"Novel Stilbene Analogs"

Field of the invention:

The present invention relates to novel stilbene derivatives and their pharmaceutically acceptable salts thereof. Furthermore, the purpose of this invention is also to provide a process for the preparation of said novel derivatives.

Back ground of the invention

Various analogs of stilbene as core moiety are mentioned in WO 01/21165 Al, US 5,525,632 as anti-tumor substances. The substance, the synthesis, the use and the advantages of 3, 5, 3', 4', 5 '-substituted and related analogs of the present invention, are not disclosed in the art. The present inventors have already accomplished the 4'-O- tetrahydropyranyl stilbene derivatives and mentioned in their co pending Indian application numbered 1766/CHE/2008.

Resveratrol (trans-3, 5, 4'- Trihydroxy stilbene), a compound found largely in the skins of red grapes, has been shown to have chemo preventive activity against cardiovascular disease and a variety of cancers, but it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans.

Pterostilbene (trans-3, 5-dimethoxy-4-hydroxystilbene), is a dimethylated analogue of resveratrol, a stilbene shown to have anti-cancer activity across many cell lines and it is a naturally occurring stilbene found in deer berry and rabbit eye blueberries, several varieties of grapes, and in the tree species Pterocarpusmarsupium and Guibourtia tessmanii. In addition, pterostilbene has also been demonstrated to have anti-diabetic and anti-oxidant properties. Hypoglycemic activity of a naturally occurring pterostilbene, trans-l-(3,5-dimethoxyphenyl)-2-(4-hydroxy phenyl ) -ethylene, isolated from the heartwood of pterocarpus marsupium has been reported by Manickam et al., J. Nat. Prod.,

1997, 60:609-610.

H. Yang et al performed in vitro screens for stilbenes that could modulate human SIRTl and Howitz et al examined structure-activity relationship of SIRTl activation by stilbenes. Resveratrol derivatives such as 4' hydroxyl is replaced with thiomethyl group

(3,5-dihydroxy-4'-thiomethyl-trα»5-stilbene), methyl (3,5-dihydroxy-4'-methyl-/rα«5- stilbene) and ethyl (3, 5-dihydroxy-4'-ethyl-frww-stilbene) have been disclosed by H.

Yang et al. Methoxy group at 4' position (3, 5-dihydroxy-4'-methoxy-trαw-stilbene) , showing similar resveratrol activity, but the derivative 3, 5-dihydroxy-4'-acetoxy-trø/7.ϊ-

stilbene is the least potent due to the presence of an ester group, which is relatively large volume at the 4'- position.

It is evident by the art that the resveratrol as well as pterostilbene have less absorption due to low water solubility and bioavailability. Due to less bioavailability and low solubility of the drugs mentioned, the fraction of an administered dose of unchanged drug that reaches the systemic circulation is less. It is particularly due to incomplete absorption and first-pass metabolism.

Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration. The two major hurdles including low water solubility found with the known compounds need to be resolved. As an alternative, these novel derivatives have been made. The said novel compounds have proven their value as active ingredients since they act as anti- tumor substances and been shown to have advantageous properties such as high water solubility and bioavailability that must be required in order to determine that the compounds are pharmacokinetically acceptable.

Summary of the invention

The Stilbene derivatives according to the present invention correspond to the general formula I

Wherein

R ¹ , R ² which may be the same or different each represent -OR ⁷ , in which R ⁷ is hydrogen, an alkyl group having 1 to 3 carbon atoms; R represents hydrogen, -OR , in which R is an alkyl group having 1 to 3 carbon atoms- or tetrahydropyranyl; R ³ is a halogen atom, an alkyl group having 1 to 3 carbon atoms with proviso that when R ⁴ , R ⁵ are solely hydrogen; R ⁴ represents nitro, mono alkyl amino, carbamic acid alkyl ester group, alkyl or aryl amido, aryl amino, diphenyl amino, diaryl amino, alkyl sulphanamino, phenyl or aryl sulphanamino, sulphamic acid group or its sodium salt, alkyl or aryl carbamic acid group, morpholino, N-alkyl substituted or unsubstituted piperzinyl; R ⁴ further represents hydroxy with proviso that R ⁵ is exclusively halogen; R ⁴ further represents amino, dialkyl amino , only when R ¹ , R ² are hydroxy; R ⁴ further represents hydrogen with proviso that R ⁵ is not hydrogen, alkoxy and R ⁴ further represents halogen with proviso that when R ⁶ is solely a halogen atom; R ⁴ further represents -OR ⁹ in which R ⁹ represents

tetrahydropyranyl with proviso that R ³ is not hydrogen; Furthermore R ⁹ represents an alkyl group having 1 to 3 carbon atoms, (2-4C) alkanoyl when R ⁵ is exclusively a halogen atom; R ⁹ further represents alkyl morphonyl, alkyldiamino, vinyl, allyl, suphonyl and its corresponding sulphonate salts, phenyl sulphonyl, aryl sulphonyl, suphonic acid group, amino acid group, alkoxy carbonyl amino acid group, alkanoic acid group, alkanoic acid alkyl ester group and its corresponding alkali metal salts; R represents hydrogen, a halogen atom , alkoxy; R ⁶ represents hydrogen;

Detailed description of the invention

In formula (I), the term "an alkyl group having 1 to 3 carbon atoms" means methyl, ethyl and propyl; the term "a halogen atom" means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; the term " N-alkyl" means N-methyl, N-ethyl; the term " alkoxy" means methoxy, ethoxy and propoxy; a suitable value for the substituent when it is (2-4C) alkanoyl is, for example, acetyl, propionyl and butyryl;

The preferred compounds of the present invention wherein, R ¹ , R ² are preferably methoxy groups or hydroxyl groups.

A suitable pharmaceutically acceptable salt of general formula I of the invention is, for example, an acid-addition salt with, for example, inorganic acid or organic .acid, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, citric and the like. When the compound of the present invention is acidic, then the salts derived from inorganic bases include sodium, potassium, lithium, ammonium and the like.

The specific preferred compounds of the invention are the following stilbene derivatives, which correspond to general formula I, or a pharmaceutically acceptable salt thereof.

2-[5-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-2-(tetrahyd ro-2H-2-pyranyloxy)phenoxy] tetrahydro-2H-pyran;

2-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-2-methoxyphen oxytetrahydro-2H-pyran;

2-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-2,5-dimethoxy phenoxytetrahydro-2H- pyran;

4-(2-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyeth yl)morpholine;

N-(2-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyeth yl)-iV,iV-dimethylamine;

N-(2-4-[(E)-2-(3 ,5-dimethoxyphenyl)- 1 -ethenyl]phenoxyethyl)-N,N-dimethylaniine;

l-(£)-2-[4-(allyloxy) phenyl]-l-ethenyl-3,5-dimethoxybenzene;

4-[(£)-2-(3,5-dimethoxyphenyl)- 1 -ethenyl]phenyl methanesulfonate;

4-[(£)-2-(3, 5-dimethoxyphenyl)-l-ethenyl]phenyl 1-benzenesulfonate;

4-[(£)-2-(3 ,5 -dimethoxyphenyl)- 1 -ethenyl]phenyl 4-methyl- 1 -benzenesulfonate;

4-[(ϋT)-2-(3 ,5-dimethoxyphenyl)- 1 -ethenyl]phenyl hydrogen sulfate;

4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl 2-aminoacetatehydrochloride;

4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl 2-aminopropanoatehydrochloride;

4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl 2-[(tert-butoxycarbonyl)amino] propanoate;

4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl 2-amino-3-hydroxypropanoate hydrochloride;

2-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyacetic acid;

Ethyl 2-4-[(£)-2-(3 ,5 -dimethoxyphenyl)- 1 -ethenyljphenoxyacetate;

5-(E)-2-[4-(2-morpholinoethoxy)phenyl]- 1 -ethenyl- 1 ,3-benzenediol;

5-((£)-2-4- [2-(dimethylamino)ethoxy]phenyl- 1 -ethenyl)- 1 ,3-benzenediol;

l,3-dimethoxy-5-[(E)-2-(4-nitrophenyl)-l-ethenyl]benzene;

N-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-iV-meth ylaminehydrochloride;

tert-Butyl iV-4-[(E)-2-(3,5-dimethoxyphenyl)- 1 -ethenyl] phenylcarbamate;

M -4-[(£)-2-(3 ,5 -dimethoxyphenyl)- 1 -ethenyljphenylacetamide;

Nl -4-[(E)-2-(3 ,5-dimethoxyphenyl)- 1 -ethenyl]phenylbenzamide;

λ ^r -benzyl-N-4- [(E)-2-(3 ,5 -dimethoxyphenyl)- 1 -ethenyl] phenylamine N, N-dibenzyl-N-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]pheny lamine; N-4-[(£)-2-(3,5-dimethoxyphenyl)- 1 -ethenyl]phenylmethanesulfonamide; N-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenylsulfamic acid;

M-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-l-benz enesulfonamide;

Benzyl N-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenylcarbamate;

4-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenylmorpholi ne; 1 -4-[(E)-2-(3 ,5-dimethoxyphenyl)- 1 -ethenyl]phenyl-4-methylpiperazine; l-[(£)-2-(3-bromophenyl)-l-ethenyl]-3,5-dimethoxybenzene;

5-(E)-2-[4-(dimethylamino)phenyl]- 1 -ethenyl- 1 ,3 -benzenediol;

5-[(£)-2-(4-morpholinophenyl)- 1 -ethenyl]- 1 ,3 -benzenediol;

5-{(E)-2-[4-(4-Methyl-piperzin-l -yl) -phenyl]-vinyl}-benzene-l,3-diol; 5 - [(£)-2-(4-aminophenyl)- 1 -ethenyl] - 1 ,3 -benzenediol ;

2-chloro-4-[(£)-2-(3 ,5-dimethoxyphenyl)- 1 -ethenyl]- 1 -methoxybenzene;

2-chloro-l-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-4-flu orobenzene;

2-chloro-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenol;

2-chloro-4-[(£)-2-(3,5-dihydroxyphenyl)- 1 -ethenyl]phenyl acetate; 5-[(£)-2-(3-chloro-4-hydroxyphenyl)-l-ethenyl]-l,3-benzened iol; l,3-Dimethoxy-5-[(E)-2-(3-methylphenyl)-l-ethenyl]benzene;

In the synthesis of stilbene analogs of the present invention, the general method typically involves the condensation of aromatic aldeheyde with phosphonate esters leads to olefins with excellent ^-selectivity.

Using Wittig-Horner reaction, aromatic aldehyde (V) is condensed with phopshonate ester (IV) in a suitable solvent such as terahydrofuran (THF) in presence of suitable bases for forming the ylide. Butyl lithium (BuLi), sodium hydride (NaH) and sodium methoxide (NaOMe) are identified as suitable bases. Out of which, NaH in THF at optimized conditions affords the acceptable yield of single (E)-stilbene analog (I) as compared to the other bases.

The resulting phosphate byproduct is readily separated by simply washing with water leaving the desired selective trans isomer.

Starting from substituted benzoic acid (II), the methyl ester compounds (III) are prepared in good yield using methylating agents such as dimethyl sulphate, dimethyl carbonate and the like. In order to be eco-friendly, or green, DMC is a safe substitute for dimethyl sulfate as it yields by-products that are hard to dispose of. Preparation of methyl ester from substituted carboxylic acids is carried out efficiently with dimethyl carbonate (DMC) which can be accelerated by using sulphuric acid as catalyst.

The methyl ester thus obtained now is subjected to reduction in order to obtain corresponding alcohol compound. The reducing agents used for this purpose are sodium borohydride or lithium aluminum hydride or the like, preferably in ether solvents. The primary alcohol can optionally be isolated or it can be used without being isolated for further reaction.

The substituted benzyl alcohol is now halogenated in a suitable solvents for example toluene or dichloromethane, in presence of halogenating agents such as thionyl chloride or Phosphorus tribromide leads to the formation of substituted benzyl halide. In view of economic aspects and corrosive nature of halide compounds, it is recommended not to isolate these halo compounds.

The phosphonate esters (IV), which serve as key precursors for Wittig-Horner reaction, are prepared from the reaction between triethyl phosphite P(OEt) ₃ and ^v foregoing substituted benzyl halide in presence of suitable solvents for example dioxane, THF or toluene. The total process is depicted in the following scheme:

Phosphonate ester

Reagents and conditions: (a) dimethyl carbonate, catalytic amount of H ₂ SO ₄ , reflux, 6hr. (b) NaBH/THF, MeOH, reflux, 3hr.(c) PBr ₃ , toluene, room temperature, 1 hr. (d) triphenyl phosphate, toluene, reflux , 3 hr.(e) NaH ₁ THF

The present invention will now be defined in more detail by way of following examples, which are intended to be illustrative and not limiting.

EXAMPLES

Example-1: Preparation of 1, 3-dimethoxy-5-[(£)-2-(3-methyIphenyl)-l-etheαyl] benzene

To an ice cold suspension of sodium hydride (6 g, 0.249 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath, 3, 5-dimethoxybenzylphosphonate ester (24 g, 0.083 mol, 1 eq) diluted in THF (30 mL) was added slowly using addition flask. The solution was slowly allowed to warm to room temperature and stirred for 30 min. After cooling the solution to 0° C, 3-methyl benzaldehyde (10 g, 0.083 mol, 1 eq) in THF (20 mL) was added and stirred at ice cold temperature for 30 min. and at room temperature for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethyl acetate (2 x 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure l,3-dimethoxy-5-[(£)-2-(3-methylphenyl)-l-ethenyl]benzene Yield 13.3g (60 %).

η NMR (CDCl ₃ , 300 Mz): δ 7.33 -7.24 (m, 3H), 7.04 (m, 3H,), 6.67-6.66 (d, 2H, ^' J= 2.2 Hz), 6.4-6.39 (m, IH, J = 2.2 Hz;, 3.8 (s, 6H), 2.37 (s, 3H). LCMS: 255 (M ⁺ ); HPLC: 99.77%

ExampIe-2: Preparation of 2-[5-[(E)-2-(β, 5-dimethoxyphenyl)-l-ethenyl]-2-(tetrahydro-2H- 2-pyranyloxy) phenoxy] tetrahydro-2H-pyran a) TηP protection of 3, 4-dihydroxybenzaldehyde To a solution of 3, 4-dihydroxybenzaldehyde (10 g, 0.072 mol, 1 eq) in DCM (100 mL) was added DηP (18.2 g,, 0.217 mol, 3 eq) and PPTS (1.8 g, 0.001 mol, 0.2 eq) at room temperature and stirred for overnight at room temperature. Reaction mass poured in water, separated DCM layer and washed with 10% NaOH solution (20 mL), water (twice) and finally with brine, dried over sodium sulfate. Removal of the solvent in vacuo provided colorless oil. Yield: 16.5 g (75%).

b) Preparation of 2-[5-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-2-(tetrahydro- 2H-2- pyranyloxy)phenoxy]tetrahydro-2H-pyran

To an ice cold suspension of sodium hydride (2.3 g, 0.097 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath, 3, 5-dimethoxybenzylphosphonate ester (9.4 g, 0.032 mol, 1 eq) diluted in TηF (30 mL) was added slowly using addition flask. The solution was slowly allowed to warm to room temperature and stirred for 30 min. After cooling the solution to O ⁰ C, 3, 4-bis(tetrahydro-2η-pyran-2-yloxy) benzaldehyde (10 g, 0.032 mol, 1 eq) in THF (20 mL) was added and stirred at ice cold temperature for 30 min. and at room temperature for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethyl acetate (2 X 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure 2-[5-[(£)-2-(3,5-dimethoxyphenyl)-l- ethenyl]-2-(tetrahydro-2H ^" -2-pyranyloxy) phenoxy]tetrahydro-2H-pyran. Yield 8.2 g (60%).

η NMR (DMSO, 300 Mz): δ 7.34-7.33 (d, 1η, J= 1.6 Hz), 7.19-6.97 (m, 5H), 6.73-6.72 (d, 2H, J= 2.1 Hz), 6.36-6.35 (t, IH, J= 2.1 Hz), 5.54-5.53(t, IH, J=2.6 Hz),5.47-5.46 (t, IH, J=3 Hz),3.9-3.8 (m, 2H), 3.8 (s, 6H), 3.6-3.5 (m, 2H), 2.0-1.79 (m, 6H), 1.78-1.53 (m, 6H). LCMS: 441 (M ⁺ ); HPLC: 98.65%

ExampIe-3: Preparation of 2-4-[(£)-2-(3, 5-dimethoxyphenyl)-l-ethenyl]-2-methoxyphenoxy tetra hydro-2//-pyran a) THP protection of 4-hydroxy-3-methoxybenzaldehyde (vanillin)

To a solution of 4-hydroxy-3-methoxybenzaldehyde (10 g, 0.065 mol, 1 eq) in DCM (100 mL) was added DHP (8.2 g, 0.098 mol, 1.5 eq) and PPTS (1.6 g, 0.006 mol, 0.1 eq) at room temperature and continued stirring for overnight at room temperature. Reaction

progress was monitored by TLC. Reaction mass poured in water, separated DCM layer and washed with 10% NaOH solution (20 mL), water (twice) and finally with brine, dried over sodium sulfate. Removal of the solvent in vacuo provided colourless oil. Yield 16.5 g (75%).

b) Preparation of 2-4-[(E)-2-(3, 5-dimethoxyphenyl)-l-ethenyl]-2-methoxy phenoxy tetra hydro-2//-pyran

To an ice cold suspension of sodium hydride (3 g, 0.126 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath, 3, 5-dimethoxybenzylphosphonate ester (12.2 g, 0.042 mol, 1 eq) diluted in THF (30 mL) was added slowly using addition flask. The solution was slowly allowed to warm room temperature and stirred for 30 min. After cooling the solution to O ⁰ C, 3-methoxy-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (10 g, 0.0423 mol, 1 eq) in THF (20 mL) was added and stirred at ice cold temperature for 30 min. and at room temperature for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethyl acetate (2 x 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure 2-4-[(£)-2-(3, 5-dimethoxyphenyl)-l- ethenyl]-2-methoxy phenoxy tetra hydro-2H-pyran Yield 8.2 g (55 %).

η NMR (CDCl ₃ , 300 Mz): δ 7.12-6.87 (m, 5η), 6.65-6.64 (d, 2H J= 2.2 Hz) ₃ 6.38-6.37 (t, IH, J= 2.2 Hz), 5.43-5.40 (t, IH, J=3.1 Hz), 4.0 (m, IH), 3.9 (s, 3H), 3.8 (s, 6H), 3.7- 3.5 (m, IH), 2.1-1.8 (m, 3H), 1.81-1.58 (m, 3H). LCMS: 370 (M ⁺ ); HPLC: 99.66%

Example-4: Preparation of 2-4-[(2s)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-2,6-diinethoxy phenoxy tetrahydro-2H-pyran a) TηP protection of 4-hydroxy-3, 5-dimethoxybenzaldehyde (Syringaldehyde): To a solution of 4-hydroxy-3, 5-dimethoxybenzaldehyde (10 g, 0.055 mol, 1 eq) in DCM (100 mL) was added DηP (6.9 g, 0.082 mol, 1.5 eq) and PPTS (1.3 g, 0.005 mol, 0.1 eq) at room temperature and stirring continued for overnight at room temperature. Reaction progress was monitored by TLC. Reaction mass poured in water, separated DCM layer and washed with 10% NaOH solution (20 mL), water (twice) and finally with brine, dried over sodium sulfate. Removal of the solvent in vacuo provided colorless oil. Yield 10.9 g, (75%)

b) Preparation of 2-4-[(2J)-2-(3,5-dimethoxyphenyi)-l-ethenyl]-2,6-dimethoxy phenoxy tetrahydro-2H-pyran

To an ice cold suspension of sodium hydride (2.7 g, 0.112 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath, 3, 5-dimethoxybenzylphosphonate ester (10.8 g, 0.037 mol, 1 eq) diluted in THF (30 mL) was added slowly using addition flask. The solution was slowly allowed to warm to room temperature and stirred for 30 min. After cooling the solution to 0° C, 3, 5-dimethoxy-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (10 g,0.037 mol, 1 eq) in TηF (20 mL) was added and stirred at ice cold temperature for 30 min. and room temperature for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated TηF layer, aqueous layer extracted with ethyl acetate (2 X 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure 2-4-[(£)-2-(3,5-dirnethoxyphenyl)-l- ethenyl]-2,6-dimethoxy phenoxy tetrahydro-2H-pyran. Yield 8.2 g (55 %). η NMR (CDCl ₃ , 300 Mz): δ 6.97-6.93 (dd, 2η, J= 11.6 Hz), 6.72 (s, 2H), 6.65-6.64 (d, 2H, J = 2.2 Hz), 6.39-6.37 (t, IH, J = 2.2 Hz), 5.44 (m, 1H),4.3 (m, IH), 3.88 (s, 6H), 3.82 (s, 6H), 3.47 (m, 4H), 2.02 -1.98 (m, 2H), 1.96 (m, IH). LCMS: 401 (M ⁺ ); HPLC: 98.89%

ExampIe-5: Preparation of 2-chloro-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-l-methox y benzene a) Methyl protection of 3-chloro-4-hydroxybenzaldehyde

Finely powdered potassium carbonate (18.1 g, 0.131 mol, 2 eq) was added to a well stirred solution of 3-chloro-4-hydroxybenzaldehyde (10 g, 0.064 mol, 1 eq) in acetone (80 mL) under nitrogen. After 10 min., dimethylsulphate (8 g, 0.064 mol, 1 eq) was added slowly at room temperature and stirred for 30 min. The reaction mixture was allowed to reflux for 2h. Reaction progress was monitored by TLC, Reaction mixture cooled to room temperature and K ₂ CO ₃ was filtered, acetone was distilled out in vacuo to obtain residue and was triturated with hexane (20 mL) at O ⁰ C for 30 min. to result pale green colored solid. Yield 9.2 g (85%).

b) Preparation of 2-chloro-4-[(£)-2-(3,5-dimethoxyphenyI)-l-ethenyl]-l-methox ybenzene

To an ice cold suspension of sodium hydride (4.2 g, 0.175 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath, 3, 5-dimethoxybenzylphosphonate ester (16.9 g, 0.058 mol, 1 eq) diluted in THF (30 mL) was added slowly using addition flask. The solution was slowly allowed to warm to room temperature and stirred for 30 min. After cooling the solution to 0° C, 3-chloro-4-methoxy benzaldehyde (10 g, 0.058 mol, 1 eq) in THF (20 mL) was added and stirred at ice cold temperature for 30 min. and room temperature for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated THF layer, aqueous layer

extracted with ethylacetate (2 x 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure 2-chloro-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-l- methoxybenzene. Yield 10.7 g (60 %). 'H NMR (CDCl ₃ , 300 Mz): δ 7.55-7.54 (d, IH, J= 2.1 Hz), 7.34-7.32 (m, IH), 6.94-6.89 (m, 3H), 6.64-6.63 (d, 2H, J =2.1 Hz), 6.39-6.37 (t, IH, J=2.1 Hz), 3.91 (s, 3H), 3.82 (s, 6H). LCMS: 305 (M ⁺ ); HPLC: 98.24%

Example-6: Preparation of 5-[(£)-2-(3-chloro-4-hydroxyphenyl)-l-ethenyI]-l, 3-benzenediol

The solution of 4-(3, 5-dimethoxystyryl)-2-chlorophenol (2 g, 0.006 mol, 1 eq) in DCM (15 mL) was cooled to 0° C in an ice bath. BBr ₃ (6.8 g, 0.027 mol, 4 eq) diluted in DCM (5 mL) was added slowly to the reaction mass at 0° C. The solution was slowly allowed to room temperature and stirred for overnight at room temperature. Reaction mass poured in ice-cold water and compound extracted with ethyl acetate, organic layer was washed with water and brine. Removal of solvent afforded crude product and purified by silica-gel column chromatography (ethyl acetate/hexane-2:8 as eluent) to obtain pure product. Yield 0.63 g (35%).

¹ H NMR (DMSO, 300 Mz): δ 10.24 (s, -OH), 9.2 (s, 2-OH), 7.55-7.54 (d, IH, J = 2.1 Hz), 7.35-7.31 (m, IH), 6. 92-6. 87 (m, 3H), 6.36-6.35 (d, 2H, J =2.1 Hz), 6.1-6.09 (t, IH, J= 2.1 Hz). LCMS: 263 (M ⁺ ); HPLC: 93.22% Example-7: Preparation of 2-chloro-4-[(£)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenol a) THP protection of 3-chloro-4-hydroxybenzaldehyde

To a solution of 3-chloro-4-hydroxybenzaldehyde (1O g, 0.064 mol, 1 eq) in DCM (100 mL) was added DHP (8 g, 0.096 mol, 1.5 eq) and PPTS (1.6 g, 0.006 mol, 0.1 eq) at room temperature. The solution was stirred for overnight at room temperature. The reaction mixture was poured in water, organic layer was separated and treated with 10% NaOH (20 mL), water (twice) and finally with brine, dried over sodium sulfate. Removal of the solvent in vacuo provided brown colored oil. Yield: 16.5 g (75%).

b) Preparation of 2-{2-Chloro-4-[(E)-2-(3,5-diinethoxyphenyI)-vinyl]-phenoxy}- tetrahydropyran To an ice cold suspension of sodium hydride (3 g, 0.124 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath, 3, 5-dimethoxybenzylphosphonate ester (11.9 g, 0.041 mol, 1 eq) diluted in THF (30 mL) was added slowly using addition flask. The solution was slowly allowed to room temperature and stirred for 30 min. After cooling the solution to O ⁰ C, 3-chloro-4-(tetrahydro-2H-pyran-2-yloxy) benzaldehyde (10 g, 0.041 mol, 1 eq) in THF (20 mL) was added and stirred at ice cold temperature for 30 min. and room

temperature for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethyl acetate (2 x 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure 2-{2-Chloro-4-[(E)-2-(3,5-dimethoxyphenyl)-vinyl]- phenoxy}-tetrahydropyran. Yield 6.2 g (40%). c) Preparation of 2-chloro-4-[(£)-2-(3,5-dimethoxyphenyl)-l-etheny-]phenol

To a solution of 2-{2-Chloro-4-[(E)-2-(3,5-dimethoxyphenyl)-vinyl]-phenoxy}- tetrahydropyran (10 g, 0.026 mol, 1 eq ) in methanol (100 mL) was added pyridinium p- toluenesulphonate (0.67 g, 0.002 mol, 0.1 eq) at room temperature and refluxed for 1 h. Removal of methanol in vacuo, to result crude product and was diluted in ethyl acetate and washed with 10% NaHCO ₃ , 5% HCl, water and finally with brine. Organic layer was distilled in vacuo to get residue and purified by column chromatography (ethyl acetate- hexane, 1:3, v/v) to give pure 2-chloro-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenol. Yield 5.4g (70 %).

¹ H NMR (CDCl ₃ , 300 Mz): δ 7 '.48-7.47 (d, IH, J= 2.1 Hz), 7.33-7.29 (m, IH), 7.01-6.9 (m, 3H), 6.63-6.62 (d, 2H, /=2.1 Hz), 6.39-6.38 (t, IH, J=2.1 Hz), 5.63(s, -OH), 3.82 (s, 6H). LCMS: 291 (M ⁺ ); HPLC: 99.35%

εxample-8: Preparation of 2-chloro-4-[(jE)-2-(3,5-dihydroxyphenyl)-l-ethenyl] phenyl acetate

To a solution of 2-chloro-4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenol (10 g, 0.034 mol, 1 eq) in DCM (100 mL) at O ⁰ C added triethylamine (5.4 g, 0.068 mol, 2 eq) and stirred for 30 min. Acetyl chloride (2.96 g, 0.037, 1.1 eq) was added slowly at 0 ⁰ C and slowly reaction mass was allowed to warm to room temperature, and stirred for 2 h.

Reaction progress was monitored by TLC. Reaction mass poured in ice-cold water, separated DCM layer, washed with 10% NaHCO ₃ . Crude product was obtained on removal of solvent in vacuo and triturated with diisopropylether to get pure title product

4-(3, 5-dimethoxystyryl)-2-chlorophenyl acetate. Yield 6.8 g (60%).

¹ H NMR (CDCl ₃ , 300 Mz): δ 7.58-7.57 (d, IH, J = 2 Hz), 7.40-7.36 (dd, IH, J =2 Hz), 7.12-7.10 (dd, IH, J= 8.4 Hz), 6.98 (s, 2H), 6.65-6.64 (d, 2H, J= 2.0 Hz), 6.41-6.40 (t, IH, J= 2.0 Hz), 3.82 (s, 6H), 2.35 (s, 3H). LCMS: 333 (M ⁺ ); HPLC: 96.07%

Example-9: Preparation of iV-(2-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyI] phenoxyethyl)- λyV-dimethylamine

To a solution of pterostilbene (5 g, 0.019 mol, 1 eq) in DMF (50 ml), potassium

carbonate (8 g, 0.058 mol, 3 eq), N, N-Dimethyl-2-chloroethane (3 g, 0.021 mol, 1.1 eq) was added at room temperature, and then the reaction mass was heated to 70° C for Ih. Reaction mass was filtered, washed with saturated ammonium chloride and product extracted with ethyl acetate. Removal of solvent in vacuo to obtain residue, and it was purified by silica-gel column chromatography (ethyl acetate/hexane-l:3) to obtain pure title product as solid. Yield: 3.6 g (50%).

¹ H νMR (CDCl ₃ , 300 Mz): δ 7.44-7.41 (d, IH, J= 8.7 Hz), 7.00-6.92 (d, IH, J= 24 Hz), 6.92-6.89 (m, 3H), 6.64-6.63 (d, 2H, J = 2.2 Hz), 6.36 (m, IH) , 4.08 (t, 2H), 3.82 (s, 6H), 2.73 (t, 2H), 2.34 (s, 6H). LCMS: 328 (M ⁺ ); HPLC: 97.66%

Example-10: Preparation of 4-(2-4-[(jE)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenoxyethyl) morpholine

To a solution of pterostilbene (5 g, 0.019 mol, 1 eq) in DMF (50 ml), potassium carbonate (8 g, 0.058 mol, 3 eq) was added. 4-(2-Chloro ethane) morpholine (3.9 g, 0.020 mol, 1.1 eq) at room temperature. The reaction mass was heated to 7O ⁰ C. The reaction mass was filtered and treated with saturated ammonium chloride solution and extracted product with ethyl acetate (100 mL). Removal of solvent gave crude product, which was triturated by methanol at 0 ⁰ C to obtain pure title product as solid. Yield 3.6 g (50%).

¹ H νMR (CDCl ₃ , 300 Mz): δ 1.44-7.41 (d, 2H, J= 8.7 Hz) ₅ 7.00-6.92 (d, IH, J= 24 Hz), 6.87-6.86 (m, 3H), 6.64-6.63 (d, 2H, J= 2.2 Hz), 6.37-6.37 (t, IH, 2.2 Hz) , 4.10-4.12 (t, 2H, 5.7 Hz),3.82 (s, 6H), 3.72-3.73 (t, 4H, 4.7 Hz),2.80-2.82 (t, 2H, J= 5.7 Hz),2.58-2.59 (t, 4H, J= 4.7 Hzj. LCMS: 370 (M ⁺ ); HPLC: 99.66%

Example-11: Preparation of l-(2j)-2-[4-(allyIoxy) phenyI]-l-ethenyI-3, 5-dimethoxybenzene

To a solution of pterostilbene (5 g, 0.019 mol, 1 eq) in acetone (40 mL), potassium carbonate (8 g, 0.058 mol, 3 eq), allyl bromide (2.5 g, 0.021 mol, 1.1 eq) was added at rt and stirred for 5 h at room temperature. The reaction mass was filtered and solvent was evaporated to give residue. The residue was diluted with ethyl acetate (100 mL) and washed with water and brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and purified by silica-gel column chromatography (ethyl acetate/hexane 5:95 as eluent) to afford l-(E)-2-[4-(allyloxy)phenyl]-l-ethenyl-3,5- dimethoxybenzene as solid. Yield 4.0 g (70%).

¹ H νMR (DMSO, 300 Mz): δ 7.51-7.48 (d, 2H, J= 8.4 Hz), 7.21-7.16 (d, IH, J= 16 Hz), 6.96-6.91 (m, 3H), 6.71 (s, 2H), 6.36 (s, IH) ,6.0 (m, IH), 5.4-5.34 (d, 1H,17 Hz) , 5.25- 5.22 (d, IH, 10.5 Hz), 4.55-4.54 (d, 2H, 5 HzJ, 3.74 (s, 6H). LCMS: 297 (M ⁺ ); HPLC: 99.87%

Example-12: Preparation of 4-[(JET)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyl ^' 1-benzene sulfonate

To a solution of pterostilbene (5 g, 0.019 mol, 1 eq) in dichloromethane (50 ml), pyridine (4.7 g, 0.058 mol, 3 eq) was added at rt and stirred for 30 min. Benzenesulfonyl chloride (3.8 g, 0.021 mol, 1.1 eq) was slowly added to reaction mass at 0° C and was allowed to rt for 2 h. Reaction mass was poured in water, separated dichloromethane layer and treated with IN hydrochloric acid (25 mL). Separated organic layer was washed with water and neutralized with 10% sodium bicarbonate solution and washed with water. Removal ^' of solvent gave crude product, which was triturated with hexane to obtain 4-[(E)-2-(3, 5- dimethoxyphenyl)-l-ethenyl] phenyl 1-benzenesulfonate as solid. Yield 2.3 g (30%).

¹ H NMR (CDCl ₃ , 300 Mz): δ 7.85-7.77 (m, 3H), 1.61-1.62 (m, 5H), 7.19-7.14 (dd, 2H, J = 13 Hz), 7.0 -6.97 (d, 2H, J= 8.7 Hzj, 6.73-6.72 (d, 2H, J= 2.2 Hz), 6.40-6.39 (t, IH, J = 2.1 Hz), 3.74(s, 6H). LCMS: 397 (M ⁺ ); HPLC: 96.98%

Example-13: Preparation of 4-{(.E)-2-(3,5-diinethoxyphenyl)-l-ethenyI]phenyI hydrogen sulfate

To a solution of pterostilbene (5 g, 0.019 mol, 1 eq) in dichloromethane (50 mL) triethyl amine (5.9 g, 0.058 mol, 3 eq) was added at rt. Chloro sulphonic acid (2.5 g, 0.021 mol, 1.1 eq) was added to the solution at 0° C and stirred at rt for 2 h. Removal of solvent gave residue, which was purified by silica-gel column chromatography (ethyl acetate/hexane 1:1 as eluent) to obtain pure product 4-[(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl hydrogen sulfate. Yield 1.0 g (15%).

¹ H NMR (CDCl ₃ , 300 Mz): δ 7.49-7.46 (d, IH, J= 8.7 Hz), 7.18-7.06 (m, 4H), 6.74-6.73 (d, 2H, J= 2.2 HzJ, 6.36 (m, IH), 3.74 (s, 6H). LCMS: 337 (M ⁺ ); HPLC: 98.42%

Example-14: Preparation of 4-[(£)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyl 4-methyl-l- benzenesulfonate

To a solution of pterostilbene (5 g, 0.019 mol, 1 eq) in dichloromethane (50 mL), pyridine (4.7g, 0.058 mol, 3 eq) was added at room temperature. /7-toluene sulfonyl chloride (3.7 g, 0.019 mol, 1 eq) was added to the solution at 0° C. The mixture was stirred at room temperature for 6 h. The reaction mass was poured in water, separated dichloromethane layer treated with IN hydrochloric acid (50 mL) and washed with water.

Evaporation of solvent gave crude product, which was triturated with hexane to obtain pure product 4-[(£)-2-(3,5-dimethoxyρhenyl)-l-ethenyl] phenyl 4-methyl-l- benzenesulfonate as solid. Yield 5.4 g (70%).

Example-15: Preparation of 4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyI]phenyI methane sulfonate

To a solution of pterostilbene (5 g, 0.019 mol, 1 eq) in dichloromethane (50 mL) pyridine (4.7 g, 3 eq, 0.058 mol) was added at rt. Methane sulfonyl chloride (4.5 g, 0.039 mol, 2 eq) was added to the solution at 0° C. The solution was stirred at room temperature for 6 h. the reaction mass was poured in water and washed with IN hydrochloric acid (25 mL) and water. Evaporation of solvent gave crude product, which was triturated with hexane to obtain 4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl methanesulfonate as solid. Yield 3.2 g (50%).

¹ H NMR (CDCl ₃ , 300 Mz): δ 7.54-7.52 (d, 2H, J= 8.7 Hz), 7.28-7.25 (d, 2H, J = 9 Hz), 7.03-7.02 (d, 2H, J =4.3Hz), 6.66-6.65 (d, 2H, J =2.2 Hz), 6.41 (m, IH), 3.82 (s, 6H), 3.15 (S, 3H). LCMS: 335 (M ⁺ ); HPLC: 96.46%

Exaniple-16: Preparation of ethyl 2-4-[(£)-2-(3^-dimethoxyphenyI)-l-ethenyl] phenoxy acetate

To a solution of pterostilbene (10 g, 0.039 mol, 1 eq) in acetone (80 mL), potassium carbonate (16 g, 0.117 mol, 3 eq), ethylbromoacetate (7.1 g, 0.042 mol, 1.1 eq) diluted in acetone (20 mL) were added at rt. The reaction mass was refluxed for 3 h. The reaction mass was filtered and evaporated solvent to yield residue. The residue was diluted with ethyl acetate (100 mL) and washed with water and brine. Removal of organic solvent resulted crude product, which was triturated with isopropyl ether to obtain pure ethyl 2-4- [(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyacetate as solid. Yield 7.5 g (58%).

¹ H NMR (CDCl ₃ , 300 Mz): δ 7.45-7.42 (d, 2H, J = 8.7 Hz), 7.00 (s, IH), 6.93-6.87 (m, 3H), 6.64-6.63 (d, 2H, J = 2.2 Hz), 6.38-6.36 (t, IH, J= 2.2 Hz), 4.63 (s, 2H), 4.28-4.24 (q, 2H), 3.82 (s, 6H), 1.32-1.27 (t, 3H, J= 7.2Hz; LCMS: 343 (M ⁺ ); HPLC: 86.43%

εxample-17: Preparation of 2-4-[(£)-2-(3,5-diinethoxyphenyl)-l-etheny-] phenoxyacetic acid

ethyl 2-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyacetate (4 g, 0.011 mol, 1 eq) was dissolved in 5% NaOH solution (20 mL) and refluxed for 1 h. Product was extracted with ethyl acetate, organic layer was washed with water and brine, removal of solvent afforded crude product, which was triturated with diisopropylether to obtain pure 2-4- [(E)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenoxyacetic acid. Yield 2 g (55%).

¹ H NMR (DMSO, 300 Mz): δ 1.5-1 Al (d, 2H, J = 8.7Hz), 7.15 (s, IH), 7.0-2 (s, IH), 6.89-6.86 (m, 2H, J = 8.7 Hz), 6.71-6.70 (d, 2H, J =2.2 Hz), 6.36-6.34 (t, IH, J = 2.1 Hz),4.62 (s, 2H), 3.74 (s, 6H). LCMS: 315(M ⁺ ); HPLC: 97.10%

Example-18: Preparation of 4-[(£)-2-(3,5-dimethoxyphenyI)-l-ethenyl]phenyl 2- aminoacetate hydrochloride

a) BOC protection of Glycine

To a solution of glycine (10 g, 0.133 mol, 1 eq) in water (70 mL), NaOH (5.3 g, 0.133 mol, 1 eq), in 40 ml water solution was added and cooled to 0° C. BOC anhydride (29 g, 0.133 mol, 0.112 eq) was diluted in acetone (50 mL) and added dropwise to the reaction mass at 0°C. Reaction mass stirred at it for 3 h. Acetone was removed in vacuo to get residue and triturated with hexane to obtain solid product. Yield 22 g (95%).

b) Coupling reaction of 4-[(E)-2-(3, 5-Dimethoxyphenyl)-vinyI] phenol & BOC-Glycine

To a solution of 4-[(E)-2-(3, 5-Dimethoxyphenyl)-vinyl] phenol (10 g, 0.039 mol, 1 eq) in DCM (100 mL), HOBT (5.2 g, 0.039 mol, 1 eq), DCC (8 g, 0.039 mol, 1 eq), DMAP (0.47 g, 0.003 mol, 0.1 eq) were added at 0°C and stirred for 30 min. BOC-Glycine (6.8 g, 0.039 mol, 1 eq) diluted in CH ₂ Cl ₂ (50 mL) was added slowly to the reaction mass at 0° C. Reaction mass was slowly allowed to warm to rt and stirred for 4 h. Acetic acid (2 mL) was added and stirred for 5 min and filtered. The organic layer washed with 5% sodium carbonate (20 mL), IN HCl (20 mL). Organic solvent evaporated to give crude product, which was triturated with hexane to obtain pure desired product as solid. Yield 10 g (42%).

c) Preparation of 4-[(£)-2-(3,5-dimethoxyphenyI)-l-ethenyI]phenyl 2-amino acetate hydrochloride

Compound (4 g, 0.011 mol, 1 eq), obtained from step-b of this example, was added to the pre cooled HCl in ethyl acetate at 0° C. The reaction mass allowed to rt and stirred for 3 h at it. The precipitate filtered and washed with hexane and dried to obtain title product. Yield 2 g (66 %).

¹ H NMR (DMSO, 300 Mz): δ 8.41 (s, 2H), 7.67-7.64 (d, 2H, J = 8.7 Hz), 7.30-7.12 (m, 4H), 6.76-6.75 (d, 2H, J = 2.2 Hz), 6.71-6.70 (d, 2H, J =2.2 Hz), 6.41-6.4 (t, IH, J = 2.1 Hz),4.05 (s, 2H), 3.82 (s, 6H). LCMS: 314 (M ⁺ ); HPLC: 84.06%

Example-19: Preparation of 2-tert-ButoxycarbonyIamino-propionic acid 4-[(E)-2-(3,5- dimethoxy-phenyl)-vinyl]-phenyl ester

a) BOC protection of alanine

To a solution of alanine (10 g, 0.112 mol, 1 eq) in water (70 mL), NaOH (4.8 g, 0.112 mol, 1 eq), in 40 mL water, solution was added and cooled to O ⁰ C. BOC anhydride (24.5 g, 0.112 mol, 1 eq) was diluted in acetone (50 mL) and added drop wise to the reaction mass at 0° C. Reaction mass stirred at it for 3 h. Acetone was removed in vacuo to get residue and triturated with hexane to obtain solid desired product. Yield 20 g (94 %)

b) Coupling reaction of 4-[(E)-2-(3, 5-Dimethoxyphenyl)-vinyl] phenol & BOC-Alanine

To a solution of 4-[(E)-2-(3, 5-Dimethoxyphenyl)-vinyl] phenol (10 g, 0.039 mol, 1 eq) in dichloromethane ( 100 mL), HOBT (5.2 g, 0.039 mol, 1 eq), DCC (8 g, 0.039 mol, 1 eq), DMAP (0.47 g, 0.0039 mol, 0.1 eq) were added at O ⁰ C and stirred for 30 min. BOC- alanine (7.3 g, 0.039 mol, 1 eq) diluted in dichloromethane (50 mL) was added slowly to the reaction mass at 0° C. Reaction mass was slowly allowed to warm to rt and stirred for 4 h. Acetic acid (2 mL) was added and stirred for 5 min and filtered. The organic layer washed with 5% sodium carbonate (20 mL), IN HCl (20 mL). Organic solvent evaporated to give crude product, which was triturated with hexane to obtain pure 2-tert- Butoxycarbonylamino-propionic acid 4-[(E)-2-(3,5-dimethoxy-phenyl)-viny ^' l]-phenyl ester (Ala-(BOC)-OH-Pterostilbene) as solid. Yield 10 g (60%).

Example-20: Preparation of 4-[(jE)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-2-ainino propanoate hydrochloride

Ala-(BOC)-OH-pterostilbene (1O g, 0.023 mol, 1 eq) was dissolved in ethyl acetate and cooled to temperature 0° C. HCl was added to the reaction mixture. The reaction maintained at rt for 3 h. Precipitated compound was filtered and washed with ethyl acetate to get pure product. Yield 6 O g (70%).

¹ H NMR (DMSO, 300 Mz): δ 8.76 (s, 2H), 7.67-7.64 (d, 2H, J =8.7 Hz), 7.25-7.18 (m, 4H), 6.76-6.75 (d, 2H, J =2.2 Hz), 6.71-6.70 (d, 2H, J =2.2 Hz), 6.41-6.39.(t, IH, J =2.1 Hz), 4.35-4.32 (d, IH, J = 7Hz), 3.75 (s, 6H), 1.58-1.55 (d, 3H, J = 7.0 Hz). LCMS-: 328(M>, HPLC: 88.03%

Example-21: Preparation of 4-[(2T)-2-(3,5-dimethoxypheny-)-l-ethenyl] phenyl 2-amino-3- hydroxy propanoate hydrochloride

a) BOC protection of serine

To a solution of serine (10 g, 0.095 mol, 1 eq) in water (70 mL), NaOH (3.8 g, 0.095 mol, leq) in 40 mL water, solution was added and cooled to O ⁰ C. BOC anhydride (20.7 g, 0.095 mol, 1 eq) was diluted in acetone (50 mL) and added dropwise to the reaction mass

at 0° C. Reaction mass stirred at rt for 3 h. Acetone was removed in vacuo to get residue and triturated with hexane to obtain desired product as solid. Yield 17.5 g (90%)

b) THP protection of BOC-Serine To a solution of BOC-serine (1O g, 0.048 mol, 1 eq) in dichloromethane (100 mL) was added DHP (4 g, 0.048 mol, 1 eq) and PPTS (1.2 g, 0.004 mol, 0.1 eq) at room temperature. The solution was stirred for 6 h at rt. The reaction mixture was poured in water, organic layer was separated and treated with 10% NaOH (20 mL), water (twice) and finally with brine, dried over sodium sulfate. Removal of the solvent in vacuo provided colorless oil. Yield H g (75%).

c) Coupling reaction of 4-[(E)-2-(3, 5-Dimethoxyphenyl)-vinyl] phenol & BOC-Ser-(THP)- OH

To a solution of 4-[(E)-2-(3, 5-Dimethoxyphenyl)-vinyl] phenol (10 g, 0.039 mol, 1 eq) in dichloromethane ( 100 mL), HOBT (5.2 g, 0.039 mol, 1 eq), DCC (8 g, 0.039 mol, 1 eq), DMAP (0.47 g, 0.003 mol, 0.1 eq) were added at 0° C and stirred for 30 min. BOC- ser-(THP)-OH (11.8 g, 0.039 mol, 1 eq) diluted in 50 ml of dichloromethane was added slowly to the reaction mass at 0° C. Reaction mass was slowly allowed to warm to rt and stirred for 4 h. Acetic acid (2 mL) was added and stirred for 5 min and filtered. The organic layer washed with 5% sodium carbonate (20 mL), IN HCl (20 mL). Organic solvent was evaporated to give crude product, which was triturated with hexane to obtain pure desired product as solid. Yield 13.0 g (60%).

d) Preparation of 4-[(2j)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl 2-amino-3-hydroxy propanoate hydrochloride

Ser-BOC-OH-THP-pterostilbene (compound obtained from step-c) (10 g, 0.017 mol, 1 eq) was dissolved in ethyl acetate and cooled to 0° C. The HCl in isopropyl alcohol was added dropwise to the reaction mass and maintained at rt for 3 h. Precipitated compound was filtered and washed with ethyl acetate to get pure title compound. Yield: 4.2 g, 60 %.

¹ H NMR (DMSO, 300 Mz): δ 8.77 (s, 2H), 7.67-7.64 (d, 2H, J = 8.7 Hz), 7.31-7.13 (m, 4H), 6.76-6.75 (d, 2H, J = 2.2 Hz), 6.41-6.39 (t, IH/ = 2.1 Hz), 5.83 (s, OH), 4.39 (t, IH), 4.07-4.02 (m, 2H), 3.75 (s, 6H). LCMS: 344 (M ⁺ ); HPLC: 90.61%

ExampIe-22: Preparation of l,3-dimethoxy-5-[(/ϊ)-2-(4-nitrophenyl)-l-ethenyl]benzene

To an ice cold suspension of sodium hydride (4.7 g, 0.198 mol, 3 eq) in tetrahydrofuran

(30 mL) cooled in an ice bath, 3, 5-dimethoxybenzylphosphonate ester (19 g, 0.066 mol, 1 eq) diluted in THF (30 mL) was added slowly using addition flask. The solution was

slowly allowed to warm to room temperature and stirred for 30 min. After cooling the solution to 0° C, 4-nitro benzaldehyde (10 g, 0.066 mol, 1 eq) in THF (20 mL) was added and stirred at ice cold temperature for 30 min. and at room temperature for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted - with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethyl acetate (2 x 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure l,3-dimethoxy-5-[(£)-2-(4-nitropheny])-l-ethenyl]benzene. Yield 13.7 g (70%).

1H NMR (CDCl ₃ , 300 Mz): δ 8.23-8.20 (d, 2H, J= 8.8 Hz), 7.84-7.81 (d, 2H, J = 8.8 Hz), 7.43 (s, IH), 6.84-6.83 (d, 2H, J= 2.2 Hz), 6.46-6.45 (t, IH, J= 2.1 Hz) 3.76 (s, 6H). LCMS: 286 (M ⁺ ); HPLC: 97.99% ExampIe-23: Preparation of 5-[(£)-2-(4-aminophenyl)-l-ethenyl]-l, 3-benzenedioI a) Preparation of 4-[(E)-2-(3,5-Dimethoxy-phenyl)-vinyI]-phenyl amine l,3-Dimethoxy-5-[(E)-2-(4-nitrophenyl)-vinyl] benzene (10 g, 0.035 mol, 1 eq) was dissolved in acetic acid (50 mL) and cooled to O ⁰ C. Zinc dust (10.2 g, 0.140 mol, 4 eq) was added slowly at 0° C and allowed to warm to rt for 30 min in stirring. The reaction mass was refluxed for 1 h. Acetic acid was distilled in vacuo and residue was diluted with water. Compound extracted with ethyl acetate, washed with water and brine. Removal of solvent gave residue which was purified by silica-gel column chromatography (ethyacetate/hexane-1 :3 as eluent) to obtain pure title product. Yield 2.7 g (30%).

η NMR (CDCl ₃ , 300 Mz): δ 7.33-7.30 (d, 2H, J = 8.4 Hz), 7.25 (s, IH), 6.86 (s, lH),6.68-6.62(m, 4H), 6.35-6.34 (t, IH, J = 2.2Hz ), 7.84-7.81 (d, 2H, J = 8.8 Hz), 7.43 (s, IH), 6.84-6.83 (d, 2H, J= 2.2 Hz), 6.46-6.45 (t, IH, J= 2.1 Hz) 3.81(s, 6H). LCMS: 256 (M ⁺ ); HPLC: 98.63%

b) Preparation of 5-[(£)-2-(4-aminophenyl)-l-ethenyl]-l,3-benzenediol The solution of 4-[(E)-2-(3,5-Dimethoxy-phenyl)-vinyl]-phenyl amine (5 g, 0.019 mol, 1 eq) in dichloromethane (40 mL) was cooled to 0° C. BBr ₃ (14.7 g, 0.058 mol, 3 eq) was diluted in dichloromethane (10 mL) and added slowly to reaction mass at 0° C. The solution was slowly allowed to warm to rt and continued stirring for overnight at rt. The reaction mass was poured in ice-cold water, compound extracted with ethyl acetate and organic layer washed with water and brine. Removal of solvent in vacuo afforded crude product, and purified by silica-gel column chromatography (ethyl acetate/hexane-2:8 as eluent) to obtain pure title compound. Yield 1.76 g (40%).

η NMR (DMSO, 300 Mz): «$ 9.10 (s, 2-OH), 7.22-7.19 (d, 2H, J= 8.4 Hz), 6.74-6.78 (d, IH, J= 16 Hz), 6.68-6.62 (d, 4H, J= 16 Hz), 6.52-6.49 (d, 2H, J = 8.4 Hz), 6.31-6.3 (d, 2H, J= 2.2 Hz), 6.06-6.04 (t, IH, J = 1.9 Hz), 5.24 (s, 2H). LCMS: 228 (M ⁺ ); HPLC: 96.58%

Example-24: Preparation of _V-benzyl-iV-4-[(2i)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyl amine

To a solution of 4-[(E)-2-(3,5-Dimethoxy-phenyl)-vinyl]-phenyl amine (5g, 0.0196mol, leq) in dichloromethane (50 mL), Triethyl amine (3.1 g, 0.0392 mol, 2 eq) was added at rt and cooled to O ⁰ C ₅ . Benzoyl chloride (3 g, 0.0215 mol, 1.1 eq) was added to the solution at O ⁰ C. The reaction mass was stirred at rt for 2hours. Reaction mass was poured in water. The organic layer washed with IN hydrochloric acid (25 mL), water and solvent evaporated to give crude product, which was triturated with isopropyl ether to obtain pure title compound. Yield 3.5 g (50%).

Example-25: Preparation of M-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl acetamide

To a solution of 4-[(E)-2-(3,5-Dimethoxy-phenyl)-vinyl]-phenyl amine (5 g, 0.019 mol, 1 eq) in dichloromethane (50 mL), triethylamine ((3.1 g, 0.039 mol, 2 eq) was added at rt and reaction mass cooled to 0° C with stirring. After 30 min, acetyl chloride (1.7 g, 0.021 mol, 1.1 eq,) was slowly added to reaction mass at 0° C and stirred at rt for 2 h. Reaction mass was poured into water and organic layer washed with IN hydrochloric acid and water. The organic layer evaporated in vacuo to give crude product, which was triturated with isopropyl ether to obtain Nl-4-[(E)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyl acetamide as solid. Yield 5.3 g (95%).

Example-26: Preparation of benzyl iV-4-[(2j)-2-(3,5-dimethoxyphenyI)-l-ethenyI] phenylcarbamate

To a solution of 4-[(E)-2-(3,5-Dimethoxy-phenyl)-vinyl]-phenyl amine (5 g, 0.019 mol, 1 eq) in acetone (50 mL). 10% sodium bicarbonate solution (3.3 g, 0.039 mol, 2 eq) was added at rt and cooled to 0° C with stirring. Benzyl chloroformate (1.7 g, 0.021 mol, 1.1 eq,) was added to the solution at 0° C. Reaction mass was allowed to warm to rt and stirred at rt for 2 h. Acetone was distilled in vacuo to get residue. Residue diluted with water and washed with IN hydrochloric acid (25 mL), and water, the organic layer was separated, and removed to afford crude product, which on trituration with isopropyl alcohol gave pure title compound. Yield 2.9 g (50%).

¹ H NMR (DMSO, 300 Mz): δ 9.84 (s, H), 7.5-7.3 (m, 9H), 7.20-6.99 (m, 2H), 6.72-6.71 (d, 2H, J = 2 Hz), 6.36 (m, IH), 5.13 (s, 2H), 3.74 (s, 6H).

LCMS: 390 (M ⁺ ); HPLC: 92.35%

Example-27: Preparation of tert-butyl λ^-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyI carbamate

To a solution of 4-[(E)-2-(3,5-Dimethoxy-phenyl)-vinyl]-phenyl amine (5 g, 0.019 mol, 1 eq) in acetone (50 mL), 10% sodium bicarbonate solution (1.62 g, 0.019 mol, 1 eq) was added at rt, stirred for 10 min, BOC anhydride (4.7 g, 0.021 mol, 1.1 eq) diluted in acetone was slowly added to reaction mass at rt and stirred for overnight. Acetone was removed in vacuo to get residue, which on trituration with isopropyl ether gave pure title product. Yield 6.5 g (93%).

¹ H NMR (CDCl ₃ , 300 Mz): δ 7.44-7.41 (d, 2H J= 8.7 Hz), 7.35-7.33 (d, 2H J = 8.7Hz), 7.1 -6.9 (m, 2η), 6.65-6.64 (d, 2H, J = 2 Hz), 6.51 (s, lH),6.38-6.36(t, IH, J = 2.0 Hz), 3.82 (s, 6H), 1.60 (s, 9H). LCMS: 356 (M ⁺ ); HPLC: 98.37%

Example-28: Preparation of N-4-[(E)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyWV- methylamine hydrochloride a) Methylation of tert-butyl iV-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl] phenyl carbamate

To a cooled suspension of sodium hydride (1.4 g, 0.058 mol, 3 eq) in THF (20 mL) at 0° C, BOC protected 4-(3, 5-dimethoxystyryl)benzenamine diluted in THF (30 mL) was added to reaction mass at 0° C and stirred for 30 min. Methyl iodide was added slowly and reaction was allowed to warm to it and stirred for 1 h. Reaction mass was poured in ice-cold water, compound extracted with ethyl acetate. Organic layer washed with water and brine, on removal of organic solvent obtained pure desired product. Yield 4.6 g (90%).

b) Preparation of λ ^r -4-[( _J E)-2-(3,5-dimethoxyphenyl)-l-ethenyI]phenyl-λ' ^' -methylamine hydrochloride

Compound (4 g, 0.01126 mol, 1 eq), obtained from step-a of this example, was added to the pre cooled hydrochloride in ethyl acetate at 0° C. The reaction mass allowed to warm to rt and stirred for 3 h at rt. The precipitate filtered and washed with hexane to obtain title product. Yield 2 g (66%).

¹ H NMR (CDCl ₃ , 300 Mz): δ 7.57-7.54 (d, 2H, J= 8.5 Hz), 7.24-7.03(m, 4H), 6.73-6.72 (t, IH, J = 2.1 Hz), 6.37-6.36 (t, IH, J= 2.1 Hz), 3.74 (s, 6H), 2.8 (s, 3H). LCMS: 270 (M ⁺ ); HPLC: 96.85%

ExampIe-29: Preparation of 5-(£)-2-[4-(dimethylamiπo) phenyl]-l-ethenyl-l, 3-benzenediol

The solution of 4-(3, 5-bis (benzyloxy)styryl)-N,iV-dimethylbenzenamine (5 g, 0.009 mol, 1 eq) in HBr/acetic acid (30 mL) was refluxed for 4 h and aollowed to warm to it for overnight under stirring. The crude product was filtered and washed with water to obtain pure product as solid. Yield 1.1 g (50%).

η νMR (DMSO, 300 Mz): δ 9.13 (s, 2-OH), 7.37-7.35 (d, 2H, J= 8.8 Hz), 6.85-6.75 (m, 4H), 6.34-6.33 (d, 2H, J= 2 Hz), 6.05 (m, 1 H), 2.89 (s, 6H). LCMS: 256 (M ⁺ ); HPLC: 98.41%

Example-30: Preparation of N, iV-dibenzyl-iV-4-[(2s)-2-(3,5-diinethoxypheny-)-l-ethenyl] phenyl amine

To the solution of 4-[(E)-2-(3, 5-Dimethoxy-phenyl) vinyl] phenylamine (5 g, 0.019 mol, 1 eq) in acetone (50 mL). K ₂ CO ₃ (8.11 g, 0.058 mol, 3 eq) was added and stirred for 30 min. Benzyl bromide (3.7 g, 0.021 mol, 1.1 eq) was added at it and refluxed for 4 h. Reaction mass was filtered and solvent evaporated to get residue. The residue was purified by silica-gel column chromatography (ethyl acetate/hexane 1:9 as eluent) to obtain pure product. Yield 2 g (20%).

¹ H νMR (CDCl ₃ , 300 Mz): δ 9.98 (s, H), 7.37-7.24 (m, 12H), 7.02 -6.96 (d, IH, J = 16 Hz), 6.83-6.78 (d, IH, J = 16 Hz), 6.74-6.71 (d, 2H, J = 8.8 Hz), 6.63-6.62 (d, 2H, J = 2.1 Hz), 4.68 (s, 4H), 3.81 (s, 6H). LCMS: 437 (M ⁺ ); HPLC: 96.17%

Example-31: Preparation of N-4-[(E)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyl methane sulfonamide

To a solution of 4-[(E)-2-(3, 5-Dimethoxy-phenyl) vinyl] phenyl amine (5 g, 0.019 mol, 1 eq) in dichloromethane (50 mL), pyridine (1.85 g, 0.023 mol, 1.2 eq) was added at it and stirred for 30 min. Methane sulfonyl chloride (2.2 g, 0.019 mol, 1 eq) was added to the solution at 0° C and stirred at it for 6 h. Reaction mass was poured in water, organic layer washed with IN hydrochloric acid (25 mL) and water. Removal of solvent gave crude product, which was triturated with isopropyl alcohol to obtain pure product as solid. Yield 6.2 g (95%).

¹ H νMR (CDCl ₃ , 300 Mz): δ 1.5-1 Al (d, 2H, J=6.7 Hz), 7.25-7.2 (d, IH, J= 17 Hz), 7.01- 6.99 (d, IH, J = 5.4 Hz), 6.67-6.65 (m, 3H), 6.4-6.390 (t, IH, J= 2.2 Hz), 3.82 (s, 6H), 3.02 (s, 3H). HPLC: 95.98%

Example-32: Preparation of M-4-[(2?)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyl-1- benzene sulfonamide

To a solution of 4-[(E)-2-(3, 5-Dimethoxy-phenyl) vinyl] phenyl amine (5 g, 0.019 mol, 1 eq) in dichloromethane (50 mL), pyridine (1.85 g, 0.023 mol, 1.2 eq) was added at rt and stirred for 30 min. Benzene sulfonyl chloride (3.4 g, 0.019 mol, 1 eq) was slowly added to reaction mass at 0° C and was allowed to warm to rt for 6 h under stirring. Reaction mass was poured in water, separated dichloromethane layer was treated with IN hydrochloric acid (25 mL). Organic layer was washed with water and neutralized with 10% sodium bicarbonate solution and washed with water. Removal of solvent gave crude product, which was triturated with hexane to obtain pure product as solid. Yield: 6.2 g

(80%).

¹ H NMR (CDCl ₃ , 300 Mz): δ 7 '.79-7.76 (d, 2H, J = 7 Hz), 7.53-7.51 (m, IH), 7.46-7.38 (m, 4H), 7.06-7.03 (d, 2H, J = 8.3 Hz), 6.95-6.94 (d, 2H, J = 3.4 Hz), 6.62-6.61 (d, 2H, J = 10.3 Hz), 6.39-6.37 (t, IH ₅ J = 3.2 Hz), 3.81 (s, 6H). LCMS: 396 (M ⁺ ); HPLC: 98.97%

Example-33: Preparation of l-[(£)-2-(3-bromophenyI)-l-ethenyl]-3,5-dimethoxybenzene

To an ice cold suspension of sodium hydride (3.9 g, 0.162 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath. 3, 5-dimethoxybenzylphosphonate ester (15.5 g, 0.054 mol, 1 eq) diluted in tetrahydrofuran (30 mL) was added slowly using addition flask. The solution was slowly allowed to warm to rt and stirred for 30 min. After cooling the solution to 0° C, 3-bromobenzaldehyde (10 g, 0.054 mol, 1 eq) in tetrahydrofuran (20 mL) was added and stirred at ice cold temperature for 30 min. and at rt for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethylacetate (2 x 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure l-[(E)-2-(3-bromophenyl)-l-ethenyl]-3,5-dimethoxybenzene. Yield 12.0 g (70%).

η NMR (CDCl ₃ , 300 Mz): δ 7.66-7.65 (t, 2H, J = 1.6 Hz), 7.39-7.36 (t, 2H, J = 8.7 Hz), 7.25-7.21 (m, 2H), 7.01-7.00 (d, 2H, J = 3 Hz), 6.66-6.65 (d, 2H, J = 2.2 Hz), 6.42-6.41 (t, IH ₅ J = 2.2 Hz) ₅ 3.82 (s, 6H). LCMS: 319 (M ⁺ ); HPLC: 98.98%

Example-34: Preparation of 2-chloro-l-[(£)-2-(3, 5-dimethoxyphenyI)-l-ethenyl]-4-fluoro benzene

To an ice cold suspension of sodium hydride (3.9 g, 0.162 mol, 3 eq) in tetrahydrofuran (30 mL) cooled in an ice bath. 3, 5-dimethoxybenzylphosphonate ester (18.3 g, 0.063mol,

1 eq) diluted in tetrahydrofuran (30 mL) was added slowly using addition flask. The

solution was slowly allowed to warm to rt and stirred for 30 min. After cooling the solution to 0° C, 2-chloro 4-Fluoro benzaldehyde (10 g, 0.063 mol, 1 eq) in tetrahydrofuran (20 mL) was added and stirred at ice cold temperature for 30 min. and at rt for 2 h. Methanol (3 mL) was added to quench the excess sodium hydride, the reaction mass was diluted with ice cold water (20 mL) and separated THF layer, aqueous layer extracted with ethyl acetate (2 x 25 mL). Combined organic layers were dried over sodium sulfate and evaporated in vacuo to obtain residue, which was triturated with methanol (20 mL) to get pure 2-chloro- l-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]-4- fluoro benzene. Yield 9.3 g (50%).

¹ H NMR (CDCl ₃ , 300 Mz): δ 7.65-7.60 (m, IH), 7.41-7.35 (d, 2H, J = 16 Hz), 7.15-7.11 (m, IH), 6.99-6.95 (m, 2H), 6.68-6.67 (d, 2H, J = 2.2 Hz), 6.42-6.41 (t, IH, J = 2.1 Hz), 3.83 (s, 6H). LCMS: 293 (M ⁺ ); HPLC: 99.14%

Example-35: Preparation of 4-4-[(£)-2-(3, 5-dimethoxyphenyl)-l-ethenyl] phenyl morpholine hydro chloride

a) Preparation of 4-4-[(2ϊ)-2-(3,5-dimethoxy phenyl)-l-ethenyl]phenyl morpholine

An oven-dried RB flask was charged with Pd ₂ (dba) ₃ (0.58 g, 0.00062 mol, 0.02 eq), xanthphos (0.09 g, 0.00015 mol, 0.005 eq), l-[(£)-2-(4-bromophenyl)-l-ethenyl]-3,5- dimethoxybenzene (10 g, 0.031 mol, leq), cesium carbonate (20 g, 0.062 mol, 2 eq), morpholine (2.7 g, 0.031 mol, 1 eq), toluene (100 mL) was degassed for about 30 min. The mixture refluxed for 8 h, during which time the solution turned from purple to deep brown. The reaction was monitored by removing small aliquots, which were analyzed by TLC. The reaction mass was filtered through a short pad of silica and toluene removed in vacuo, the residue was purified by column chromatography (ethyl acetate-hexane, 1:3, v/v) to give 4-(4-3, 5-dimethoxy styryl phenyl) morpholine as a pale yellow-colored solid. Yield 4. I g (40%).

¹ H NMR (CDCl ₃ , 300 Mz): δ 7.44-7.41 (d, 2H, J = 8.7 Hz), 6.99-6.86 (m, 4H), 6.64-6.63 (d, 2H, J = 2.2 Hz), 6.36-6.35 (t, IH, J = 2.2 Hz), 3.8 (m, 10H), 3.17-3.2 (t, 4H, J = 4.5 Hz).LCMS: 326 (M ⁺ ); HPLC: 99.46% b) Preparation of 4-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl morpholine hydrochloride

To a mixture of HCl-EtOAc (9% solution) (2 mL) cooled in an ice bath, 4-4-[(E)-2-(3, 5- dimethoxyphenyl)-l-ethenyl] phenyl morpholine (1 g, 0.003 mol, leq) was dissolved in ethyl acetate (5 mL) and added slowly at 0° C, the reaction mass was slowly allowed to warm to room temperature and stirring continued for 4 h at room temperature. The

precipitated product was filtered and washed with cold ethyl acetate to obtain pure product. Yield: 0.8 g, (70%).

Example-36: Preparation of l-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-4-methyl piperazine dihydrochloride

a) Preparation of l-4-[(jE)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-4-methyl piperazine

An oven-dried RB flask was charged with Pd ₂ (dba) ₃ (0.58 g, 0.00062 mol, 0.02 eq), xanthphos (0.09 g, 0.00015 mol, 0.005 eq), l-[(£)-2-(4-bromophenyl)-l-ethenyl]-3,5- ^" dimethoxybenzene (10 g, 0.031 mol, 1 eq), cesium carbonate (20 g, 0.062 mol, 2 eq), N- methylpiperizene (3.13 g, 0.031 mol, 1 eq), toluene (100 mL) was degassed for about 30 min. The mixture refluxed for 1O h, during which time the solution turned from purple to deep brown. The reaction was monitored by removing small aliquots, which were analyzed by TLC. The reaction mass was filtered through a short pad of silica and toluene removed in vacuo, the residue was purified by column chromatography (ethylacetate- hexane, 1:3, v/v) to give l-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-4-methyl piperazine as a greenish yellow-colored solid. Yield 4.0 g (40%).

η NMR (CDCl ₃ , 300 Mz): δ 7.42-7.39 (d, 2H, J = 8.6 Hz), 6.98-6.88 (m, 4H), 6.64-6.63 (d, 2H, J = 2 Hz), 6.35 (m, IH), 3.82 (m, 6H), 3.26-3.23 (t, 4H, J = 4.8 Hz), 2.59-2.55 (t, 4H, J = 4.8 Hz), 2.35 (s, 3H). LCMS: 339 (M ⁺ ); HPLC: 95.49%

b) Preparation of l-4-[(£)-2-(3,5-dimethoxyphenyl)-l-ethenyl]phenyl-4-methyI piperazine dihydrochloride

To a mixture of HCl-EtOAc (9% solution) (2 mL) cooled in an ice bath, l-4-[(E)-2-(3,5- dimethoxyphenyl)-l-ethenyl]phenyl-4-methyl piperazine (1 g, 0.002- mol, 1 eq) was dissolved in ethyl acetate (5 mL) and added slowly at 0° C, solution was slowly allowed to warm to room temperature and stirring continued for 4 h at room temperature. The precipitated product was filtered and washed with cold ethyl acetate to obtain pure product. Yield 1 g (80%).

Example-37: Preparation of 5-[(E)-2-(4-Bromophenyl) vinyl] benzene-1, 3-dioI

To the solution of l-[(E)-2-(4-bromophenyl)-l-ethenyl]-3, 5-dimethoxybenzene (5 g, 0.015 mol, 1 eq) in dichloromethane (80 mL) was cooled to O ⁰ C. BBr ₃ (11.7 g, 0.047 mol, 3 eq) was diluted in dichloromethane (20 mL) and added slowly to reaction mass at 0° C. Reaction mass slowly allowed to warm to room temperature and stirred overnight at room temperature. Reaction mass poured in ice-cold water and extracted compound with ethyl acetate. Removal of solvent in vacuo gave crude product, which was triturated with CH ₂ Cl ₂ to obtain pure product as solid. Yield 6.0 g (70%).

¹ H NMR (DMSO, 300 Mz): δ 9.25 (s, 2-OH), 7.51(s, 4H), 7.04-7.01 (dd, 2H, J = 11.3 Hz), 6.42-6.41 (d, 2H, J= 2 Hz), 6.15-6.14 (d, 2H ₅ J= 1.8 Hz). LCMS: 290 (M ⁺ ); HPLC: 99.17%

Example-38:

The following list of compounds can be prepared according to the process described in the examples 36 and 37 by using 5-[(E)-2-(4-Bromophenyl) vinyl] benzene-1, 3-diol (compound of example-38).

The said compounds are 5-[(£)-2-(4-morpholinophenyl)-l-ethenyl]-l, 3-benzenediol; 5- [(E)-2-(4-morpholinophenyl)-l-ethenyl]-l, 3-benzenediol hydrochloride; 5-{(ε)-2-[4-(4- Methyl-piperzin-l-yl)-phenyl]-vinyl}-benzene-l,3-diol;5-{(E) -2-[4-(4-Methyl-piperzin-l -yl) -phenyl] -vinyl} -benzene-1, 3-diol dihydrochloride;