DESC:Title of the Invention
An improved process for the preparation of Tapinarof.

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

Background of the Invention
TAPINAROF (also known as Benvitimod; DMVT-505; 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 obtained 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 is difficult to operate, handling, 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 101648851 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 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) reduction of Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2 in the presence of Borane dimethylsulfide complex (BMS) and suitable solvent to obtain Methyl 3,5-dimethoxy-4-isopropylbenzyl alcohol compound of Formula-3;

iii) oxidation of 3,5-dimethoxy-4-isopropylbenzyl alcohol compound of Formula-3 in the presence of oxidizing agent and suitable solvent to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4;

iv) condensation 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4 with compound of Formula-5 in the presence of sodium hydroxide powder and suitable solvent to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ene compound of Formula-6;

v) demethylation of 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ene compound of Formula-6 in the presence of pyridinium chloride and solvent to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound of Formula I.

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 or toluene; alcohol solvents such as isopropyl alcohol or methanol, ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or methyl acetate; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether or ethyl-tert-butyl ether; ketone solvents such as acetone or methyl ethyl ketone, chloro solvents such as dichloromethane, chloroform, ethylene chloride or carbon tetrachloride, polar aprotic solvents such as dimethyl sulfoxide or dimethyl formamide.

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.

Oxidizing agents are used throughout the invention is selected from Pyridinium chlorochromate or oxalyl chloride.

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

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

Scheme-II

In stage-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;

In stage-ii), reducing Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2 by using Borane dimethylsulfide complex (BMS) in the presence of suitable solvent to obtain Methyl 3,5-dimethoxy-4-isopropylbenzyl alcohol compound of Formula-3;

In stage-iii), oxidation of 3,5-dimethoxy-4-isopropylbenzyl alcohol compound of Formula-3 in the presence of oxidizing agent and suitable solvent to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4;

In stage-iv), condensation 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4 with compound of Formula-5 in the presence of sodium hydroxide powder and suitable solvent to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ene compound of Formula-6;

In stage-v), demethylation of 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ene compound of Formula-6 in the presence of pyridinium chloride and suitable solvent to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound of Formula I.

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:
Stage-1: Preparation of 4-isopropyl-3,5-dimethoxybenzoic acid (Formula - 2)
The solution of methyl 3,5-dimethoxybenzoate (200 grams) in 80% sulphuric acid at 25-30 °C was heated to 60-65 °C. To the above solution, added Isopropanol (80 mL) and maintained for 5.0 hours at 60-65 °C. After completion of the reaction, purified water (2000 mL) was added to the reaction mixture at 60-65 °C and stirred for 30 minutes and cooled to 25-30 °C. Filtered the solid and washed the solid with purified water (200 mL). Solid was dissolved in MTBE (1000 mL) and added Purified water (800 mL). Separated organic layer and again extracted aqueous layer with MTBE (400 mL). Distilled the solvent under reduced pressure below 40 °C and co-distilled with n-heptane (200 mL), finally isolated with n-Heptane (1000 mL) to give brown colour solid. (Yield: 75 %).

Stage-2: Preparation of 4-isopropyl-3,5-dimethoxyphenyl) methanol (Formula – 3)
4-isopropyl-3,5-dimethoxybenzoic acid (300 grams) was dissolved in THF (1500 mL) and the mixture was heated to 50-55 °C. To the above reaction mass, Borane DMS complex 10 M in toluene (256 mL, 2.0 equivalents) was added and maintained for 2.0 hours at 50-55 °C. After completion of the reaction, quenched reaction mass with 2N HCl solution (1500 mL) below 10 °C. Filtered the mass through celite and washed the bed with Ethyl acetate (600 mL). Layers were separated and extracted aqueous layer with Ethyl acetate (600 mL). Combined organic layer was washed with 10% sodium chloride solution twice (2x1500 mL). The organic layer was distilled under reduced pressure below 45 °C up to maximum extent and co-distilled with n-heptane (300 mL). Finally isolated with n-Heptane (900 mL) to give brown colour solid. (Yield: 75 %).

Stage-3: Preparation of 4-isopropyl-3,5-dimethoxybenzaldehyde (Formula – 4)
To the solution of 4-isopropyl-3,5-dimethoxyphenyl) methanol (150 grams) in MDC (1500 mL) at 20-30 °C, Pyridinium chlorochromate (154 grams, 1.0 equivalents) was added lot wise below 25 °C for 2.0 hours and maintained for 2.0-4.0 hours at 25-30 °C. The reaction mass was filtered through hyflo and washed bed with MDC (300 mL). Distilled MDC under reduced pressure below 35 °C and co-distilled with diisopropylether (150 mL). Diisopropylether (900 mL) was added to the crude and stirred for 1.0 hour. Filtered the mass and washed with diisopropylether (75 mL). The filtrate was distilled and co-distilled with n-heptane (150 mL). Finally isolated with n-Heptane (750 mL) to give light brown colour solid. (Yield: 60 %).

Stage-4: Preparation of (E)-2-isopropyl-1,3-dimethoxy-5-styrylbenzene (Formula – 6)
To the solution of Diethyl benzyl phosphonate (44 grams, 1.0 equivalents) in DMSO (80 mL) at 10-20 °C, charged NaOH powder (21.6 grams, 2.0 equivalents). Stirred the reaction mass for 2 hours and added 4-isopropyl-3,5-dimethoxybenzaldehyde (40 grams) in DMSO (80 mL) solution below 20 °C and maintained for 3.0 hours at 25-30 °C. After completion of the reaction, added purified water (400 mL) Hexanes (400 mL) to the reaction mass below 20 °C respectively. The reaction mass was allowed to stir for 30 minutes and separated organic layer. Extracted aqueous layer again with hexanes (200 mL) and filtered the organic layer through celite and washed with hexanes (80 mL). Separated the organic layer and washed the organic layer with water (320 mL). Distilled the organic layer and co-distilled with n-heptane (40 mL), finally isolated with n-Heptane (80 mL) to give light brown colour solid. (Yield: 65 %)

Stage-5: Preparation of (E)-2-isopropyl-5-styrylbenzene-1,3-diol (Formula - I)
The mixture of (E)-2-isopropyl-1,3-dimethoxy-5-styrylbenzene (30 grams) and pyridinium chloride (90 grams) was heated to 160-170 °C and stirred for 6.0-8.0 hours. After completion of the reaction, cooled the reaction mass to 30-35 °C and added water (120 mL) and Ethyl acetate (300 mL). Stirred the mass for 15 minutes. Separated the organic layer and extracted aq.layer with Ethyl actetate (150 mL). washed the combined organic layer with 8 % NaHCO3 solution (25 mL) followed by water (600 mL). Separated the organic layer and distilled the solvent completely under reduced pressure. wet solid finally isolated with n-heptane (90 mL) to give brown colour solid. (Yield: 55 %).
,CLAIMS:We claim:
1. 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 acid to obtain Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2;

ii) reduction of Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2 in the presence of Borane dimethyl sulfide complex (BMS) and solvent to obtain Methyl 3,5-dimethoxy-4-isopropylbenzyl alcohol compound of Formula-3;

iii) oxidation of 3,5-dimethoxy-4-isopropylbenzyl alcohol compound of Formula-3 in the presence of oxidizing agent and solvent to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4;

iv) condensation of 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula-4 with compound of Formula-5 in the presence of sodium hydroxide powder and solvent to obtain 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ene compound of Formula-6;

v) demethylation of 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ene compound of Formula-6 in the presence of pyridinium chloride and solvent to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound of Formula I.

2. The process as claimed in claim 1, wherein acid is 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.

3. The process as claimed in claim 1, wherein solvent is selected from the group consisting of hexane, heptane, ethyl acetate, tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, isopropyl alcohol, methanol, acetone, dichloromethane, dichloroethane, dimethyl sulphoxide, dimethyl formamide or water.

4. The process as claimed in claim 1, wherein Oxidizing agent is selected from the group consisting of Pyridinium chlorochromate or oxalyl chloride.