowly for a period of 60-90 min at 25-30 °C and stirred for 30 min. The reaction mass was cooled to 5-10 °C and 100 g of hexanal was added for a period of 2 h at 5-10 °C. The reaction mass was initially heated to 15-20 °C, stirred for 15-20 min and further heated to 25-30 °C, maintained for 45 min. The reaction mass heated to 70-75 °C and stirred for 2 to 3 h. After completion of the reaction the reaction mixture was cooled to 25-30 °C, dilute hydrochloric acid was added. The reaction mixture was extracted with dichloromethane and the solvent was evaporated under vacuum to obtain crude (E)-non-3-en-2-one (12) which was purified by high vacuum distillation at 60-70 °C.
Yield: 85%

EXAMPLE 5
Preparation of ethyl 2-hydroxy-4-oxo-6-pentylcyclohex-2-enecarboxylate (13)
To a stirred solution of 63.09 g of sodium ethoxide in 800 mL of ethanol, 165.6 g of diethyl malonate was added slowly for a period of lh at 25-30 °C under nitrogen atmosphere. The reaction mass was heated to 80-85 °C and 100 g of (E)-non-3-en-2-one (12) was added slowly over a period of 1-2 h at 80-85 °C, stirred for 4-5 h. After completion of the reaction, the reaction mixture was cooled to 25-30 °C and the solvent was removed under reduced pressure to afford crude compound. The reaction mixture was dissolved in dichloromethane and the pH was adjusted to 3 by hydrochloric acid. The reaction mixture was extracted with dichloromethane and the solvent was removed under reduced pressure to afford ethyl 2-hydroxy-4-oxo-6-pentylcyclohex-2-enecarboxylate (13).
Yield: 85%
EXAMPLE 6
Preparation of ethyl 2,4-dihydroxy-6-pentylbenzoate (Ethyl olivetol) (5)
100 g of ethyl 2-hydroxy-4-oxo-6-pentylcyclohex-2-enecarboxylate (13) was dissolved in 400 mL of dimethylformamide at 25-30 °C. The reaction mass was cooled to -5 to 0 °C and 21.5 mL of bromine was added slowly over a period of 2-3 h at -5 to 0 °C. The reaction mass was warmed slowly to 25-30 °C and stirred for 3-4 hto form ethyl 3-bromo-2-hydroxy-4-oxo-6-pentylcyclohex-2-enecarboxylate (14). The reaction mass was cooled to 5-10 °C, water and ethyl acetate was added. The organic layer was extracted, and 20 g of neutral charcoal was added and stirred for 30 min at 25-30 °C. The reaction mass was filtered through hyflo bed using ethyl acetate. The filtrate was taken, and solvent was distilled off. The reaction mass was cooled to 25-30 °C and hexane was added, further cooled to -10 to 0 °C and stirred for 8- 10 h. The solid obtained was filtered and washed with chilled hexane to obtain crude ethyl 2,4-dihydroxy-6-pentylbenzoate. To the crude ethyl 2,4-dihydroxy-6-pentylbenzoate cyclohexane and pure ethyl 2,4-dihydroxy-6-pentylbenzoate was added. The reaction mixture was heated to 60-65 °C, cooled to

25-30 °C and further cooled to 5-10 °C, stirred for lh. The solid obtained was washed with chilled cyclohexane and dried to afford ethyl 2,4-dihydroxy-6-pentylbenzoate (Ethyl olivetol) (5).
Yield: 33%