DESC:Title of the Invention
An improved process for the preparation of Tapinarof and its novel intermediate.

Field of the Invention
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 3(B) 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 – 3(B).

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 has the disadvantage is that it 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 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 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 Carbonyldiimidazole in presence of solvent to obtain compound of Formula – 3(A) in-situ or optionally isolated;

iii) reacting (1H-imidazol-1-yl)(4-isopropyl-3,5-dimethoxyphenyl)methanone compound of Formula - 3(A) with N,O-dimethylhydroxylamine hydrochloride in presence of solvent to obtain 4-isopropyl-N-3,5-trimethoxy-N-methylbenzamide compound of Formula – 3(B);

iv) reduction of 4-isopropyl-N-3,5-trimethoxy-N-methylbenzamide compound of Formula – 3(B) in presence of reducing agent and solvent to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula - 4;

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

vi) reacting the 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ene compound of Formula - 6 in the presence of acid 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; alcoholic solvent such as methanol, ethanol, propanol or isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether or ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone or diethyl ketone; amide solvent such as dimethylacetamide, dimethylformamide, formamide or N-Methylformamide; chloro solvents such as dichloromethane, chloroform, ethylene chloride or carbon tetrachloride; polar aprotic solvents such as dimethyl sulfoxide, dimethyl formamide or dichloromethane.

Reducing agents used throughout the invention is selected from the group consisting of Borane reagents like Borane dimethylsulfide complex, sodium borohydride (NaBH4), potassium borohydride (KBH4) or lithium borohydride (LiBH4) and Aluminium reagents like lithium aluminium hydride (LiAlH4), Sodium bis(2-methoxyethoxy)aluminium hydride (Red Al or Vitride) or Diisobutylaluminium hydride (DIBAL) etc.

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

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

Alkaline hydroxides used throughout the invention is selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium hydroxide powder and caesium hydroxide preferably potassium hydroxide or potassium hydroxide powder.

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 of compound of Formula I, 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 acid to obtain Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2;
Wherein stage (i) reaction is carried out at temperature 50 °C to 70 °C and reaction time is 4 to 6 hours.

In stage ii), reacting Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2 with Carbonyldiimidazole in presence of solvent to obtain compound of Formula – 3(A) in-situ or optionally isolated;

Wherein stage (ii) reaction is carried out at temperature 20 °C to 40 °C and reaction time is 1 to 5 hours.

In stage iii), reacting (1H-imidazol-1-yl)(4-isopropyl-3,5-dimethoxyphenyl) methanone compound of Formula-3(A) with N,O-dimethylhydroxylamine hydrochloride in presence of solvent to obtain 4-isopropyl-N-3,5-trimethoxy-N-methylbenzamide compound of Formula – 3(B);

Wherein stage (iii) reaction is carried out at ambient temperature and reaction time is 12 to 18 hours.

In stage iv), reduction of 4-isopropyl-N-3,5-trimethoxy-N-methylbenzamide compound of Formula – 3(B) in presence of reducing agent and solvent to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula - 4;

Wherein stage (iv) reaction is carried out at temperature 0-10 °C and reaction time is 20 to 40 minutes.

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

Wherein stage (v) reaction is carried out at temperature 10 to 25 °C and reaction time is 1 to 2 hours.

In stage vi), reacting the 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ene compound of Formula-6 in the presence of acid and solvent to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound of Formula - I.

Wherein stage (vi) reaction is carried out at temperature 150 to 180 °C and reaction time is 5 to 9 hours.

The another embodiment of the present invention provides an improved process for the preparation of 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula - 3(B), which is outlined below in Scheme-III:

Scheme - III

In stage 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;

Wherein stage (i) reaction is carried out at temperature 50 °C to 70 °C and reaction time is 4 to 6 hours.

In stage ii), reacting Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula-2 with Carbonyldiimidazole in presence of solvent to obtain compound of Formula – 3(A) in-situ or optionally isolated;

Wherein stage (ii) reaction is carried out at temperature 20 °C to 40 °C and reaction time is 1 to 5 hours.

In stage iii), reacting (1H-imidazol-1-yl)(4-isopropyl-3,5-dimethoxyphenyl) methanone compound of Formula - 3(A) with N,O-dimethylhydroxylamine hydrochloride in presence of solvent to obtain 4-isopropyl-N-3,5-trimethoxy-N-methylbenzamide compound of Formula – 3(B);

Wherein stage (iii) reaction is carried out at ambient temperature and reaction time is 12 to 18 hours.

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:
Stage-1: Preparation of 4-isopropyl-3,5-dimethoxybenzoic acid
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 Methyl tert-butyl ether (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 (a): Preparation of (1H-imidazol-1-yl)(4-isopropyl-3,5-dimethoxy phenyl) methanone
To the solution of 4-isopropyl-3,5-dimethoxybenzoic acid (5.0 grams) in MDC (50 mL) at 25-30 °C, CDI (4.52 grams, 1.25 equivalents) was added lot wise. The mixture was allowed to stir for 2-4 hours and resulted compound further involved in reaction with out isolation or optionally isolated.

Stage-2 (b): Preparation of 4-isopropyl-N-3,5-trimethoxy-N-methylbenzamide
To the solution of 4-isopropyl-3,5-dimethoxybenzoic acid (5.0 grams) in MDC (50 mL) at 25-30 °C, CDI (4.52 grams, 1.25 equivalents) was added lot wise. The mixture was allowed to stir for 2-4 hours. after completion of the reaction, N, O dimethyl hydroxyl amine HCl (2.72 grams, 1.25 equivalents) was added and stirred for 14-16 hours at ambient temperature. To the reaction mass, water (25 mL) and MDC (25 mL) were added. washed the separated organic layer with 1N HCl solution (45 mL), water (25 mL) and 10% NaHCO3 solution (50 mL) sequentially. Distilled out separated MDC layer under reduced pressure below 40°C to get crude compound of formula 3(B).

Stage-3: Preparation of 4-isopropyl-3,5-dimethoxybenzaldehyde
To the solution of 4-isopropyl-3,5-dimethoxybenzoic acid (5.0 grams) in MDC (50 mL) at 25-30 °C, CDI (4.52 grams, 1.25 equivalents) was added lot wise. The mixture was allowed to stir for 2-4 hours. after completion of the reaction, N, O dimethyl hydroxyl amine HCl (2.72 grams, 1.25 equivalents) was added and stirred for 14-16 hours at ambient temperature. To the reaction mass, water (25 mL) and MDC (25 mL) were added. washed the separated organic layer with 1N HCl solution (45 mL), water (25 mL) and 10% NaHCO3 solution (50 mL) sequentially. Distilled out separated MDC layer under reduced pressure below 40°C to get crude which was dissolved in MDC (50 mL). cooled the reaction mass and added 70% vitride solution in toluene (8.1 grams, 1.5equivalents) at 0-5 °C. After completion of the reaction, quenched the reaction mass with 10% Ammonium chloride solution (30 mL) and stirred for 25-30 minutes. Raised the reaction mass temperature to 25-30 °C and stirred for 15 minutes. Filtered the reaction mass through celite and washed with MDC (50 mL). Separated two layers and organic layer was washed with water (30 mL). Organic layer distilled completely and co-distilled with hexanes (15 mL), finally isolated with hexanes (15 mL) at 0-5 °C to give Cream colour solid. (wt: 2.35 grams, Yield: 50 %).

Stage-4: Preparation of 4-isopropyl-3,5-dimethoxybenzaldehyde
To the crude (formula 3(B)) added MDC (50 mL) and cooled the reaction mass and added 70% vitride solution in toluene (8.1 grams, 1.5equivalents) at 0-5 °C. After completion of the reaction, quenched the reaction mass with 10% Ammonium chloride solution (30 mL) and stirred for 25-30 minutes. Raised the reaction mass temperature to 25-30 °C and stirred for 15 minutes. Filtered the reaction mass through celite and washed with MDC (50 mL). Separated two layers and organic layer was washed with water (30 mL). Organic layer distilled completely and co-distilled with hexanes (15 mL), finally isolated with hexanes (15 mL) at 0-5 °C to give Cream colour solid. (wt: 2.35 grams, Yield: 50 %).

Stage-5: Preparation of (E)-2-isopropyl-1,3-dimethoxy-5-styrylbenzene
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-6: Preparation of (E)-2-isopropyl-5-styrylbenzene-1,3-diol
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 (300mL). Stirred the mass for 15 minutes. Separated the organic layer and extracted aqueous 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) reacting Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula - 2 with Carbonyldiimidazole in presence of solvent to obtain compound of Formula – 3(A) in-situ or optionally isolated;

iii) reacting (1H-imidazol-1-yl)(4-isopropyl-3,5-dimethoxyphenyl)methanone compound of Formula - 3(A) with N,O-dimethylhydroxylamine hydrochloride in presence of solvent to obtain 4-isopropyl-N-3,5-trimethoxy-N-methylbenzamide compound of Formula – 3(B);

iv) reduction of 4-isopropyl-N-3,5-trimethoxy-N-methylbenzamide compound of Formula – 3(B) in presence of reducing agent and solvent to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde compound of Formula - 4;

v) 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;

vi) reacting the 1-(4-isopropyl-3,5-dimethoxyphenyl)-2-phenylethan-1-ene compound of Formula - 6 in the presence of acid 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, methyl tert-butyl ether, isopropyl alcohol, methanol, acetone, toluene, dichloromethane, 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.

5. A novel intermediate compound of formula - 3(B)

6. A process for preparation of compound of Formula – 3(B)
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) reacting Methyl 3,5-dimethoxy-4-isopropylbenzoate compound of Formula - 2 with Carbonyldiimidazole in presence of solvent to obtain compound of Formula – 3(A) in-situ or optionally isolated;

iii) reacting (1H-imidazol-1-yl)(4-isopropyl-3,5-dimethoxyphenyl)methanone compound of Formula - 3(A) with N,O-dimethylhydroxylamine hydrochloride in presence of solvent to obtain 4-isopropyl-N-3,5-trimethoxy-N-methylbenzamide compound of Formula – 3(B).