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

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 process for preparation of novel intermediate compounds of Formulae – 2, 3, 4 and 6.

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, CN 101648851 B1, CN 103265412 A, European Journal of Organic Chemistry 2014, 8026-8028 and Journal of Natural Products, Volume 74, Issue 4, Pages 644-649, 2011. 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 3,5-dihydroxy-4-isopropylbenzoic acid compound of Formula-1

with chloromethyl methyl ether (MOM-Cl) in presence of suitable base to obtain Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2;

ii) reduction of Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2 in the presence of reducing agent and suitable solvent to obtain (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3;

iii) oxidation of (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3 in the presence of oxidizing agent and suitable solvents to obtain 3,5-dimethoxymethyl-4-isopropylbenzaldehyde compound of Formula-4;

iv) condensation of 3,5-dimethoxymethyl-4-isopropylbenzaldehyde compound of Formula-4 with compound of Formula-5 in the presence of alkaline hydroxide or alkaline hydroxide powder and suitable solvent to obtain (E)-2-isopropyl-1,3-bis(methoxy methyl)-5-styrylbenzene compound of Formula-6;

v) reacting the (E)-2-isopropyl-1,3-bis(methoxymethyl)-5-styrylbenzene compound of Formula-6 in the presence of suitable acid and solvent to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound of Formula-I.

In another aspect, the present invention provides a process for the preparation of Tapinarof intermediate compound of Formula-6.

which comprises:
i) reacting 3,5-dihydroxy-4-isopropylbenzoic acid compound of Formula-1

with chloromethyl methyl ether (MOM-Cl) in presence of suitable base to obtain Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2;

ii) reduction of Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2 in the presence of reducing agent and suitable solvent to obtain (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3;

iii) oxidation of (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3 in the presence of oxidizing agent and suitable solvents to obtain 3,5-dimethoxymethyl-4-isopropylbenzaldehyde compound of Formula-4;

iv) condensation of 3,5-dimethoxymethyl-4-isopropylbenzaldehyde compound of Formula-4 with compound of Formula-5 in the presence of alkaline hydroxide or alkaline hydroxide powder and suitable solvent to obtain (E)-2-isopropyl-1,3-bis(methoxy methyl)-5-styrylbenzene compound of Formula-6.

In another aspect, the present invention provides a process for the preparation of Tapinarof intermediate compound of Formula-4.

which comprises:
i) reacting 3,5-dihydroxy-4-isopropylbenzoic acid compound of Formula-1

with chloromethyl methyl ether (MOM-Cl) in presence of suitable base to obtain Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2;

ii) reduction of Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2 in the presence of reducing agent and suitable solvent to obtain (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3;

iii) oxidation of (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3 in the presence of oxidizing agent and suitable solvents to obtain 3,5-dimethoxymethyl-4-isopropylbenzaldehyde compound of Formula-4.

In another aspect, the present invention provides a process for the preparation of Tapinarof intermediate compound of Formula-3.

which comprises:
i) reacting 3,5-dihydroxy-4-isopropylbenzoic acid compound of Formula-1

with chloromethyl methyl ether (MOM-Cl) in presence of suitable base to obtain methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2;

ii) reduction of Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2 in the presence of reducing agent and suitable solvent to obtain (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3.
In another aspect, the present invention provides a process for the preparation of Tapinarof intermediate compound of Formula-2.

which comprises:
i) reacting 3,5-dihydroxy-4-isopropylbenzoic acid compound of Formula-1;

with chloromethyl methyl ether (MOM-Cl) in presence of suitable base to obtain Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2.

In another aspect, the present invention relates to novel intermediate compounds of Formulae - 2, 3, 4 and 6.

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 are 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 diisobutylaluminium hydride (DIBAL).

Acids are used throughout the invention selected from the group consisting of para toluene sulphonic acid, dilute HCl, pyridinium p-toluenesulfonate, trichloroacetic acid, pyridine hydrochloride, 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, pyridinium dichromate, pyridinium sulphur trioxide, TEMPO, manganese dioxide, 2-Iodoxybenzoic acid (IBX), Dess–Martin periodinane (DMP) or oxalyl chloride.

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

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 3,5-dihydroxy-4-isopropylbenzoic acid compound of Formula-1 with chloromethyl methyl ether (MOM-Cl) in presence of suitable base to obtain Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2;

In stage-ii), reduction of Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2 in the presence of reducing agent and suitable solvent to obtain (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3;

In stage-iii), oxidation of (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3 in the presence of oxidizing agent and suitable solvents to obtain 3,5-dimethoxymethyl-4-isopropylbenzaldehyde compound of Formula-4;

In stage-iv), condensation of 3,5-dimethoxymethyl-4-isopropylbenzaldehyde compound of Formula-4 with compound of Formula-5 in the presence of alkaline hydroxide or alkaline hydroxide powder and suitable solvent to obtain (E)-2-isopropyl-1,3-bis(methoxy methyl)-5-styrylbenzene compound of Formula-6;

In stage-v), reacting the (E)-2-isopropyl-1,3-bis(methoxymethyl)-5-styrylbenzene compound of Formula-6 in the presence of suitable acid and suitable solvent to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound of Formula-I.

The another embodiment of the present invention provides a process for the preparation of (E)-2-isopropyl-1,3-bis(methoxymethyl)-5-styrylbenzene compound of Formula-6, which is outlined below in Scheme-III:

Scheme-III

In stage-i), reacting 3,5-dihydroxy-4-isopropylbenzoic acid compound of Formula-1 with chloromethyl methyl ether (MOM-Cl) in presence of suitable base to obtain Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2;

In stage-ii), reduction of Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2 in the presence of reducing agent and suitable solvent to obtain (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3;

In stage-iii), oxidation of (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3 in the presence of oxidizing agent and suitable solvents to obtain 3,5-dimethoxymethyl-4-isopropylbenzaldehyde compound of Formula-4;

In stage-iv), condensation of 3,5-dimethoxymethyl-4-isopropylbenzaldehyde compound of Formula-4 with compound of Formula-5 in the presence of alkaline hydroxide or alkaline hydroxide powder and suitable solvent to obtain (E)-2-isopropyl-1,3-bis(methoxymethyl)-5-styrylbenzene compound of Formula-6.
In preferred embodiment, the present invention provides a process for the preparation of 3,5-dimethoxymethyl-4-isopropylbenzaldehyde compound of Formula-4, which is outlined below in Scheme-IV:

Scheme-IV

In stage-i), reacting 3,5-dihydroxy-4-isopropylbenzoic acid compound of Formula-1 with chloromethyl methyl ether (MOM-Cl) in presence of suitable base to obtain Methoxymethyl 4-isopropyl-3,5-bis(methoxymethyl)benzoate compound of Formula-2;

In stage-ii), reduction of Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2 in the presence of reducing agent and suitable solvent to obtain (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3;

In stage-iii), oxidation of (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3 in the presence of oxidizing agent and suitable solvents to obtain 3,5-dimethoxymethyl-4-isopropylbenzaldehyde compound of Formula-4.

In another preferred embodiment, the present invention provides a process for the preparation of (4-isopropyl-3,5-bis(methoxymethyl)phenyl) methanol compound of Formula-3, which is outlined below in Scheme-V:

Scheme-V

In stage-i), reacting 3,5-dihydroxy-4-isopropylbenzoic acid compound of Formula-1 with chloromethyl methyl ether (MOM-Cl) in presence of suitable base to obtain Methoxymethyl 4-isopropyl-3,5-bis(methoxymethyl)benzoate compound of Formula-2;

In stage-ii), reduction of Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2 in the presence of reducing agent and suitable solvent to obtain (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3.

In another preferred embodiment, the present invention provides a process for the preparation of methoxymethyl-4-isopropyl-3,5-bis(methoxymethyl)benzoate compound of Formula-2, which is outlined below in Scheme-VI:

Scheme-VI
In above process, reacting 3,5-dihydroxy-4-isopropylbenzoic acid compound of Formula-1 with chloromethyl methyl ether (MOM-Cl) in presence of suitable base and suitable solvent to obtain Methoxymethyl 4-isopropyl-3,5-bis(methoxymethyl)benzoate compound of Formula-2.

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:
Example - 1: Process for the preparation of Tapinarof
Stage-1: Preparation of Methoxymethyl 4-isopropyl-3,5-bis(methoxymethyl) benzoate (Formula-2)
The solution of 3,5-dihydroxy-4-isopropylbenzoic acid (20 grams, 0.102 moles) in Dichloromethane at -5 to 5 °C were added MOM-Cl (49.3 grams, 0.612 moles) followed by Diisopropylethylamine (82.57 grams, 0.816 moles). The reaction mass temperature was raised to 25-35 °C and stirred for 2 hours. Purified water (200 mL) was added to the reaction mixture and stirred for 15 minutes. The organic layer was separated, washed with purified water (100 mL) and concentrated under reduced pressure below 40 °C to obtain crude compound which was used for next stage.

Stage-2: Preparation of 4-isopropyl-3,5-bis(methoxymethyl)phenyl) methanol (Formula-3)
To a solution of Stage-1 (5.0 grams, 0.0152 moles) in Dichloromethane at -70 to -50 °C, added DIBAL-H (0.0457 moles) and maintained for 2.0 hours at -70 to -50 °C. After completion of the reaction, saturated ammonium chloride solution (50 mL) was added to the reaction mixture below 40 °C and stirred for 30 minutes. The organic layer was separated and concentrated under reduced pressure below 40 °C to obtain crude compound which was used for next stage.

Stage-3: Preparation of 4-isopropyl-3,5-bis(methoxymethyl)benzaldehyde (Formula-4)
To a solution of Stage-2 (5.0 grams, 0.0185 moles) in MDC (50 mL) at 25-30 °C was added Pyridiniumchloro chromate (4.0 grams, 0.0185 moles) lot wise at 25-30 °C and the reaction mass was maintained for 2.0 hours at 25-30 °C. After completion of the reaction, the salts were filtered through celite and washed the bed with MDC (30 mL). The organic layer was distilled under reduced pressure below 35 °C to obtain crude which was further dissolved in diisopropylether (60 mL) to remove salts. The Diisopropylether layer was distilled under reduced pressure below 35 °C to obtain crude which was used for next stage.

Stage-4: Preparation of (E)-2-isopropyl-1,3-bis(methoxymethyl)-5-styryl benzene (Formula-6)
NaOH powder (1.04 grams, 0.0260 moles) was added to the solution Diethyl benzyl phosphonate (Formula-5) (2.97 grams, 0.0130 moles) in DMSO (16.0 mL) at 25-30°C. The solution was cooled to 10-20°C, added Stage-3 (3.5 grams, 0.0130 moles) in DMSO (8.0 mL) and maintained for 2.0 hours at 20-30 °C. Purified water (60 mL) and MTBE (60 mL) were added to the reaction mass and allowed to stir for 15 minutes. The organic layer was separated and washed with water (40 mL) and concentrated under reduced pressure below 45 °C to yield crude compound which was proceed for next stage.

Stage-5: Preparation of Tapinarof (Formula -I)
p-Toluenesulfonic acid was added to the solution of Stage-4 (2.5 grams, 0.0073 moles) in Methanol (25 mL) at 10-20 °C and the solution was allowed to stir for 15 minutes. The reaction temperature was raised to 25-30 °C and stirred for 3 hours. After completion of the reaction, pH of the solution was adjusted to 7.0-8.0 with sodium bicarbonate solution. The reaction mass was extracted with MTBE (25 mL) and the organic layer was washed with water (20 mL) and distilled under reduced pressure below 45 °C to obtain crude which was isolated with MTBE & n-Heptane to give brown color solid. (Yield: 55 %).
,CLAIMS:We claim:

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


which comprises:
i) reacting 3,5-dihydroxy-4-isopropylbenzoic acid compound of Formula-1

with chloromethyl methyl ether (MOM-Cl) in presence of suitable base to obtain Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2;

ii) reduction of Methoxymethyl 4-isopropyl-3,5-bis (methoxymethyl) benzoate compound of Formula-2 in the presence of reducing agent and suitable solvent to obtain (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3;

iii) oxidation of (4-isopropyl-3,5-bis(methoxymethyl)phenyl)methanol compound of Formula-3 in the presence of oxidizing agent and suitable solvents to obtain 3,5-dimethoxymethyl-4-isopropylbenzaldehyde compound of Formula-4;

iv) condensation of 3,5-dimethoxymethyl-4-isopropylbenzaldehyde compound of Formula-4 with compound of Formula-5 in the presence of alkaline hydroxide or alkaline hydroxide powder and suitable solvent to obtain (E)-2-isopropyl-1,3-bis(methoxy methyl)-5-styrylbenzene compound of Formula-6;

v) reacting the (E)-2-isopropyl-1,3-bis(methoxymethyl)-5-styrylbenzene compound of Formula-6 in the presence of suitable acid and solvent to obtain (E)-2-isopropyl-5-styrylbenzene-1,3-diol compound of Formula-I.

2. A novel intermediate compound of Formulae – 2, 3, 4 and 6.