DESC:The present invention relates to an improved process for the preparation of Tapinarof compound of Formula-I.

The present invention also relates to novel intermediate compound of Formula-5 used in the preparation of Tapinarof compound of Formula-I

The present invention also relates to process for the preparation of intermediate compound of Formula-5

Background of the Invention
TAPINAROF (also known as Benvitimod; WB-1001; GSK-2894512 and WBI-1001) is chemically known as 3,5-Dihydroxy-4-isopropyl-trans-stilbene or 5-[(E)-2-Phenylethen-1-yl]-2-(propan-2-yl) benzene-1,3-diol. The molecular formula is C17H18O2 and the molecular weight is 254.329 grams per mole. The structural Formula is:

Tapinarof is a bacterial stilbenoid produced in Photorhabdus bacterial symbionts of Heterorhabditis nematodes. It is a product of an alternative ketosynthase-directed stilbenoids biosynthesis pathway. It is derived from the condensation of two ß-ketoacyl thioesters. It is produced by the Photorhabdus luminescens bacterial symbiont species of the entomopathogenic nematode, Heterorhabditis megidis.

Tapinarof is an investigational, novel, therapeutic aryl hydrocarbon receptor modulating agent, in development as a once-daily, steroid-free and cosmetically elegant topical cream for the treatment of plaque psoriasis and atopic dermatitis.

Psoriasis is a chronic, systemic, inflammatory skin disease characterized by red patches and plaques with silvery scales on the skin. Psoriasis affects approximately 8 million people in the United States and 125 million worldwide.

Psoriasis can begin at any age, but typically has two peaks of onset, the first at age 20 to 30 years and the second at age 50 to 60 years. People with psoriasis are at an increased risk of developing other chronic and serious health conditions. Comorbidities include psoriatic arthritis, inflammatory bowel disease, hypertension, diabetes, obesity, and depression. Psoriasis has a significant impact on quality of life and on psychological health.

Tapinarof is a non-steroidal anti-inflammatory drug originated by Welichem Biotech. Tianji Pharma and Shenzen Celestial Pharmaceuticals obtain rights to the product in the Greater China region in 2005. In May 2019, the drug was approved in China for the treatment of moderate stable psoriasis vulgaris in adults and, in July 2019, Tianji Pharma (subsidiary of Guanhao Biotech) launched the product in China for the treatment of moderate stable psoriasis vulgaris in adults.

Tapinarof is first time disclosed in Journal of Chemical Ecology 1981, Volume: 7, Number: 3, Pages: 589 – 597, isolated from Xenorhabdus sp. (strain Hb). However, this compound has not been shown to other biological activity.

US 7,321,050 B2 (WO 0142231 A2, Welichem Biotech Inc.,) discloses Tapinarof or a salt thereof. This patent discloses process for the preparation of Tapinarof compound of Formula-I, synthesized from commercially available 3, 4-dihydroxybenzoic acid compound of Formula A, which is schematically shown below in Scheme-I:

SCHEME-I

The synthesis disclosed in this prior art has the disadvantage is that it is difficult to operate, a longer time is generally needed, and the reagents are expensive, finally the product was purified by column chromatography.

Further, several routes to the synthesis of Tapinarof compound of Formula-I are known in the art, which are US 10,647,649 B2 (WO 2019094934 A1), CN 10164885 B1, CN 103265412 A, European Journal of Organic Chemistry 2014, 8026-8028. The process disclosed in above references should undergo repeated purification procedures and also uses expensive reagents.

Therefore, it would be desirable and of paramount importance to have a process for the preparation of Tapinarof compound of Formula-I, by employing inexpensive, readily available, easy to handle reagents. It would also be desirable to have a process that can be readily scaled up and which does not require a special purification step, thereby making it more suitable for industrial scale preparation.

Summary of the Invention

The present invention provides a cost effective, novel and an efficient process for the preparation of Tapinarof compound of Formula-I with higher yields and better purity.

In one aspect, the present invention relates to the novel intermediate of the compound of Formula-5, which is useful in the preparation of Tapinarof compound of Formula-I

In another aspect, the present invention provides an improved process for the preparation of Tapinarof compound of Formula-I.


which comprises:
i) reacting Methyl 3,5-dimethoxy benzoate compound of Formula-1

with Isopropanol in presence of suitable acid to obtain Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2;

ii) reacting Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2 with reducing agent in the presence of suitable solvents to obtain Methyl 3,5-dimethoxy-4-isopropylbenzyl alcohol compound of Formula-3;

iii) reacting 3,5-dimethoxy-4-isopropylbenzyl alcohol compound of Formula-3 with acetic anhydride in the presence of suitable solvents to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4;

iv) condensation 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4 with aryl magnesium halide in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5;

v) reacting 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5 with suitable acid in the presence of suitable solvents to obtain 3,5-dimethoxy-4-isopropyl-trans-stilbene compound of Formula-6; and

vi) reacting the 3,5-Dimethoxy4-isopropyl-trans-stilbene compound of Formula-6 with boron tribromide in the presence of suitable solvent to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound of Formula I.

In another aspect, the present invention provides an improved process for the preparation of Tapinarof compound of Formula-I.

which comprises:
i) reacting Methyl 3,5-dimethoxy benzoate compound of Formula-1

with Isopropanol in presence of presence of suitable acid to obtain Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2;

ii) condensation of Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2 with aryl magnesium halide in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-one compound of Formula-8;

iii) reduction 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-one compound of Formula-8 with suitable reducing agent in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5;

iv) reacting 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5 with suitable acid in the presence of suitable solvents to obtain 3,5-dimethoxy-4-isopropyl-trans-stilbene compound of Formula-6; and

v) reacting the 3,5-Dimethoxy4-isopropyl-trans-stilbene compound of Formula-6 with boron tribromide in the presence of suitable solvents to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound of Formula I.

In another aspect, the present invention provides an improved process for the preparation of Tapinarof compound of Formula-5.

which comprises:
i) condensation of Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2

with aryl magnesium halide in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-one compound of Formula-8; and

ii) reduction 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-one compound of Formula-8 with suitable reducing agents in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5;

In another aspect, the present invention provides an improved process for the preparation of Tapinarof intermediate compound of Formula-5.

which comprises:
i) reacting 3,5-dimethoxy-4-isopropylbenzyl alcohol compound of Formula-3

with acetic anhydride suitable in the presence of suitable solvents and to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde compound Formula-4; and

ii) condensation 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4 with aryl magnesium halide in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5;

Detailed Description of the Invention

Unless otherwise stated, the following terms used in the specification have the meanings given below:

Solvents used throughout the invention is selected from the group consisting of hydrocarbon solvents such as pentane, hexane, heptane, xylene, toluene; alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, amide solvent such as dimethylacetamide, dimethylformamide, formamide, N-Methylformamide, chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride, organosulfur solvent such as dimethyl sulfoxide, dimethyl sulfone, acetic acid, water and its mixture thereof.

Base used throughout the invention is selected from the group consisting of include, but are not limited to alkylmetal base such as methyllithium, n-butyllithium, tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, and phenyl potassium; metal amide bases such as lithium amide, sodium amide, potassium amide, lithium tetramethylpiperidide, diisopropylamine, lithium diisopropylamide, lithium diethylamide or lithium dicyclohexylamide. sodium hydride, potassium hydride, NaOPt, n-butyllithium, tert-butyllithium, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide or caesium hydroxide.

Reducing agent are used throughout the invention selected from the group consisting of sodium borohydride (NaBH4), potassium borohydride (KBH4) or lithium borohydride (LiBH4).

Acids are used throughout the invention selected from the group consisting of sulphuric acid, sulphurous acid, nitric acid, nitrous acid, hydrochloric acid, hydrobromic acid, acetic acid, sulfonic acids or phosphoric acids.

Accordingly, the present invention provides an improved process for the preparation of Tapinarof compound of Formula I.

The process for the preparation of compound of Formula-2, which is outlined below in Scheme-II:

Scheme-II
The main embodiment of the present invention provides an improved process for the preparation of Tapinarof, which is outlined below in Scheme-III:

Scheme-III

In step-i), reacting Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2 with reducing agent in the presence of suitable solvents to obtain Methyl 3,5-dimethoxy-4-isopropylbenzyl alcohol compound of Formula-3;
In step-ii), reacting 3,5-dimethoxy-4-isopropylbenzyl alcohol compound of Formula-3 with suitable solvent and acetic anhydride to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4;

In step-iii), condensation 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4 with aryl magnesium halide in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5;

In step-iv), reacting 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5 with suitable acid in the presence of suitable solvents to obtain 3,5-dimethoxy-4-isopropyl-trans-stilbene compound of Formula-6; and

In step-v), reacting the 3,5-Dimethoxy4-isopropyl-trans-stilbene compound of Formula-6 with boron tribromide in the presence of suitable solvent to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound of Formula I.

The embodiment of the present invention provides an improved process for the preparation of Tapinarof, which is outlined below in Scheme-IV:

Scheme-IV
In step-i), condensation of Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2 with aryl magnesium halide in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-one compound of Formula-8;

In step-ii), reduction 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-one compound of Formula-8 with suitable reducing agent in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5;

In step-iii), reacting 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5 with suitable acid in the presence of suitable solvents to obtain 3,5-dimethoxy-4-isopropyl-trans-stilbene compound of Formula-6; and

In step-iv), reacting the 3,5-Dimethoxy4-isopropyl-trans-stilbene compound of Formula-6 with boron tribromide in the presence of suitable solvents to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound of Formula I.

In yet another aspect the present invention provides an improved process for the preparation of Tapinarof compound of Formula 5.

The embodiment of the present invention provides an improved process for the preparation of Tapinarof, which is outlined below in Scheme-V:

Scheme-V

In step-i), reacting 3,5-dimethoxy-4-isopropylbenzyl alcohol compound of Formula-3 with suitable solvent and acetic anhydride to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4; and

In step-ii), condensation 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4 with aryl magnesium halide in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5.

In yet another aspect the present invention provides an improved process for the preparation of Tapinarof compound of Formula 5.

The embodiment of the present invention provides an improved process for the preparation of Tapinarof, which is outlined below in Scheme-VI:

Scheme-VI
In step-i), condensation 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-2 with aryl magnesium halide in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-8; and
In step-ii), reduction 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-8 with suitable reducing agent in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5.

EXPERIMENTAL PORTION:
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.
EXAMPLES:
Preparation-1: Process for the preparation of Methyl 3,5-dimethoxy-4-isopropylbenzoate (Formula 2)
Methyl 3,5-dimethoxy benzoate (1) reacted with 80% H2SO4 in presence of isopropanol was added dropwise to the above reaction mixture over a period. After addition of isopropanol, the mixture was stirred for 3 to 4 hours. The mixture was carefully poured into ice-water and pH was adjusted to 7 with saturated Na2CO3 solution then filter by using celite bed. After filtration, the filtrate was acidified with HCl and extracted with ethyl acetate. The combined extract was dried over anhydrous Na2SO4 and concentrated to obtain Methyl 3,5-dimethoxy-4-isopropylbenzoate (2) as faint yellow solid.
Example-1:
Step-i): Process for the preparation of 3,5-dimethoxy-4-isopropylbenzyl alcohol (Formula 3)
Methyl 3,5-dimethoxy-4-isopropylbenzoate 2 (obtained from preparation -1), reacted with NaBH4 in presence of THF, and the temperature of the mixture was gradually increased to reflux. Methanol was added dropwise to the mixture over a period and maintained for 4 to 5 hours. After completion of the reaction, the mixture was poured into water with stirring. Separate the organic layer and the aqueous layer extracted with ethyl acetate. Combined the organic layer and was washed with water until it was neutral and dried over anhydrous sodium sulphate and remove the solvent under reduced pressure to obtain residue. The residue was recrystallised from ethanol/water to obtain 3,5-Dimethoxy-4-isopropylbenzyl alcohol (3) as a white needle crystals.
Step-ii): Process for the preparation of 3,5-dimethoxy-4-isopropylbenzaldehyde (Formula 4)
3,5-Dimethoxy-4-isopropylbenzyl alcohol 3 (obtained from step-i), dissolved in DMSO and acetic anhydride at room temperature, then stirred the reaction mixture at same temperature for 2 to 3 hours. After the reaction mixture was diluted with water and separated the organic layer. Aqueous layer was extracted with ethyl acetate. Combined the organic layer and washed with water until it was to neutral and dried over anhydrous sodium sulphate and remove the solvent under reduced pressure to obtain crude compound (off-white solid). The crude solid was recrystallised from hexane/ethyl acetate to obtain pure compound of 3,5-Dimethoxy-4-isopropylbenzaldehyde (4).
Step-iii): Process for the preparation of 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol (Formula 5)
3,5-Dimethoxy-4-isopropylbenzaldehyde 4 (obtained from step-ii), reacted with benzyl magnesium bromide in Tetrahydrofuran at room temperature. After completion of the reaction, cool to 0-10 °C and the reaction mixture was poured into 20% aqueous hydrochloric acid solution and ethyl acetate was poured into the reaction then stirred vigorously. Separate the organic and aqueous layer, then separate the organic layer dried over sodium sulphate and remove the solvent under reduced pressure to obtain crude compound. The crude compound was recrystallized from hexane/ethyl acetate to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol (5).
Step-iv): Process for the preparation of 3,5-dimethoxy4-isopropyl-trans-stilbene (Formula 6)
1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol 5 (btained from step-iii), was treated with sulphuric acid in Toluene under reflux condition. After reaction complies cooled the reaction mass slowly added purified. Then slowly charged saturated aqueous sodium bicarbonate solution to the reaction mass and stirred for few minutes. Separated the organic layer from aqueous layer. Aqueous layer extracted with toluene. Concentrated the organic layer under vacuum at 55 °C. The product was crystallized from ether/hexanes to obtain 3,5-dimethoxy4-isopropyl-trans-stilbene (6).
Step-v): Process for the preparation of (E)-2-isopropyl-5-styrylbenzene-1,3-diol (Formula I)
BBr3 dissolved in dry CH2Cl2 was added dropwise into 3,5-dimethoxy4-isopropyl-trans-stilbene 6 (obtained from step-iv), in dry CH2Cl2 and maintained for 18 hours. The mixture was then poured on the ice and the organic layer was separated and aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with saturated NaCl, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to dryness to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol (I).
Example 2:
Step-i): Process for the preparation of 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-one (Formula 8)
Methyl 3,5-dimethoxy-4-isopropylbenzoate 2 (obtained from preparation-1), reacted with benzyl magnesium bromide in Tetrahydrofuran at room temperature. After completion of the reaction, cool to 0-10 °C and the reaction mixture was poured into 20% aqueous hydrochloric acid solution and ethyl acetate was poured into the reaction then stirred vigorously. Separate the organic and aqueous layer, then separate the organic layer dried over sodium sulphate and remove the solvent under reduced pressure to obtain crude compound. The crude compound was recrystallized from hexane/ethyl acetate to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-one (8).
Step-ii): Process for the preparation of 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol (Formula 5)
1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-one 8 (obtained from step-i), reacted with NaBH4 in presence of THF, and the temperature of the mixture was gradually increased to reflux. Methanol was added dropwise to the mixture over a period and maintained for 4 to 5 hours. After completion of the reaction, the mixture was poured into water with stirring. Separate the organic layer and the aqueous layer extracted with ethyl acetate. Combined the organic layer and was washed with water until it was neutral and dried over anhydrous sodium sulphate and remove the solvent under reduced pressure to obtain residue. The residue was recrystallised from ethanol/water to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol (5) as a white needle crystals.
Step-iii): Process for the preparation of 3,5-dimethoxy4-isopropyl-trans-stilbene (Formula 6)
1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol 5 (obtained from step-ii), was treated with sulphuric acid in Toluene under reflux condition. After reaction complies cooled the reaction mass slowly added purified. Then slowly charged saturated aqueous sodium bicarbonate solution to the reaction mass and stirred for few minutes. Separated the organic layer from aqueous layer. Aqueous layer extracted with toluene. Concentrated the organic layer under vacuum at 55 °C. The product was crystallized from ether/hexanes to obtain 3,5-dimethoxy4-isopropyl-trans-stilbene (6).
Step-iv): Process for the preparation of (E)-2-isopropyl-5-styrylbenzene-1,3-diol (Formula I)
BBr3 dissolved in dry CH2Cl2 was added dropwise into 3,5-dimethoxy4-isopropyl-trans-stilbene 6 (obtained from step-iii), in dry CH2Cl2 and maintained for 18 hours. The mixture was then poured on the ice and the organic layer was separated and aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with saturated NaCl, dried over anhydrous sodium sulphate, and evaporated under reduced pressure to dryness to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol (I).
,CLAIMS:1. A process for preparing Tapinarof of compound of Formula-I,

Wherein the process comprises:
i) reacting Methyl 3,5-dimethoxy benzoate compound of Formula-1

with Isopropanol in presence of suitable acid to obtain Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2;

ii) reacting Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2 with reducing agent in the presence of suitable solvents to obtain Methyl 3,5-dimethoxy-4-isopropylbenzyl alcohol compound of Formula-3;

iii) reacting 3,5-dimethoxy-4-isopropylbenzyl alcohol compound of Formula-3 with acetic anhydride in the presence of suitable solvents to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4;

iv) condensation 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4 with aryl magnesium halide in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5;

v) reacting 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5 with suitable acid in the presence of suitable solvents to obtain 3,5-dimethoxy-4-isopropyl-trans-stilbene compound of Formula-6; and

vi) reacting the 3,5-Dimethoxy4-isopropyl-trans-stilbene compound of Formula-6 with boron tribromide in the presence of suitable solvent to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound of Formula I.

2. An improved process for the preparation of Tapinarof compound of Formula-I.

which comprises:
i) reacting Methyl 3,5-dimethoxy benzoate compound of Formula-1

with Isopropanol in presence of presence of suitable acid to obtain Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2;

ii) condensation of Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2 with aryl magnesium halide in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-one compound of Formula-8;

iii) reduction 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-one compound of Formula-8 with suitable reducing agent in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5;

iv) reacting 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5 with suitable acid in the presence of suitable solvents to obtain 3,5-dimethoxy-4-isopropyl-trans-stilbene compound of Formula-6; and

v) reacting the 3,5-Dimethoxy4-isopropyl-trans-stilbene compound of Formula-6 with boron tribromide in the presence of suitable solvents to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound of Formula I.

3. The process as claimed in claims 1 and 2, wherein, acid is selected from sulphuric acid, sulphurous acid, nitric acid, nitrous acid, hydrochloric acid, hydrobromic acid, acetic acid, sulfonic acids or phosphoric acids and reducing agent is selected from sodium borohydride, potassium borohydride or lithium borohydride.

4. The process as claimed in claims 1 and 2, wherein, solvent used in all the stages is selected form hydrocarbon solvents, alcoholic solvents, ester solvents, nitrile solvents, ether solvents, ketone solvents, amide solvents, chloro solvents, organosulfur solvents or water.

5. Tapinarof intermediate compound of Formula-5.

6. A process for the preparation of Tapinarof intermediate compound of Formula-5.

which comprises:
i) condensation of Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2

with aryl magnesium halide in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-one compound of Formula-8; and

ii) reduction 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-one compound of Formula-8 with suitable reducing agents in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5.

7. An improved process for the preparation of Tapinarof intermediate compound of Formula-5.

which comprises:
i) reacting 3,5-dimethoxy-4-isopropylbenzyl alcohol compound of Formula-3

with acetic anhydride suitable in the presence of suitable solvents and to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde compound Formula-4; and

ii) condensation 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4 with aryl magnesium halide in the presence of suitable solvents to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ol compound of Formula-5.

8. The process as claimed in claims 6 and 7, wherein, reducing agent is selected from sodium borohydride, potassium borohydride or lithium borohydride.

9. The process as claimed in claims 6 and 7, wherein, solvent used in all the stages is selected form hydrocarbon solvents, alcoholic solvents, ester solvents, nitrile solvents, ether solvents, ketone solvents, amide solvents, chloro solvents, organosulfur solvents or water.