DESC:AN IMPROVED PROCESS FOR THE PREPARATION OF TAPINAROF AND ITS INTERMEDIATES
FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Tapinarof and a process for the preparation of Tapinarof intermediates.

BACKGROUND OF THE INVENTION

Tapinarof (INN; trade name Vtama®) is a topical drug for treatment of mild to moderate plaque psoriasis and atopic dermatitis. Tapinarof was approved for medical use in the United States in May 2022 and the US Food and Drug Administration (FDA) considers it to be a first-in-class medication. The medication acts as an aryl hydrocarbon receptor agonist.
Tapinarof is chemically known as 3,5-dihydroxy-4-isopropyl-trans-stilbene, having formula (I):

Tapinarof is a white to pale brown powder. Tapinarof is practically insoluble in water and freely soluble in methanol, ethanol and acetone.

US7321050 B2 of Dermavant Sciences discloses a process for the preparation of Tapinarof, which involves compound of formula (X) is treating with dimethyl sulfate (Me2SO4) in presence of potassium carbonate (K2CO3) in acetone to produce compound of formula (IX). Compound of formula (IX) is treating with 2-bromopropane in presence of anhydrous Aluminum chloride (AlCl3)/ Carbon disulfide (CS2) to produce compound of formula (VIII). Compound of formula (VIII) is treating with Lithium aluminium hydride (LiAlH4) in anhydrous diethyl ether to produce compound of formula (VII). Compound of formula (VII) is treating with pyridinium chlorochromate in dichloromethane (CH2Cl2) to produce compound of formula (VI). Compound of formula (VI) is reacting with compound of formula (V) in presence of sodium hydride (NaH) and dry Tetrahydrofuran (THF) to produce compound of formula (IV). Compound of formula (IV) is treating with Boron tribromide (BBr3) in dry dichloromethane (CH2Cl2) at -78ºC to produce Tapinarof as shown in below scheme:

The drawbacks of the above-mentioned process is highly toxic and hazardous chemicals are used, such as dimethyl sulfate (Me2SO4), Lithium aluminium hydride (LiAlH4), sodium hydride (NaH), organic chromium reagent and boron tribromide (BBr3), etc. causing great harm to the human body and the environment. The reaction conditions are harsh, and the reaction time is long, for example, the steps-i and ii processes take 12hrs and 7 days’ time, and the final demethylation step needs to be carried out at -78°C. Which leads to low yield, makes the process more expensive and commercially non-viable.
Hence, there is a need for a simple, cost-effective alternative process for the preparation of Tapinarof. The process of the present invention is less expensive, industrially feasible, overcomes.
The above disadvantages and provides Tapinarof with high purity and higher yields.

OBJECT OF THE INVENTION
The object of the present invention is to provide an improved process for the preparation of Tapinarof and a process for the preparation of Tapinarof intermediates.
SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of Tapinarof and a process for the preparation of Tapinarof intermediates.
One embodiment of the present invention provides an improved process for the preparation of Tapinarof (I) comprising the steps of,
a) treating compound of formula (VII) with triethylphosphite in presence of an alkali metal halide, a phase transfer catalyst in the absence of solvent to produce an in-situ compound of formula (III),

b) treating the in-situ compound of formula (III) with benzaldehyde in presence of a base and a solvent to produce a compound of formula (IV), and

c) treating the compound of formula (IV) with lewis acid in presence of a solvent and a base to produce Tapinarof of formula (I).

In second embodiment of the present invention, provides a process for the preparation of Tapinarof intermediate (4-isopropyl-3,5-dimethoxy phenyl) methanol (VII)) comprising the steps of,
a) treating compound of formula (III) with acid in presence of a solvent to produce a compound of formula (II),

b) treating the compound of formula (II) with solvent in presence of an acid to produce a compound of formula (VIII), and

c) treating the compound of formula (VIII) with reducing agent and a solvent to produce compound of formula (VII).

Third embodiment of the invention, provides an improved process for the preparation crystalline Form 1 of Tapinarof comprises the steps of,
a. dissolving the Tapinarof in first solvent,
b. heating the reaction mass at suitable temperature,
c. optionally, completely distillation of the first solvent,
d. adding second solvent,
e. cooling the obtained solution in step d), and
f. isolating the crystalline Form 1 of Tapinarof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Tapinarof and a process for the preparation of Tapinarof intermediates.
One embodiment of the present invention provides an improved process for the preparation of Tapinarof (I) comprising the steps of,

a) treating compound of formula (VII) with triethylphosphite in presence of an alkali metal halide, a phase transfer catalyst and an absence of solvent to produce in-situ compound of formula (III),

b) treating in-situ compound of formula (III) with benzaldehyde in presence of a base and a solvent to produce compound of formula (IV), and

c) treating compound of formula (IV) with lewis acid in presence of a solvent and a base to produce Tapinarof of formula (I).

According to an embodiment of the present invention, reaction compound of formula (VII) with triethylphosphite in presence of an alkali metal halide, a phase transfer catalyst and an absence of solvent, carried out at a temperature of 125ºC to 150ºC for 10-15 hrs. to produce in-situ compound of formula (III). Reaction in-situ compound of formula (III) with benzaldehyde in presence of a base and a solvent to produce compound of formula (IV), carried out at a temperature of 0°C to 15°C for 1-4 hrs. reaction compound of formula (IV) with lewis acid in presence of a solvent, carried out at a temperature of 80 to 105ºC for 3-6 hrs to produce crude Tapinarof of formula (I). The reaction crude Tapinarof was dissolved in solvent at 35º to 55ºC, then distilled the solvent under vacuum at below 50ºC and add solvent, cool to room temperature to get pure Tapinarof.

In second embodiment of the present invention, provides a process for the preparation of Tapinarof intermediate (4-isopropyl-3,5-dimethoxy phenyl) methanol (VII)) comprising the steps of,

a) treating compound of formula (III) with acid in presence of a solvent to produce compound of formula (II),
b) treating compound of formula (II) with solvent in presence of an acid to produce compound of formula (VIII), and
c) treating compound of formula (VIII) with reducing agent and a solvent to produce compound of formula (VII).

According to an embodiment of the present invention, reaction compound of formula (III) with acid in presence of a solvent, carried out at a temperature of 45º to 65ºC for 1-3 hrs. to obtain compound of formula (II). Reaction compound of formula (II) with solvent in presence of an acid, carried out at a temperature of 0 to 10ºC and stir for 2 to 5 hrs. to produce compound of formula (VIII). Reaction compound of formula (VIII) with reducing agent in presence of solvent, carried out at a temperature of 50º to 65? for 3 hrs. to produce compound of formula (VII).

Third embodiment of the invention, provides an improved process for the preparation crystalline Form 1 of Tapinarof comprises the steps of,
a. dissolving the Tapinarof in first solvent,
b. heating the reaction mass at suitable temperature,
c. optionally, completely distillation of the first solvent,
d. adding second solvent,
e. cooling the obtained solution in step d), and
f. isolating the crystalline Form 1 of Tapinarof.

According to the embodiment of the present invention, dissolving the Tapinarof in first solvent, reaction mixture was heated to 35ºC to 60ºC and stir for 15 to 45 minutes, then distil out the first solvent completely under vacuum at below 45 to 55ºC. The obtained reaction mass add with the second solvent at 45º to 55ºC and stir the reaction mass for 15 to 40 minutes. The obtained crude allowed to cool at 20º to 35ºC, the obtained solid filtered and washed with solvent to produce crystalline Form 1 of Tapinarof.
According to the embodiment of the present invention, wherein the alkali metal halide is selected from but not limited to NaCl, NaBr, sodium iodide (NaI), potassium chloride (KCl), potassium bromide (KBr), potassium iodide (KI), CsCl, CsBr, CsI and or mixtures thereof.
According to the embodiment of the present invention, wherein the phase transfer catalyst is selected from but not limited to tetra butyl ammonium bromide (TBAB), tetra butyl ammonium iodide (TBAI), tetrapropyl ammonium bromide (TPAB), tributyl benzyl ammonium bromide, tetraoctyl ammonium bromide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, preferably tetra butyl ammonium iodide (TBAI).
According to the embodiment of the present invention, wherein the base is selected from but not limited to inorganic bases like alkali metal carbonates selected from sodium carbonate, potassium carbonate, lithium carbonate thereof; alkali metal bicarbonates selected from sodium bicarbonate, potassium bicarbonate thereof; alkali metal hydroxides selected from sodium hydroxide, potassium hydroxide, lithium hydroxide thereof; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide thereof; alkali metal hydrides selected from sodium hydride, potassium hydride, lithium hydride thereof; alkali metal amides selected from sodium amide, potassium amide, lithium amide or mixtures thereof; organic bases selected from ammonia, diethylamine, triethylamine, tributylamine, isopropyl ethylamine, diisoproylamine, diisopropylethylamine, piperidine, pyridine, 4-dimethylamino pyridine, N-methyl morpholine thereof.
According to the embodiment of the present invention, wherein the solvent is selected from but not limited to alcohols such as methanol, ethanol, propanol, butanol, n-propyl alcohol, isopropyl alcohol, and t-butyl alcohol; nitriles such as acetonitrile and propionitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; and aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as n-heptane and n-hexane; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, dioxane or water, cyclohexane and or mixtures thereof.
According to the embodiment of the present invention, wherein the Lewis acid is selected from but not limited to aluminium chloride (AlCl3), aluminium bromide (AlBr3), boron trifluroide (BF3), boron trichloride (BCl3), ferric chloride (FeCl3), tin(IV) chloride (SnCl4), calcium chloride (CaCl2) and calcium chloride dihydrate (CaCl2-2H2O) or mixtures thereof.
According to the embodiment of the present invention, wherein the acid is selected from but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, capric acid, oxalic acid, malonic acid, maleic acid, fumaric acid, succinic acid, citric acid, tartaric acid, benzoic acid, salicylic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid or mixtures thereof.
According to the embodiment of the present invention, wherein the reducing agent is selected from but not limited to Ni, Raney Ni, Pd/C, Pt/C, PtO2, Fe, Zinc dust, DIBAL-H, lithium aluminium hydride (LiAlH4), sodium borohydride (NaBH4), potassium borohydride (KBH4), lithium borohydride, sodium aluminium hydride, diborane, hydrazine hydrate, sodium dithionate, sodium sulfide, ammonium sulfide, dimethyl sulfide or mixtures thereof.
According to the embodiment of the present invention, wherein the first solvent is selected from but not limited to ethanol, acetonitrile, ethyl acetate or methyl tert-butyl ether (MTBE), and the second solvent is selected from but not limited to water or n-heptane.
According to the embodiment of the present invention, wherein the suitable temperature is between 35ºC to 60ºC, preferably 45ºC to 50ºC.
According to the embodiment of the present invention, wherein the cooling temperature is between 25 ºC to 30ºC.
In yet another embodiment, the present invention provides a pharmaceutical composition comprising crystalline Form 1 of Tapinarof and one or more pharmaceutically acceptable excipients.
According to the embodiment of the present invention, provided a pharmaceutical compositions comprising a therapeutically effective amount of crystalline Form 1 of Tapinarof in combination with pharmaceutically acceptable excipients. The crystalline Form 1 of Tapinarof in combination with a pharmaceutically acceptable carrier may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

EXPERIMENTAL PROCEDURE:

Example-1: Preparation of 4-isopropyl-3,5-dimethoxy-benzoic acid (II):

3,5-Dimethoxy benzoic acid (100 gm) was suspended in Aq. 80% w/w sulfuric acid (255mL) and mixture was heated to 55-60°C, then isopropanol (40ml) was added dropwise. The mixture was cooled to room temperature and water (185ml) was added. The mixture was maintained at room temperature for 2-5 hours. The obtained solid was isolated by filtration under vacuum, washing with water (150ml). The resultant solid was recrystallized from toluene (10ml) to get title of the compound (II).
Yield: 80%) (98 gm)
HPLC purity: 99%.

Example-2: Preparation of methyl-4-isopropyl-3,5-dimethoxy benzoate (VIII):

4-Isopropyl-3,5-dimethoxy-benzoic acid (100 g), methanol (300mL) and sulfuric acid (44g) were charged into a round bottom flask at 0-5°C and stirred for 2-4hrs. After completion of the reaction, add purified water, filter and wash with purified water. The obtained product was recrystallized with water (20ml) to get title of the compound (VIII).
Yield: (82 gms, 77%).
HPLC purity: 99%.

Example-3: Preparation of 4-isopropyl-3,5-dimethoxy phenyl methanol (VII)

NaBH4 (15.5 gms), Dimethyl sulfide (DMS) (25.5 gms) was suspended in THF (100 mL). methyl-4-isopropyl-3,5-dimethoxy benzoate (90gms) and THF (900 mL) were added drop wise addition to the reaction mixture solution. The reaction mass was stirred at 50-65? for 3 hrs and after completion of the reaction. water (200mL) was poured into the reaction mixture and then extracted with ethyl acetate, organic layer was washed with Aq. NaCl solution and dried over with Na2SO4 to produce crude product. Crude product was purified from cyclohexane (15ml) to get title of the compound (VII).
Yield: 97% (79.3 gms).
HPLC purity: 99%.

Example-4: Preparation of (E)-2-isopropyl-1,3-dimethoxy-5-styrylbenzene:
(4-Isopropyl-3,5-dimethoxyphenyl) methanol (50gms), KI (3.95gm), TBAI (2.63gm) and triethylphosphite (100ml) were charged into a round bottom flask. The reaction mixture was heated to 135-140ºC and maintained for 12-14 hrs at the same temperature. After completion of the reaction checked by HPLC, cool the reaction mass to 25-300C. Add toluene (50ml) into the reaction mass, this reaction mass is added into the solution of THF (300ml), Sodium methoxide (38.5gm) and benzaldehyde (25.2gm) at 0-50C and stir for 2-3hrs at 5-100C, after completion of the reaction checked by HPLC. Add purified water (250ml) and ethyl acetate (200ml) into the reaction mass and stir for 5-10min. The separates the layers, extracting the material into ethyl acetate (150ml). The combine the organic layers and wash with 5% citric acid solution (200ml), 5% sodium bicarbonate solution (200ml) solution, followed by 5% sodium chloride solution, distilled out ethyl acetate and isolation by using methanol to obtain title compound as off white solid.
Yield: 70% (94g)
HPLC purity: >99.10%

Example-5: Preparation of (E)-2-isopropyl-5-styrylbenzene-1,3-diol (Tapinarof):
Charge Toluene (350ml), Aluminium chloride (106gm) into RBF, cool the reaction mass to 5-100C and add triethylamine (80.6gm) to form complex. Add a solution of (E)-2-isopropyl-1,3-dimethoxy-5-styrylbenzene (50g) and toluene (150ml) into the reaction mass at same temperature. The obtained reaction mass heated to 90-950C and stir for 4-5hrs. After completion of the reaction checked by HPLC, reaction mass was allowed to cool to 5-100C. Charge purified water (1000ml), Conc.HCl (100ml) and ethyl acetate (600ml) into another RBF, cool the reaction mass to 5-100C. Add above reaction to HCl solution at same temperature and stir for 5-10 min. The reaction mass was heated to room temperature, separate the layers, and extract the material again with ethyl acetate (150ml) and combine the organic layers wash with 5% of sodium chloride solution, followed by carbon treatment, distillation. The obtained crude material isolation with MTBE (150ml) and n-heptane (250ml). The obtained Tapinarof crude dissolved in Ethyl acetate (100 ml) at 45-50oC, then distilled the Ethyl acetate under vacuum at below 50oC and added n-heptane (175 ml), cool to room temperature, filter the material to get title compound as a light brown color solid.
Yield: 88.0% (40g)
HPLC purity: >99.5%
Example-6: Preparation of crystalline Form-1 of Tapinarof:
Crude Tapinarof (50.0 gm) HPLC purity (99.45%) was dissolved in ethyl acetate (100mL), heated at 45-50ºC, stirred for 30 minutes and filtered through micron filter. Distilled out the solvent completely, charged n-heptane (175ml) and stirred for 30 min. Then the reaction mass was allowed to cool at 25-30ºC and stirred for 1-2 hours, the resulting product was filtered and washed with heptane (25 mL) and dried at 40-50ºC for 8-10 hours to obtain pure crystalline form 1 of Tapinarof.
Yield: 96% (48.0g)
HPLC purity: >99.9%
Example-7: Preparation of crystalline Form-1 of Tapinarof:
Crude Tapinarof (50.0 gm) HPLC purity (99.45%) was dissolved in ethyl acetate (150mL), heated at 45-50ºC, stirred for 30 minutes and filtered through micron filter. Distilled out the solvent completely, charged n-heptane (200ml) and stirred for 30 min. Then the reaction mass was allowed to cool at 25-30ºC and stirred for 1-2 hours, the resulting product was filtered and washed with heptane (25 mL) and dried at 40-50ºC for 8-10 hours to obtain pure crystalline Form 1 of Tapinarof.
Yield: 94% (47.0g)
HPLC purity: >99.9%

Example-8: Preparation of crystalline Form-1 of Tapinarof:
Crude Tapinarof (50.0 gm) HPLC purity (99.45%) was dissolved in ethyl acetate (200mL), heated at 45-50ºC, stirred for 30 minutes and filtered through micron filter. Distilled out the solvent completely, charged n-heptane (250ml) and stirred for 30 min. Then the reaction mass was allowed to cool at 15-20ºC and stirred for 1-2 hours, the resulting product was filtered and washed with heptane (25 mL) and dried at 40-50ºC for 8-10 hours to obtain pure crystalline Form 1 of Tapinarof.

Yield: 92% (46.0g)
HPLC purity: >99.9%
,CLAIMS:WE CLAIM:

1. An improved process for the preparation of Tapinarof (I) comprising the steps of,
a) treating a compound of formula (VII) with triethylphosphite in presence of an alkali metal halide, a phase transfer catalyst in the absence of solvent to produce an in-situ compound of formula (III),

b) treating the in-situ compound of formula (III) with benzaldehyde in presence of a base and a solvent to produce a compound of formula (IV), and

c) treating the compound of formula (IV) with lewis acid in presence of a solvent and a base to produce Tapinarof of formula (I).

2. The process as claimed in claim 1, wherein the alkali metal halide is selected from but not limited to NaCl, NaBr, sodium iodide (NaI), potassium chloride (KCl), potassium bromide (KBr), potassium iodide (KI), CsCl, CsBr, CsI and or mixtures thereof.
3. The process as claimed in claim 1, wherein the phase transfer catalyst is selected from but not limited to tetra butyl ammonium bromide (TBAB), tetra butyl ammonium iodide (TBAI), tetrapropyl ammonium bromide (TPAB), tributyl benzyl ammonium bromide, tetraoctyl ammonium bromide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, preferably tetra butyl ammonium iodide (TBAI).
4. The process as claimed in claim 1, wherein the base is selected from but not limited to inorganic bases like alkali metal carbonates selected from sodium carbonate, potassium carbonate, lithium carbonate thereof; alkali metal bicarbonates selected from sodium bicarbonate, potassium bicarbonate thereof; alkali metal hydroxides selected from sodium hydroxide, potassium hydroxide, lithium hydroxide thereof; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide thereof; alkali metal hydrides selected from sodium hydride, potassium hydride, lithium hydride thereof; alkali metal amides selected from sodium amide, potassium amide, lithium amide or mixtures thereof; organic bases selected from ammonia, diethylamine, triethylamine, tributylamine, isopropyl ethylamine, diisoproylamine, diisopropylethylamine, piperidine, pyridine, 4-dimethylamino pyridine, N-methyl morpholine thereof.
5. The process as claimed in claim 1, wherein the solvent is selected from but not limited to alcohols such as methanol, ethanol, propanol, butanol, n-propyl alcohol, isopropyl alcohol, and t-butyl alcohol; nitriles such as acetonitrile and propionitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; and aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as n-heptane and n-hexane; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; ethers such as methyl tert-butyl ether, diethyl ether, tetrahydrofuran, dioxane or water, cyclohexane and or mixtures thereof.
6. The process as claimed in claim 1, wherein the Lewis acid is selected from but not limited to aluminium chloride (AlCl3), aluminium bromide (AlBr3), boron trifluroide (BF3), boron trichloride (BCl3), ferric chloride (FeCl3), tin(IV) chloride (SnCl4), calcium chloride (CaCl2) and calcium chloride dihydrate (CaCl2-2H2O) or mixtures thereof.

7. An improved process for the preparation crystalline Form 1 of Tapinarof comprises the steps of,
a. dissolving the Tapinarof in first solvent,
b. heating the reaction mass at suitable temperature,
c. optionally, completely distillation of the first solvent,
d. adding second solvent,
e. cooling the obtained solution in step d), and
f. isolating the crystalline Form 1 of Tapinarof.

8. The process as claimed in claim 7, wherein the first solvent is selected from but not limited to ethanol, acetonitrile, ethyl acetate or methyl tert-butyl ether (MTBE), and the second solvent is selected from but not limited to water or n-heptane.
9. The process as claimed in claim 7, wherein the suitable temperature is between 35ºC to 60ºC, preferably 45ºC to 50ºC and the cooling temperature is between 25 ºC to 30ºC.