DESC:Field of the Invention:
The present invention relates to an improved process for 2-(1-Methylethyl)-5-[(1E)-2-phenylethenyl]-1,3-benzenediol compound of formula-I and intermediates thereof, which is represented by the following structural formula:

Formula-I

Background of the Invention:
Tapinarof having chemical name of 2-(1-Methylethyl)-5-[(1E)-2-phenylethenyl]-1,3-benzenediol. It is approved in US on 23-May-2022 for the treatment of psoriasis and atopic dermatitis by Dermavant Sciences under the brand name Vtama® as 1% topical cream. The product is approved in China on May 2019

Initially, tapinarof compound of formula-I 2-(1-Methylethyl)-5-[(1E)-2-phenyl ethenyl] -1,3-benzenediol synthesis process was reported in Journal of organic chemistry Voll. 57; nb. 14; (1992); p. 4040 –4043 in multiple steps using various reagents and reported tapinarof melting range as 140-142°C.

The PCT application publication, WO2001042231A1 reported an alternative process and intermediates thereof, and the tapinarof product was isolated in ethyl acetate and n-hexane reported melting range is as 140-142°C.

The US patent US10647649B2 (herein after referred as US’649) reported crystalline form-1 and acetic acid solvated form of 2-(1-Methylethyl)-5-[(1E)-2-phenylethenyl]-1,3-benzenediol. The said patent is also reported a novel process for tapinarof and intermediates thereof.
The PCT application publication WO2019063002A1 (herein after referred as WO’002) reported various polymorphs such as crystalline form-I, II, III and IV of tapinarof. The said application also reported amorphous form of tapinarof and process thereof.
The PCT application publication WO2021236709A1 (herein after referred as WO’709) reported various co-crystals for Tapinarof.
Based on the prior art processes drawbacks, there is a need for providing an improved process for the preparation of 2-(1-Methylethyl)-5-[(1E)-2-phenylethenyl]-1,3-benzenediol, which involves simple experimental procedures, well suited to industrial production, which avoids the use of column chromatography purification, and which affords high pure 2-(1-Methylethyl)-5-[(1E)-2-phenylethenyl]-1,3-benzenediol.
The present invention provides an improved process for preparation of 2-(1-Methylethyl)-5-[(1E)-2-phenylethenyl]-1, 3-benzenediol and intermediates thereof and also processes for crystalline forms of compound of formula I

Brief Description:
The first aspect of the present invention is to provide a process for the preparation of 2-(1-Methylethyl)-5-[(1E)-2-phenylethenyl]-1, 3-benzenediol compound of formula-I.
The second aspect of the present invention is to provide a process for crystalline form 1 of compound of formula-I
The third aspect of the present invention is to provide crystalline form of compound of formula-I.
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form of compound of formula-I obtained as per example-10
Figure 2: Illustrates the PXRD pattern of crystalline form of compound of formula-I obtained as per example-11
Figure 3: Illustrates the PXRD pattern of crystalline form of compound of formula-I
obtained as per example-12

Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing reagents are selected from Lithium aluminium hydride, sodium borohydride, BF3 etherate solution, Pd/C, Ray-nickel;
The term “protecting” agent used in the present invention refers to a suitable protecting reagents that are selected selected from di-tert-butyl dicarbonate, chlorobenzyl formate, benzylbromide, benzylchloride, acetylchloride, fluorenylmethyloxycarbonyl chloride; The term “phase transfer catalyst (PTC)” used in the present invention refers are selected from triethylbenzyl ammonium chloride, tetrabutyl ammoniumbromide, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyl tributyl ammonium chloride, tetrabutyl ammonium hydroxide, tributylbenzylammonium chloride;

The first aspect of the present invention provides an improvised process for the preparation of 2-(1-Methylethyl)-5-[(1E)-2-phenylethenyl]-1, 3-benzenediol compound of formula-I.

Formula-I
Comprising of,
a) reacting the compound of formula-1 with

suitable reagent, solvent to provide the compound of formula-2,
b) reacting the compound of formula-2 with suitable reagent, solvent to provide the compound of formula-3, or optionally isolating compound of formula-3a,

c) reducing the compound-3 or 3a obtained in step-b) with suitable reagent, solvent to provide the compound of formula-4,

d) oxidizing the compound of formula-4 using a suitable reagent, solvent to provide compound of formula-5,

e) reacting the compound of formula-5 with compound-A using a suitable reagent, solvent to provide compound of formula-6,

f) deprotecting the compound of formula-6 with suitable reagent and solvent to provide compound of formula-I,
g) optionally purifying the compound using suitable solvent to provide pure compound of formula-I
Wherein in step-a) suitable reagents are dimethylsulphate, methyliodide, inorganic base, organic base mixture thereof.
Wherein in step-b) the suitable reagents are selected from isopropyl bromide, isopropyl chloride, isopropanol, aluminum chloride, sulfuric acid mixture thereof.
Wherein in step c) the reduction is carried out using reducing agent selected from sodium borohydride-iodine, diisobutylaluminium hydride, potassium borohydride, lithium borohydride, sodium bis (2-methoxy ethoxy) aluminium hydride (Red-Al or vitride), diborane (B 2H 6) and mixture thereof.
Wherein in step d) the oxidizing reagent is selected form pyridinium chlorochromate, pyridine-trioxochromium, dimethylsulfoxide-oxalyl chloride, dimethylsulfoxide-carbodiimide, DMSO-acetic anyhydride, manganese dioxide, potassium permanganate;
Wherein in step e) the suitable reagent is selected form sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, potassium hexamethyldisilazide (KHMDS), sodium hexamethyldisilazide (NaHMDS), sodium amide, n- Butyllithium (n-BuLi) and lithium diiso propylamide (LDA), inorganic base such as NaOH, KOH, LiOH and mixture thereof.
Wherein in step f) the suitable reagent is selected form pyridinium hydrobromide, pyridinium chloride, boron tribromide, aluminum chloride and sodium sulphide, trimethyl silane, HI, aq. HBr, HBr in acetic acid, organic bases and mixture thereof.
Wherein in step-a), b), c), d), e), f) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ketone solvent, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, alcohol solvent, water or any mixture thereof;
The suitable temperature is 0 to 150°C, preferably 5-140°C;
The embodiment of the present invention is to provides an improvised process for the preparation of 2-(1-Methylethyl)-5-[(1E)-2-phenylethenyl]-1, 3-benzenediol compound of formula-I.

Formula-I
Comprising of,
a) reacting the compound of formula-1 with

dimethyl sulfate, in presence of potassium carbonate in acetone to provide the compound of formula-2a,
b) reacting the compound of formula-2a with isopropyl bromide, aluminum chloride in dichloromethane to provide the compound of formula-3a

c) reducing the compound-3a obtained in step-b) with vitride in toluene to provide the compound of formula-4,

d) oxidizing the compound of formula-4 using manganese dioxide in dichloromethane, solvent to provide compound of formula-5,

e) reacting the compound of formula-5 with compound-A using KOH base in dimethyl formamide solvent to provide compound of formula-6,

f) deprotecting the compound of formula-6 with aluminum chloride, triethyl amine in toluene to provide compound of formula-I,
g) purifying the compound of formula- I in methyl tert butyl ether and n-heptane to provide pure crystalline form III of compound of formula-I
The preferred embodiment of the present invention is particle size of the crystalline form-III of compound of formula-I is D (90) < 250 µm, D (50) < 125 µm, D (10) < 50 µm

The second aspect of the present invention provides a purification process for 2-(1-methylethyl)-5-[(1E)-2-phenylethenyl]-1, 3-benzenediol compound of formula-I; comprising of:
a) stirring the compound of formula-1 at a suitable temperature, suitable solvent,
b) optionally adding the suitable anti solvent water,
c) isolating the compound obtained in step-a), b) to providers pure 2-(1-Methylethyl)-5-[(1E)-2-phenylethenyl]-1, 3-benzenediol compound of formula-I
Wherein in step-a) the suitable temperature is 90 to 150°C, preferably 130-145°C;
in step a) the solvent system may be a single solvent or mixture of solvents and is selected from ester solvents, chloro solvents, ketone solvents, alcohol solvents, polar solvent, aprotic polar solvents and mixture thereof; step-b) suitable anti solvent is selected from water, n-heptane, cyclohexane and mixture thereof.
in step c) the suitable temperature is below 40°C.
The preferred embodiment of the present invention is to provide a process for preparation of crystalline form 1 of compound of formula-I comprising of
a) Stirring the compound of formula-I in isopropanol,
b) adding the solution obtained in step-a) to water,
c) isolating the pure crystalline form–1 of compound of formula I.
The preferred embodiment of the present invention is particle size of the crystalline form-I of compound of formula-I is D (90) < 250 µm, D (50) < 125 µm, D (10) < 50 µm
The third aspect of the present invention provides crystalline form of compound of
formula-I. The crystalline form of the present invention is characterized by its powder X-ray diffraction pattern having characteristic peaks at about 5.8, 15.6 and 17.8. The said
crystalline form is further characterized by its powder X-Ray diffraction pattern substantially in accordance with figure-2. Further, the crystalline form of tapinarof may be
characterized by the PXRD pattern having peaks at 8.6, 13.9, 15.6, 16.0, 16.3, 17.4, 17.8, 18.5, 19.2, 20.7, 21.5, 22.9, 23.9, 25.3, 25.7, 26.0, 26.7, 28.0, 29.4 and 31.3 ± 0.2° 2?. The crystalline form may be solvate form, hydrate form; the crystalline form solvate.
The other aspect of the present invention provides crystalline form of compound of formula-I. The crystalline form of the present invention is characterized by its powder X-ray diffraction pattern having characteristic peaks at about 5.8, 7.6 and 16.0. The said
crystalline form is further characterized by its powder X-Ray diffraction pattern
substantially in accordance with figure-3. Further, the crystalline form of tapinarof may be
characterized by the PXRD pattern having peaks at 15.7, 17.4, 19.1, 19.7, 20.7 and 21.2, ± 0.2° 2?. The crystalline form may be solvate form, hydrate form; the crystalline form solvate.
As used herein, “hydrate” means that the referenced crystalline form has substantially water in the crystal lattice e.g., less than 50 % by weight, less than 40%, less than 30 %, less than 20%, less than 10 %, less than 5 % , less than 1% , less than 0.5 % as determined by Karl Fisher analysis.
The term “solvate form” refers to a crystalline compound wherein a stoichiometric or non-stoichiometric amount of solvent, or mixture of solvents, is incorporated into the crystal structure. e.g., the solvent may be less than 10 % by weight, less than 5%, less than 1%., less than 0.5 %.
2-(1-Methylethyl)-5-[(1E)-2-phenylethenyl]-1, 3-benzenediol compound of formula-I developed by the present inventors produces highly pure tapinarof are without nitroso amine compounds with good yield. All the related substances and residual solvents are controlled well within the limits as suggested by ICH guidelines and most of the related substances are controlled in non-detectable levels.

The compound of formula-I produced by the process of the present invention is having purity of greater than 99.5%, preferably greater than 99.7%, by HPLC; The other Z-isomer of tapinarof is having preferably < 0.5 %, more preferably < 0.15 %; Dimethoxy impurity and other related impurities are preferably < 0.5 %, more preferably < 0.15 %.


Z-Isomer Dimethoxy impurity

2-(1-Methylethyl)-5-[(1E)-2-phenylethenyl]-1, 3-benzenediol compound of formula-I produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills, milling or micronization may be performed before drying, or after the completion of drying of the product.

HPLC Method of Analysis: Tapinarof and its related substances were analyzed by HPLC with the following chromatographic conditions:

Chromatographic conditions:
Apparatus : A liquid chromatographic system, equipped with variable wavelength UV- Detector / DAD / PDA/ MWD.
Column : XBridge Shield RP18 3.5µm, 4.6 x 150 mm.
Wavelength : 210 nm
Flow rate : 1.5 mL/min
Column temperature : 25°C
Injection volume : 10 µL
Run time : 60 minutes
Diluent : Acetonitrile: Water (90: 10 v/v)
Needle wash : Diluent
Elution : Gradient
Buffer : Transfer about 1.0 mL of perchloric acid solution (70%) into a 1000 mL of Milli-Q-Water and mix well. After, filter this solution through 0.22 µm nylon membrane filter paper and sonicate to degas it.
Mobile Phase-A : Buffer (100%)
Mobile Phase-B : Acetonitrile: Water (90: 10 v/v)

The present invention is an improved process for 2-(1-Methylethyl)-5-[(1E)-2-phenyl ethenyl]-1,3-benzenediol compound of formula-I as mentioned in the schematic representation-I


The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:
Example-1: Preparation of compound of formula-2a (methyl-3, 5-dimethoxybenzoate)
A round bottom flask was charged with compound-1 (50 g), acetone (300 ml) and potassium carbonate (179.34 g) and stirred for 5-10 min at 25-35°C. Dimethyl sulfate (143.20 g) was charged slowly to the above reaction at 25-35°C and gradually heated to 50-65°C and maintained the reaction for 7 hr at the same temperature. After completion of reaction cooled to 25-35°C and filtered the unwanted solid, washed with acetone. The organic layer was distilled off to obtain the compound as residue. Further, the crude compound was charged with water and stirred for 1 hr at 25-35°C. The resulting solid was filtered and washed with water and dried to get the title compound.
Yield: 55 g
Example-2: Preparation of compound of formula-3a (methyl 3-(hydroxymethyl)-4-isopropyl-5-methoxybenzoate)
A round bottom flask was charged with compound-2a (120 g), dichloromethane (600 mL) and stirred the reaction mass to 5-10 min at 25-35°C. Charged the above solution to a mixture of isopropyl bromide (113 g) and aluminum chloride (163 g) slowly and gradually raised reaction mass temperature to 35-45°C and maintained for 7 hr at same temperature. Cooled the reaction mass to 25-35°C, quenched with cold water and conc. HCl and stirred for 30 min. Then both layers were separated; the organic layer was washed with water followed by sodium carbonate and brine solution. The organic layer was distilled off completely, further the residue was diluted in methanol and stirred for 1 hr. The precipitated solid was filtered and dried to get the title compound.
Yield: 64.6 g
Example-3: Preparation of compound of formula-4 ((4-isopropyl-5-methoxy-1,3-phenylene)dimethanol)
A round bottom flask was charged with compound-3a (5 g) and dissolved in THF (75 mL) under nitrogen atmosphere, stirred for 10 min at 25-35°C. Cooled the reaction mass to 5-15°C charged sodium borohydride (7.9 g) followed by methanol (15 mL) and stirred the reaction at 60-70°C for 12 hr. Cooled the reaction mass to 5-15°C, slowly quenched with ammonium chloride followed by addition of toluene and stirred for 30 min. Filtered the unwanted solid and the both layers were separated, and washed the organic layer with water followed by brine solution. The organic layer was dried with sodium sulfate and distilled-off the solvent completely to get the title compound.
Yield: 21 g
Example-4: Preparation of compound of formula-4 ((4-isopropyl-5-methoxy-1,3-phenylene)dimethanol)
A round bottom flask was charged with compound-3a (25 g) and dissolved in toluene (325 mL) under nitrogen atmosphere, stirred for 10 min at 25-35°C. Cooled the reaction mass to 5-15°C, charged diisobutylaluminium hydride (275 mL) in two portions wise and stirred the reaction at 25-35°C for 4 hr. Cooled the reaction mass to 5-15°C, slowly quenched with ammonium chloride further charged with toluene and stirred for 30 min. Then both layers were separated, and washed the organic layer with water followed by brine solution. The organic layer was dried with sodium sulfate and distilled-off completely to get the title compound.
Yield: 21 g
Example-5: Preparation of compound of formula-4 ((4-isopropyl-5-methoxy-1,3-phenylene)dimethanol)
A round bottom flask was charged with compound-3a (50 g) and toluene (500 mL) under nitrogen atmosphere, stirred for 10 min at 25-35°C. Cooled the reaction mass to 5-15°C charged vitirde (141.4 g) and stirred the reaction at 25-35°C for 2 hr. Cooled the reaction mass to 5-15°C, slowly quenched with ammonium chloride followed by addition of toluene and stirred for 30 min. The both layers were separated, and washed the organic layer with water followed by brine solution. The organic layer was dried with sodium sulfate and distilled-off completely to get the title compound.
Yield: 35.5 g
Example-6: Preparation of compound of formula-5
A round bottom flask was charged with compound-4 (440 g), toluene (4.4L) and stirred the reaction mass for 10 min at 25-35°C. Charged manganese dioxide (1091 g) in portion wise to the above solution and gradually heated to 35-45°C and stirred for 2 hr at the same temperature. Filtered the reaction mass through hyflow bed and wash with toluene, distilled off the solvent upto 90% under reduced pressure. The resulting solution was cooled and charged with isopropanol and heated the mixture to 75-85° and stirred for 1 hr. Further, the reaction mixture was cooled to 5-15°C, stirred for 30-45 min at same temperature. The obtained solid was filtered and dried to get the title compound.
Yield: 305 g
Example-7: Preparation of compound of formula-6
A round bottom flask was charged with compound-5 (205 g), dimethyl formamide (410 mL) and potassium hydroxide (110.3 g) and stirred the reaction mass to 5-10 min at 25-35°C. Charged diethyl benzyl phosphate of formula-A (326 mL) slowly to the above solution at 5-15°C and stirred for 1 hr. The reaction mixture was charged with water and isopropanol drop wise and stirred for 45 min at 5-15°C. Filtered the precipitated solid, washed with water and dried to obtain the title compound.
Yield: 262 g
Example-8: Preparation of compound of formula-6
A round bottom flask was charged with compound-5 (18 g), dimethyl formamide (72 ml) and sodium methoxide (9.34 g) and stirred the reaction mass to 5-10 min at 25-35°C. Charged diethyl benzyl phosphate of formula-A (28.6 ml) slowly to the above solution at 25-35°C and stirred for 1 hr. The reaction mixture was charged with water and methanol, stirred for 45 min. Filtered the precipitated solid, washed with water and dried to obtain the title compound.
Yield: 6 g
Example-9: Preparation of compound of formula-I
A round bottom flask charged with toluene (60 mL), aluminum chloride (9.44 g) at 25-35°C and stirred for 30 min. Cooled the reaction mixture to 5-10°, charged slowly triethylamine (8.06 g) followed by a solution of (E)-2-isopropyl-1, 3-dimethoxy-5-styrylbenzene (5.0 g in toluene 60 mL) and heated to 105-115°C and stirred for 8 hr . The reaction mixture was cooled to 5-15°C, charged with ethyl acetate and water, separated the two layers. The organic layer was washed with water and dried over sodium sulfate and evaporated to get a residue. The residue was stirred in n-heptane for 1 hr, the precipitated solid was filtered and dried to get the title compound.
Yield: 2.5 g
Example-10: Preparation of compound of formula-I
A round bottom flask charged with toluene (150 mL), aluminum chloride (53 g) at 25-35°C and stirred for 30 min. Cooled the reaction mixture to 5-10°, charged slowly triethylamine (40.3 g) and stirred for 2h. Further, charged a solution of (E)-2-isopropyl-1, 3-dimethoxy-5-styrylbenzene (25.0 g in toluene 50 mL) and heated to 105-115°C under azeotropic conditions stirred for 6 hr . The reaction mixture was cooled and quenched with dil HCl and stirred for 45 min. filtered the obtained solid and washed with toluene to get the wet title compound. The wet crude compound was charged with methyl tert-butyl ether, (125 mL) and filtered the undissolved solid compound. n-heptane (125 mL) was added to filtrate and stirred for 8 hr at 25-35°C. Filtered the obtained solid and washed with n-heptane and dried to get the title compound.
The PXRD of the compound was depicted in figure-1
Yield: 13 g; Purity by HPLC: 99.9 %
Example-11: Preparation of compound of formula-I
A round bottom flask charged with toluene (150 mL), aluminum chloride (53 g) at 25-35°C and stirred for 30 min. Cooled the reaction mixture to 5-10°, charged slowly triethylamine (40.3 g) and stirred for 2h. Further, charged a solution of (E)-2-isopropyl-1, 3-dimethoxy-5-styrylbenzene (25.0 g in toluene 50 mL) and heated to 105-115°C under azeotropic conditions stirred for 6 hr . The reaction mixture was cooled and quenched with dil HCl and stirred for 45 min. filtered the obtained solid and washed with toluene to get the title compound.
Yield: 24.5 g.
The title compound has the water content about 38 % w/w, toluene content is about 6% ; Purity by HPLC: 96.7 % ; The PXRD of the compound was depicted in figure-2
Example-12: Preparation of compound of formula-I
A round bottom flask charged with toluene (150 mL), aluminum chloride (53 g) at 25-35°C and stirred for 30 min. cooled the reaction mixture to 5-10°, charged slowly triethylamine (40.3 g) and stirred for 2h. Further, charged a solution of (E)-2-isopropyl-1, 3-dimethoxy-5-styrylbenzene (25.0 g in toluene 50 mL) and heated to 105-115°C under azeotropic conditions stirred for 6 hr . The reaction mixture was cooled and quenched with dil HCl and stirred for 45 min. filtered the obtained solid and washed with toluene and dried to get the title compound.
Yield: 17.2 g;
The title compound has the water content about 10 % w/w, toluene content is less than 1%; Purity by HPLC: 96.5 %; The PXRD of the compound was depicted in figure-3
Example-13: Preparation of compound of formula-I
A round bottom flask charged with toluene (60 mL), aluminum chloride (9.4 g) at 25-35°C and stirred for 30 min. cooled the reaction mixture to 5-10°, charged slowly N, N-dimethyl aniline (9.65 g) and stirred for 2h. Further, charged a solution of (E)-2-isopropyl-1, 3-dimethoxy-5-styrylbenzene (5.0 g in toluene 50 mL) and heated to 105-115°C under azeotropic conditions stirred for 5 hr. The reaction mixture was cooled and quenched with water, ethyl acetate and stirred for 45 min. The organic layer was dried and distilled off 90% of solvent, further, to resulting solution charged n-heptane and stirred for 30 min. The precipitated solid was filtered and dried to get the title compound.
The PXRD appears to be similar to figure-1
Yield: 2.5 g
Example 14: Preparation of compound of formula-2a [methyl-3,5-dimethoxy benzoate]
Around bottom flask was charged with acetone (800 ml) and potassium carbonate (313.74 g) and stirred for 5-10 min at 25-35°C. The reaction mass was gradually charged with dimethyl sulfate (245.4 ml) and 3,5-dihydroxybenzoic acid (100 g) at 25-35°C and heated to 50-60°C and stirred for 8 h at the same temperature. Cooled the reaction mass to 25-35°C and filtered the unwanted solid and washed with acetone and distilled-off the solvent. The crude compound was charged with water (400 ml) and cooled to 10-20°C, stirred for 3 h at same temperature. Filtered the solid and washed with water, dried to obtain the title compound.
Yield: 108 g
Example 15: Preparation of compound of formula-3a [Methyl-4-isopropyl-3,5-dimethoxy benzoate]
Around bottom flask was charged with compound-2a (80 g), dichloromethane (400 mL) at 25-35°C and stirred for 15 min. Charged sodium sulfate (8 g) to the reaction mass and stirred for 10 min at 20-30°C and filtered the reaction mass. Another RB flask was charged with dichloromethane (400 ml), cooled to 10-20°C and charged aluminum chloride (108.71 g) and stirred for 10 min and gradually charged the above filtrate solution and stirred at 35-45°C for 12 h. Cooled the reaction mass to 25-35°C and charged to a pre mixture solution of cold water (240 ml) and conc. HCl (160 ml) at 0-10°C and stirred for 30 min and separated into two layers. The aqueous layer was charged with dichloromethane stirred for 10 min at 25-35°C and separated into two layers. The combined organic layer was washed with sodium bicarbonate solution, sodium chloride subsequently. The organic layer was distilled off completely under reduced pressure at 30-40°C, co-distilled with methanol to get the crude compound. The crude compound was charged with methanol (240 ml) and heated to 55-65°C and stirred for 1 h. Cooled the solution to 0-10°C, stirred for 3 h, the resulting solid was filtered and washed with methanol and dried to get the title compound.
Yield: 69.67 g
Example-16: Preparation of compound of formula-5 [(4-isopropyl-3,5-dimethoxy benzaldehyde]
Around bottom flask was charged with toluene (600 ml), compound-3a (100 g), stirred the reaction mass for 10 min at 25-35°C. Cooled the reaction mass for 0-10°C , charged with vitride (210 g) and gradually raised the reaction mass temperature to 25-35°C and maintained for 2 h. Cooled the reaction mass to 0-10°C, quenched with ammonium chloride solution and stirred at 25-35°C for 1 h. Filtered the unwanted solid and washed with toluene and separated into two layers. The organic layer was charged with water (1000 ml) at 25-35°C and stirred for 10 min at 25-35°C and separated into two layers. The organic layer was dried over sodium sulfate and distilled- off completely to get compound of formula-4.
The obtained crude compound of formula-4 was charged with dichloromethane (600 g) at 25-35°C, stirred the reaction mass for 10 min and charged with manganese dioxide (218.81 g) and stirred for 10 min. The reaction mixture was gradually heated to 35-45°C, maintained for 8 h at same temperature. The reaction mass was cooled to 25-35°C, stirred for 30 min at same temperature and filtered, washed with dichloromethane, and unloaded the unwanted material. Distilled-off the filtrate completely and the obtained crude compound was cooled to 25-35°C, charged isopropyl alcohol (200 ml) and water (400 ml) and maintained the reaction mass for 1h at same temperature. Filtered the solid and washed with water and dried to obtain the wet compound.
The obtained wet compound was charged with isopropyl alcohol (200 ml) and water (200 ml) and maintained the reaction mass for 1h at 25-35°C. Filtered the solid, washed with water and dried to obtain the title compound.
Yield: 74.07 g
Example-17: Preparation of compound of formula-6 (E)-2-isopropyl-1,3-dimethoxy-5-styrylbenzene
Around bottom flask was charged with dimethyl formamide (160 ml), compound-5 (80 g), stirred for 10 min at 25-35°C, cooled the reaction mass to 0-10°C and charged potassium hydroxide (43.10 g) and stirred for 30 min at 0-10°C. The reaction mass was charged with dimethyl benzyl phosphonate (109.58 g) at 0-10°C in drop wise manner about 1 hr and gradually heated the reaction mass to 25-35°C, maintained for 6 h. Cooled the reaction mass to 0-10°C, charged with isopropyl alcohol (160 ml) and water (640 ml) at 0-10°C, stirred for 1h. Filtered the solid and washed with water and suck dried to obtain the wet compound. The above wet compound was charged into another RB flask and charged isopropyl alcohol (400 ml) maintained the reaction mass for 20 min at 45-55°C and charged with water (400 ml) at same temperature. Cooled the reaction mass stirred for 45 min and filtered the solid at 25-35°C and washed with water and dried to obtain the title compound.
Yield: 85.80 g.
Example-18: Preparation of compound of formula-I
Around bottom flask was charged with toluene (300 mL), aluminum chloride (212.48 g) at 25-35°C and stirred for 10 min. Cooled the reaction mixture to 5-10°C, charged slowly triethylamine (161.26 g) stirred for 10 min at 0-10?°C and charged with a solution of compound-6 (100 g in toluene) at the same temperature. The reaction mixture was gradually heated to 105-115°C and maintained for 6 h and the reaction mixture was cooled to 25-35°C. The reaction mixture was quenched with diluted HCl, stirred for 1h, filtered the solid and washed with water to get the wet crude compound. The wet compound was charged with methyl tert-butyl ether and dil HCl stirred for 15 min at 25-35°C. Separated both layers and organic layer was charged with diluted HCl and stirred for 30 min. The organic layer was separated and dried over sodium sulfate and distilled-off completely. Further, the obtained compound was charged with methyl tert-butylether and n-heptane stirred for 2 hr at 25-35°C. The resulting solid was filtered and washed with n-heptane and dried to get the title compound.
Yield: 74.43 g.
Example-19: Process for preparation of crystalline form- III of compound of formula-I.
A round bottom flask was charged with tapinarof (100 g), methyl- tert butyl ether (200 mL), stirred the reaction mass for 10 min and heated to 50-60°C, charged with carbon and maintained for 15 min at 50-60°C. Filtered the solution and washed with methyl tert butyl ether (50 ml) and the filtrate solution was charged with n-heptane (450 mL) and stirred for 1 hr at 15-25°C. Filtered the solid and washed with n-heptane and dried to get the title compound.
Yield: 60 g; PSD: D(90):55.7 µm, D(50):7.8 µm, D(10):1.6 µm

Example-20: Process for preparation of crystalline form- 1 of compound of formula-I.
A round bottom flask was charged with tapinarof (13 g), isopropanol (19.5 mL), stirred the reaction mass for 10 min. Filtered the solution and washed with isopropanol (6.5 ml) and the filtrate solution was charged with water (65 mL) slowly at 25-35°C, cooled the reaction mass gradually to 0-10°C and maintained for 1h at same temperature. Filtered the solid and washed with water and dried to get the title compound.
Yield: 12.02 g.
PSD: D (90):73.4 µm, D(50):24.2 µm, D(10):6.4 µm

,CLAIMS:1. A process for the preparation of crystalline form-III of compound of formula-I.

Formula-I
Comprising of,
a) reacting the compound of formula-1 with

dimethyl sulfate, in presence of potassium carbonate in acetone to provide the compound of formula-2a,
b) reacting the compound of formula-2a with isopropyl bromide, aluminum chloride in dichloromethane to provide the compound of formula-3a,

c) reducing the compound-3a obtained in step-b) with vitride in toluene to provide the compound of formula-4,

d) oxidizing the compound of formula-4 using manganese dioxide in dichloromethane, solvent to provide compound of formula-5,

e) reacting the compound of formula-5 with compound-A using KOH base in dimethyl formamide solvent to provide compound of formula-6,

f) deprotecting the compound of formula-6 with aluminum chloride, triethyl amine in toluene to provide compound of formula-I,
g) purifying the compound of formula- I in methyl tert butyl ether and n-heptane to provide pure crystalline form III of compound of formula-I

2. A process for preparation of crystalline form 1 of compound of formula-I
Comprising of,
a) reacting the compound of formula-1 with

dimethyl sulfate, in presence of potassium carbonate in acetone to provide the compound of formula-2a,
b) reacting the compound of formula-2a with isopropyl bromide, aluminum chloride in dichloromethane to provide the compound of formula-3a,

c) reducing the compound-3a obtained in step-b) with vitride in toluene to provide the compound of formula-4,

d) oxidizing the compound of formula-4 using manganese dioxide in dichloromethane, solvent to provide compound of formula-5,

e) reacting the compound of formula-5 with compound-A using KOH base in dimethyl formamide solvent to provide compound of formula-6,

f) deprotecting the compound of formula-6 with aluminum chloride, triethyl amine in toluene to provide compound of formula-I,
g) stirring the compound of formula-6 obtained in step-f) in isopropanol,
h) adding the solution obtained in step-g) to water,
i) isolating the pure crystalline form–1 of compound of formula I.

3.The crystalline form 1 and form -III of compound of formula-1 obtained according to claims 1, 2 having purity > 99% by HPLC.