DESC:Title of the Invention
Process for the preparation of Tapinarof Form-1.

Field of the Invention
The present invention relates to process for the preparation of Tapinarof Form-1 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.

Tapirnof Form-1 is innovator marketed form disclosed in US10,647,649 B2.

Tapinarof Form II is disclosed in WO 2019/063002 A1.

It would be desirable and of paramount importance to have a process for the preparation of Tapinarof Form-1 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 process for the preparation of Tapinarof Form-1 of Formula-I.


which comprises:
a) dissolve Tapinarof Form-II in Methanol;
b) add water to the above obtained clear solution;
c) cooled the above solution to 5-15 °C and maintained for 1-4 hours under stirring;
d) filter the obtained crystals and dry the crystals under vacuum.

Brief Description of the Drawings
Figure -1 is represents X-ray Diffraction spectrum of Tapinarof Form- II.
Figure -2 is a table showing the X-ray powder diffraction peaks of Tapinarof Form-
II.
Figure-3 is represents X-ray Diffraction spectrum of Tapinarof Form-1.
Figure-4 is a table showing the X-ray powder diffraction peaks of Tapinarof Form- 1.

Detailed Description of the Invention
The present invention provides process for the preparation of Tapinarof form-1 of Formula I.

which comprises:
a) dissolve Tapinarof Form-II in Methanol;
b) add water to the above obtained clear solution;
c) cooled the above solution to 5-15 °C and maintained for 1-4 hours under stirring;
d) filter the obtained crystals and dry the crystals under vacuum.

In step c) the reaction cooling temperature may range from 5-15 °C, preferably at a temperature in the range from 5-10 °C.

PXRD Analysis Method:
X-Ray Powder Diffractions were performed on PANalytical X-Ray powder diffractometer model X'Pert PRO, Cu-tube, solid state detector. PANalytical sample holder Pw1811/16 with a Pw1811/00 holder by back-loading technique using the Pw1770/10 sample preparation tool kit. Scanning parameters: range 3-40° 2?, continuous scan, Time per step: 35 seconds.

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 Form-1.
Tapinarof Form-II was dissolved in Methanol (6 volumes) at 25 °C, added cooled water at 10 °C (12 volumes) slowly under stirring. The mass was cooled to 5 °C, stirred for 2 hours and filtered, dried at 40 °C under vacuum for 12 hours to obtain light brown colour solid.
,CLAIMS:We claim:
1. A process for the preparation of Tapinarof Form-1 of Formula-I.


which comprises:
a) dissolve Tapinarof Form-II in Methanol;
b) add water to the above obtained clear solution;
c) cooled the above solution to 5-15 °C and maintained for 1-4 hours under stirring;
d) filter the obtained crystals and dry the crystals under vacuum.