DESC:FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of enantiomerically pure (4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol compound of Formula II which is a key intermediate in the synthesis of Cannabidiol.

BACKGROUND OF THE INVENTION:
Cannabidiol is a cannabinoid designated chemically as 2-[(1R,6R)-3-Methyl-6-(1-methylethenyl)-2­cyclohexen-1-yl]-5-pentyl-1,3-benzenediol and its chemical structure is depicted below in Formula I

Cannabidiol is a phytocannabinoid discovered in 1940 and was approved in June 2018 by the U.S. Food and Drug Administration for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet Syndrome in patients 2 years of age and older.
Cannabidiol is synthesized using two key intermediates “2-Cyclohexen-1-ol, 1-methyl-4-(1-methylethenyl)” and “Methyl Olivetolate”.

Among the above two intermediates, synthesis of “2-Cyclohexen-1-ol, 1-methyl-4-(1-methylethenyl)” plays a major role in the synthesis of Cannabidiol due to its stereochemical configuration and its enantiomeric purity.
“2-Cyclohexen-1-ol, 1-methyl-4-(1-methylethenyl)” exists in, but not limited to, one or more of the following isomeric forms due to its chiral environment.

S. No Structure Chemical Name
1
(1R,4S)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol
2
(1S,4S)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol
3
(1S,4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol
4
(1R,4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol
5
(4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol
6
(4S)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol

There exist prior art methods in literature disclosing the preparation of isomers of 2-Cyclohexen-1-ol-1-methyl-4-(1-methylethenyl).

The Journal of Organic Chemistry (1964), 29(1), 185-7., discloses the synthesis of Cis and trans 2-dimethylamino-p-menthen-1-ols, an intermediate for the synthesis of (4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol, which comprises treating Cis and trans equal mixture of P-menthene-1,2-epoxide with aqueous dimethylamine to obtain mixed trans isomers of 2-dimethylamino-p-menthen-1-ol. The obtained trans isomers were dissolved in methanol, benzene and picric acid to form picrate salt of 2-dimethylamino-p-menthen-1-ol, treating the obtained picrate salt with dilute aqueous sodium hydroxide followed by ether extraction to obtain isomers of 2-dimethylamino-p-menthen-1-ol from picrate salt. The reaction scheme is depicted in Scheme-1.

Scheme-1

The US Patent No 4,433,183 A1 (hereafter US ‘183) invention relates to a process for the preparation of (1R,4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol which comprises epoxidation of (+)-(R)-Limonene by means of organic per acid to yield a diastereomeric mixture of (+)-(1R, 2S,4R)-1,2-epoxy-8-p-methene and (+)-(1S, 2R,4R)-1,2-epoxy-8-p-methene, treating the mixture with thiophenol to yield (+)-(1S,2S,4R)-2-phenylthio-8-p-methene-1-ol, oxidizing the obtained compound to the corresponding sulfoxide and heating the compound between 400 °C and 450 ºC to obtain (1R,4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol. The following scheme-2 describes the process as reported in US ‘183.

Scheme-2

The US Patent No 7,323,607 B2 (hereafter US ‘607) relates to the process for the preparation of (+)-P-Mentha-2,8-Diene-1-ol, wherein the process comprises reacting (+)-limonene oxide with an amine in the presence of a Lewis acid to form amine adduct intermediates. The desired amine adduct intermediate is formed at a ratio of greater than 20:1 over other reaction products. The amino adduct is purified by converting into its Hydrochloride salt. The desired amine adduct is then oxidized to form an N-oxide that is pyrolized to form (+)-P-Mentha-2,8-diene-1-ol.

The following scheme-3 describes the process for the preparation of P-Mentha-2,8-diene-1-ol as given in US ‘607.

Scheme-3

The Indian Publication Number 202011010503 (hereafter IN ‘503) discloses the synthesis of R-(+)-Menthadienol by reacting (R)-(+)-Limonene with phenylselenyl bromide in acetonitrile to obtain (+)-1-methyl-2-(phenylselanyl)-4-(prop-1-en-2-yl)cyclohexan-1-ol. The obtained compound is treated with select flour to obtain the compound R-Menthadienol. The following scheme-4 describes the process as given in IN ‘503.

Scheme-4

Tetrahedron Asymmetry (2002), 13(14), 1477-1483, generically discloses the purification of limonene amino alcohols through the formation of corresponding oxalate salts.

The PCT Publication No WO 2021/046636 (hereafter WO ‘636) discloses the synthesis of P-Menthadienol which comprises of reacting Limonene with N-bromosuccinamide to form bromohydrin, reacting the obtained bromohydrin with alkali solution to form epoxide, reacting the epoxide with dimethyl amine to prepare amino alcohol. The final compound (1R,4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol was prepared by reacting amino alcohol with hydrogen peroxide and heat. The following scheme-5 describes the process as given in WO ‘636.

Scheme-5

When the present inventors have repeated the prior art methods, the enantiomeric purity of desired isomer of p-Mentha-2,8-diene-1-ol obtained was not satisfactory and found to contain one or more of the undesired isomers.

Therefore, there is a need in the art to provide a simple and commercially viable process for the preparation of enantiomerically pure Mentha-2,8-diene-1-ol which is industrially advantageous and economically significant.

The inventors of the present invention have achieved this long felt need by first improving the enantiomeric purity of precursor compound “2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol” and thereby achieving the high enantiomeric purity of “Mentha-2,8-diene-1-ol”; Whereas the enantiomeric purity of “2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol” is achieved by purifying the crude enantiomeric enriched compound containing undesired isomers by treating it with resolving agent.

OBJECT OF THE INVENTION:
The primary object of the present invention is to provide a process for the preparation of enantiomerically pure (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of Formula VII which is free from other undesired isomers.

Another object of the present invention is to provide a process for the preparation of enantiomerically pure (4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol compound of Formula II which is free from other undesired isomers.

Another one object of the present invention is to provide a process for the preparation of Cannabidiol using enantiomerically pure (4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol compound of Formula II.

SUMMARY OF THE INVENTION:
ASPECT-I:
First aspect of the present invention is to provide a process comprising:
a) reacting (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of formula VII

with a resolving agent to obtain a salt compound of formula VIIa
; and
b) basifying the compound of Formula VIIa to obtain enantiomerically pure (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of Formula VII.

ASPECT-II:
Second aspect of the present invention is to provide a process comprising:
a) reacting (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of formula VII

with a resolving agent to obtain a salt compound of formula VIIa;

b) basifying the compound of Formula VIIa to obtain enantiomerically pure (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of Formula VII;
c) oxidizing the enantiomerically pure compound of formula VII using an oxidizing agent to obtain a compound of formula VIII
; and
d) subjecting the compound of formula VIII to pyrolysis to obtain enantiomerically pure (4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol of Formula II.

ASPECT-III:
Third aspect of the present invention is to provide a process comprising:
a) reacting (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of formula VII

with a resolving agent to obtain a salt compound of formula VIIa
;
b) basifying the compound of Formula VIIa to obtain enantiomerically pure (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of Formula VII
; and
c) converting the enantiomerically pure compound of formula VII to cannabidiol.

DEFINITIONS All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25ºC and normal pressure unless otherwise designated.
All temperatures used herein are in degrees Celsius unless specified otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements that may or may not be recited.
The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
The covalent bond represented here as “ ” encompasses a chiral center with either an (R)-isomer; and/or an (S)-isomer; and/or a racemic center.
As used here in, the compound of formula VII encompasses, but not limited to, any one or more of the possible isomer(s) enriched compound(s) as below:

As used herein, the compound of formula VIIa encompasses, but not limited to, any one or more of the possible isomer(s) enriched compound(s) as below:

As used herein, the compound of formula VIII encompasses, but not limited to, any one or more of the possible isomer(s) enriched compound(s) as below:

As used herein, the compound of formula II encompasses, but not limited to, any one or more of the possible isomer(s) enriched compound(s) as below:

DETAILED DESCRIPTION:
The inventors of the present invention have now surprisingly found that employing the use of a resolution agent resulted in high enantiomeric purity of (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound formula VII with the absence of undesired isomers.

The inventors of the present invention have also found that employing the use of a resolution agent in the process has resulted in high enantiomeric purity of (4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol compound formula II with the absence of undesired isomers.

Further the inventors have developed a process which avoids the use of column chromatography in the entire process to prepare enantiomerically pure (4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol compound of formula II.

EMBODIMENT-I:
In one embodiment, the present invention provides a process comprising:
a) reacting (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of formula VII

with a resolving agent to obtain a salt compound of formula VIIa
; and
b) basifying the compound of Formula VIIa to obtain enantiomerically pure (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol.

In the embodiments of step a), the resolving agent may be a chiral auxiliary compound or a an optical resolving agent. In some embodiments, chiral auxiliary compounds having carboxylic acid group(s) are used. The chiral auxiliary compounds may encompass, but not limited to, camphorsulfonic acid and its derivatives, L (+) Tartaric acid, D (-) Tartaric acid, D (-) (-)-Di-P-Toluoyl-L-tartaric acid, S (+) Mandelic acid and Pyroglutamic acid. In a particular embodiment, the L (+) Tartaric acid is preferably used as chiral auxiliary resolving agent.

In the preferred embodiments, when L (+) Tartaric acid agent was used, the below salt compound was formed:

In a more preferred embodiment, when L(+) Tartaric acid agent was used, the below salt compound was formed:

The ratio of salt to the compound of formula VII formed in the above embodiments may be in the range of 1:1 to 2:1; In a preferred embodiment L-Tartaric acid salt is formed in 1:1 ratio.

In the embodiments of step a), the input material “(4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol” may be enantiomerically impure with presence of one more undesired isomers such as: (1R,4S) isomer; and/or (1S,4S) isomer; and/or (1S,4R) isomer; and/or (1R,4R) isomer; and/or (4R)-isomer; and/or (4S)-isomer. In some embodiments, the input material was rich in (4R)-isomer having enantiomeric purity of above 80% but below 99.0% by HPLC.

In the embodiments of step b), suitable base may be selected from, but not limited to, organic and inorganic bases. Preferably the base is selected from alkali metal carbonates. In a preferred embodiment, the base used is sodium carbonate.

In some embodiments, both steps a) and step b) are performed in-situ i.e., without isolating the salt compound of formula VIIa.

In the embodiments of step b), the enantiomerically pure compound of formula VII obtained preferably has enantiomeric purity > 99.0%; more preferably > 99.5% by HPLC.

In a preferred embodiment, the compound obtained in step b) is enantiomerically pure (1S, 2R, 4R)- compound.

In the embodiments of step a), the input compound of formula VII may be prepared using any of the prior art process available in the literature. In a preferred embodiment, the input compound of formula VII was prepared as below and then directly used/in-situ used in the step a).

EMBODIMENT-II:
Second embodiment of the present invention provides a process comprising:
a) reacting (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of formula VII

with a resolving agent to obtain a salt compound of formula VIIa
;
b) basifying the compound of Formula VIIa to obtain enantiomerically pure (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol;
c) oxidizing the enantiomerically pure compound of formula VII using an oxidizing agent to obtain a compound of formula VIII; and

d) subjecting the compound of formula VIII to pyrolysis to obtain enantiomerically pure (4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol of Formula II.

In the embodiments of step a), the resolving agent used is same as the agent that was described under embodiment I.

In the embodiments of step b), the base used is same as the one that was described under embodiment I.

In the embodiments of step c), the oxidizing agent may be selected from, but not limited to, peroxides such as hydrogen peroxide, Cumene Hydroperoxide, Di-tert-butyl peroxide, Dicumyl peroxide. In one embodiment, preferably hydrogen peroxide was used.

In the embodiments of step c), after the oxidation reaction is completed, the excess of reagent used, if any, is decomposed or quenched using agents such as, but not limited to, Palladium/Carbon.

In some embodiments of step c), the oxidized product is optionally isolated before proceeding for pyrolysis.

In some embodiments of step c), the product of compound of formula VIII obtained can optionally be purified.

In the embodiments of step d), pyrolysis operation is carried by pre heating the reaction flask to 70-150o C under vacuum; followed by adding the compound of formula VIII and subjecting it to fractional distillation at the same temperature. The product of formula II collected from the fractions of the fractional distillation is further subjected to a high vacuum distillation.

In the embodiments of step d), the enantiomerically pure compound of formula II obtained preferably has enantiomeric purity > 99.8% by HPLC.

In a preferred embodiment, the compound of formula II obtained in step d) is (1S, 4R)- 1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol.

EMBODIMENT-III:
Third embodiment of the present invention provides a process comprising:
a) reacting (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of formula VII

with a resolving agent to obtain a salt compound of formula VIIa
;
b) basifying the compound of Formula VIIa to obtain enantiomerically pure (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of Formula VII; and
c) converting the enantiomerically pure compound of formula VII to cannabidiol.

In the embodiments of step a), the resolving agent used is same as the agent that was described under embodiment I.

In the embodiments of step b), the base used is same as the one that was described under embodiment I.

In the embodiments of step c), the enantiomerically pure compound of formula VII can be converted to Cannabidiol by any of the known literature methods. In one embodiment, the present inventors have adopted the below process in converting enantiomerically pure compound of formula VII to Cannabidiol.

Further, in the above scheme, the methyl 2,4-dihydroxy-6-pentylbenzoate intermediate may be obtained by any of the known literature methods. In one embodiment, the present inventors have prepared it in the following way:

In the first step: Non-3-en-2-one was reacted with Dimethyl malonate in presence of sodium Methoxide in toluene. After completion of the reaction, the reaction mass was subjected to work-up procedure and the product “methyl 2,4-dioxo-6-pentylcyclohexanecarboxylate” was isolated using n-heptane.

In the second step: The “methyl 2,4-dioxo-6-pentylcyclohexanecarboxylate” product obtained in the above step was treated with Bromine in Acetic acid. After completion of the reaction, the reaction mass was subjected to work-up procedure and the product
“methyl 3,5-dibromo-2,4-dihydroxy-6-pentylbenzoate” was isolated using n-heptane.

In the third step: The “methyl 3,5-dibromo-2,4-dihydroxy-6-pentylbenzoate” product obtained in the above step was reacted with Sodium bisulphite and potassium carbonate in Methanol:water medium. After completion of the reaction, filtered the reaction mass and filtrate was partially distilled out and pH was adjusted with acetic acid and product was extracted into Methyl Tertiary butyl ether. Finally, the organic layer was distilled followed by isolating the product of formula III from n-heptane.

In few embodiments, the compound of formula III was further hydrolyzed and decarboxylated in presence of sodium hydroxide in water at temperature 90-100°C; followed by work-up procedure and finally isolating the methyl 2,4-dihydroxy-6-pentylbenzoate compound from n-heptane which was proceeded to further convert into Cannabidiol.

EXAMPLES:
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.

Example CE-01:
Preparation of (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol Mandelic acid Salt (Formula VIIa)
Charged 2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of Formula VII (5.0 gm) , 20 ml Isopropyl alcohol to the round bottomed flask. Maintained the reaction at 25 to 30°C for 5-10 minutes. Charged S (+) Mandelic acid (5.5 gm) to the stirred clear reaction mass at 25-30°C. Maintained the reaction at 25-30° C. Resulted reaction mass was cooled and stirred at 15-25°C for 4 hrs. No solid precipitation observed.

Example CE-02:
Preparation of (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol D (-) (-)-tartaric Acid Salt (Formula VIIa)
Charged 2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of Formula VII (20 gm), Methanol (40 ml) and Toluene (100 ml) at 25 to 30°C to a round bottomed flask and stirred for 5-10 minutes. Charged D (-) Tartaric acid (23.58 gm) at 25-30°C. The reaction mass was stirred at 25 to 30° C for 5-10 minutes. Resulted reaction mass was cooled and stirred at 15-25°C for 4 hrs. No solid precipitation observed.

Example CE-03:
Preparation of (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol D (-) (-)-Di-p-toluoyl-L-tartaric Acid salt (Formula VIIa)
Charged 2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of Formula VII (20 gm) (SOR: 34.53°), Methanol (40 ml) and Toluene (100 ml). Maintained the reaction at 25 to 30°C for 5-10 minutes. Charged D (-) (-)-Di-p-toluoyl-L-tartaric Acid (63.5 gm) at 25-30°C. The reaction mass was stirred at 25-30° C for 5-10 minutes. Resulted slurry mass was cooled and stirred at 15 to 25°C for 4 hrs. The reaction mass was then filtered and the solid obtained was washed with 40 ml toluene. The product was dried under vacuum at 50-60° C for 12-15 hrs.
Yield: 27 gm salt
Specific optical rotation: (+) 104.0°

Example CE-04:
Preparation of (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol (Formula VII)
Charged (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol D (-) (-)-Di-p-toluoyl-L-tartaric Acid salt (25 gm) prepared as per example CE-03, water (100 ml) and MDC (82 ml) to the round bottomed flask. Maintained the reaction at 25-35°C for 10-15 minutes. Charged slowly Na2CO3 solution in water (13.63 gm Na2CO3 dissolved in 30 mL water) to the clear biphasic solution, to adjust pH of reaction mass between 8-11. The resulted biphasic slurry mass was stirred for 10-15 minutes, filtered and filtrate was separated. Methylene dichloride Layer distilled out to get isolated product. The isolated product was degassed for 2hrs under vacuum at below 60° C to afford the title compound.
Yield: 8.0 gm oil
Specific optical rotation: (+)-32.377° (C= 1% in methanol)

Example CE-05:
Preparation of (4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol (Formula II) (Without the use of Resolution Regent)
Charged 2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of Formula VII (320 gm), water (640 ml) into the round bottomed flask. Charged 50% H2O2 Solution in water (160 ml) and resulted reaction mass was stirred at room temperature. After completion of the reaction, 5% Pd-C (3.2 gm) was added to the reaction mass and stirred at room temperature to quench excess peroxide. Reaction mass was filtered, and filtrate was directly used for pyrolysis reaction. Filtrate was concentrated at 100 to 120°C to remove water and resulted residue was heated to 140 to 155°C for 45-60 minutes. After completion of the reaction, reaction mass was cooled to 25 to 35°C. Water (640 ml) and Cyclohexane (1600 ml) was added, stirred for 15-20 minutes and separated layers. Organic layer was washed with diluted H2SO4 and concentrated under vacuum at 50°C to obtain title compound.
Yield: 165.9 gm
GC purity: >95% (Enantiomeric purity by HPLC: 89.31% (R-isomer) & 10.69% S-Isomer)

Example ME-01:
Preparation of (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol (Formula VII)
Charged epoxide compound of formula VI (320 gm), 320 ml retarder solvent, 40% aqueous dimethylamine solution (988 gm) to the round bottomed flask. Heated the reaction mass to 50 °C to 60 °C. After completion of the reaction distilled out excess solvent from the reaction followed by water addition, pH adjustment, product was extracted in Methylene dichloride. The Methylene dichloride layer was distilled out and degassing to afford the title compound.
Yield: 352 gm
GC purity: 95% (Mixture of R-Isomer enriched ~ >90% and S-Isomer ~ < 10 %,)
Specific optical rotation: (+)-34.615° (C= 1% in methanol)

Example ME-02:
Preparation of (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol (2R, 3R)-2,3-dihydroxysuccinate [L-Tartarate salt of Formula VII a].
Charged the above ME-01 example prepared “2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol” compound of Formula VII (50 gm) , 125 ml of Methanol and 250 ml of Toluene to the round botted flask. Maintained the reaction at 25°C to 30°C for 5-10 minutes. Charged slowly L (+) Tartaric acid (58.9 gm) to the reaction mass. Maintained the reaction at 25°C to 30°C for 5-10 minutes. Maintained the reaction at 15°C to 25 °C for 4 hrs. Filtered the reaction mass and washed the obtained solid with 100 ml toluene. The product was dried under vacuum at 50-60° C for 12-15 hrs.
Yield: 73 gm.

Example ME-03:
Preparation of enantiomerically pure (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol (Formula VII)
Charged L-Tartrate salt compound of formula VII a (70 gm), water (280 ml) and MDC (350 ml) to the round botted flask. Maintained the reaction at 25°C to 35° for 10-15 minutes. Charged Na2CO3 solution in water (64.15 gm Na2CO3 dissolved in 140 ml water) to the clear biphasic solution, to adjust pH of aqueous layer of reaction mass between 8-11. Resulted biphasic reaction mass was stirred for 10-15 minutes and then separated layers. Aqueous layer was further extracted with methylene dichloride (210 ml) and after layer separation combine both organic layer and distilled out methylene dichloride to get isolated product. The isolated product was degassed for 2hrs under vacuum at below 60° C to afford title compound.
Yield: 37 gm
GC purity: > 97%.
Specific optical rotation: (+) 34.53.
Enantiomeric Purity = 99.5% (by GC)

Example ME-04:
Preparation of enantiomerically pure (4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol Formula II (Using Resolution Reagent)
Charged the above ME-03 example prepared enantiomerically pure (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of Formula VII (35 gm), water (70 ml), 50% H2O2 Solution in water (17.5 ml) to the round bottomed flask. Maintained the reaction at 25 to 35°C. After completion of the reaction, 5% Pd-C (0.35 gm) was added to the reaction mass and stirred at room temperature to quench excess peroxide. Reaction mass was filtered and filtrate was directly used for pyrolysis reaction. Filtrate was concentrated at 100-120°C to remove water and resulted residue was heated to 140-155°C for 45-60 minutes. After completion of the reaction, Reaction mass was cooled to 25-35°C. Water (70 ml) and Cyclohexane (175 ml) was added, stirred for 15-20 minutes and separated layers. Organic layer was washed with dilute H2SO4 and concentrated under vacuum at 50°C to obtain the title compound.
Yield: 16.3 gm
GC purity: >95%
Enantiomeric purity by HPLC: 100% (R-isomer).

Example ME-05:
Preparation of methyl 2,4-dihydroxy-6-pentylbenzoate (III)
i) Preparation of methyl 2,4-dioxo-6-pentylcyclohexanecarboxylate
Charged Non-3-en-2-one, dimethyl malonate, toluene, and sodium methoxide to round bottomed flask and stirred for 3 hours at 55 to 65°C. After completion of the reaction, added water, toluene, and Conc. HCl to the reaction mass and separated the layers. Isolated methyl 2,4-dioxo-6-pentylcyclohexanecarboxylate using n-heptane.
ii) Preparation of methyl 3,5-dibromo-2,4-dihydroxy-6-pentylbenzoate.
Charged methyl 2,4-dioxo-6-pentylcyclohexanecarboxylate, acetic acid, bromine in acetic acid to round bottomed flask and stirred for 1 hour at 20 to 30°C. After completion of the reaction, added sodium thiosulphate pentahydrate, water, and methylene dichloride to the reaction mass and separated the layers. Isolated methyl 3,5-dibromo-2,4-dihydroxy-6-pentylbenzoate using n-heptane.
iii) Preparation of methyl 2,4-dihydroxy-6-pentylbenzoate.
Charged methyl 3,5-dibromo-2,4-dihydroxy-6-pentylbenzoate, methanol, sodium bisulfite, and sodium carbonate in water solution to round bottomed flask and stirred for 6-7 hours at 50 to 60°C. After completion of the reaction, filtered the reaction mass. Added methanol, water, acetic acid, and methyl tertiary butyl ether to the wet cake, stirred the mass and separated the layers. Isolated methyl 2,4-dihydroxy-6-pentylbenzoate using n-heptane.

Example ME-06:
Preparation of Cannabidiol
Charged methyl 2,4-dihydroxy-6-pentylbenzoate, methylene dichloride, (4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol, BF3.Etherate to round bottomed flask and stirred for 4 hours at 20 to 30°C. After completion of the reaction, charged NaOH, NaHCO3 to the reaction mass. Separated the layers. Distilled out methylene dichloride under vacuum to obtain compound of IV as an oily mass.
Charged methanol to the oily mass in a round bottomed flask, added NaOH, n-heptane. Stirred and separated layers. To the aqueous layer added L-Ascorbic acid, NaOH and stirred. After the completion of the reaction, the compound was isolated using n-heptane to give pure Cannabidiol compound of formula I.

Example ME-07:
Purification of Cannabidiol
Charged Cannabidiol and n-decane to the round bottomed flask and heated to 30 to 40°C for 30 minutes. Cooled and filtered to obtain pure Cannabidiol of formula I.

Example ME-08:
Purification of Cannabidiol
Charged Cannabidiol and Isooctane to the round bottomed flask and heated to 30 to 40°C for 30 minutes. Cooled and filtered to obtain pure Cannabidiol of formula I.

Dated this 20th day of June 2023.

T. Srinivasa Reddy,
Deputy General Manager,
ZCL Chemicals Ltd.
,CLAIMS:We claim:
1. A process comprising:
a) reacting (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of formula VII

with a resolving agent to obtain a salt compound of formula VIIa
; and
b) basifying the compound of Formula VIIa to obtain enantiomerically pure (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of Formula VII.

2. The process according to claim 1, wherein the resolving agent is selected from a chiral auxiliary compound or an optical resolving agent.

3. The process according to claim 1, wherein the base is an organic or inorganic base.

4. A process comprising:
a) reacting (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of formula VII

with a resolving agent to obtain a salt compound of formula VIIa
;
b) basifying the compound of Formula VIIa to obtain enantiomerically pure (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of formula VII;

c) oxidizing the enantiomerically pure compound of formula VII using an oxidizing agent to obtain a compound of formula VIII; and

d) subjecting the compound of formula VIII to pyrolysis to obtain enantiomerically pure (4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol compound of Formula II.

5. The process according to claim 5, wherein the resolving agent is a chiral auxiliary compound or an optical resolving agent.

6. The process according to claim 5, wherein the base is an organic or an inorganic base.

7. The process according to claim 5, wherein the Oxidizing agent is selected from peroxides such as hydrogen peroxide, Cumene Hydroperoxide, Di-tert-butyl peroxide, Dicumyl peroxide.
8. The process according to claim 5, wherein the enantiomeric purity of (4R)-1-Methyl-4-(1-methylethenyl)-2-cyclohexen-1-ol compound of Formula II is greater than 99.8%.

9. A process for the preparation of Cannabidiol comprising:
a) reacting (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of formula VII

with a resolving agent to obtain a salt compound of formula VIIa

;
b) basifying the compound of Formula VIIa to obtain enantiomerically pure (4R)-2-(dimethyl amino)-1-methyl-4-(prop-1-en-2-yl) cyclohexanol compound of Formula VII; and
c) converting the enantiomerically pure compound of formula VII to cannabidiol.

10. The process according to claim 1, wherein Cannabidiol is prepared from the enantiomerically pure compound of formula VII.

Dated this 20th day of June 2023.

T. Srinivasa Reddy,
Deputy General Manager,
ZCL Chemicals Ltd.