DESC:benzyl phosphonate to obtain
1, 3-dimethoxy-5-[(E)-2-phenylethenyl]-2-(propan-2-yl) benzene, a compound of
formula II
10
II; diethyl benzyl phosphonate; and
e) demethylation of compound of formula II to obtain benvitimod, the compound
of formula I.
BRIEF DESCRIPTION OF THE DRAWINGS
15 Figure 1. XRPD pattern of benvitimod as obtained in Ex 7.
Figure 2. XRPD pattern of benvitimod as obtained in Ex 8.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of benvitimod, a
compound of formula I, comprising:
20
I
4
a) converting methyl 3, 5-dimethoxybenzoate, a compound of formula VI to
methyl 3, 5-dimethoxy-4-(propan-2-y l) benzoate, a compound of formula V
VI V;
b) reducing the compound of formula V to 3, 5-dimethoxy-5 4-(propan-2-yl) phenyl]
methanol, a compound of formula IV
IV;
c) oxidation of compound of formula IV to obtain 3, 5-dimethoxy-4-(propan-2-yl)
10 benzaldehyde, a compound of formula III
III;
d) coupling the compound of formula III with diethyl benzyl phosphonate to obtain
1, 3-dimethoxy-5-[(E)-2-phenylethenyl]-2-(propan-2-yl) benzene, a compound of
15 formula II
II; and
e) demethylation of compound of formula II to obtain benvitimod, the compound
of formula I.
20 In one embodiment, in step a) the conversion of compound of formula VI to
compound of formula V is carried out in presence of isopropyl alcohol.
5
In one embodiment, in step a) the reaction may be carried out in presence of a mineral acid. The mineral acid may be selected from the group consisting of sulfuric acid, hydrochloric acid, acetic acid and polyphosphoric acid.
In one embodiment, the mineral acid is sulfuric acid.
In one embodiment, the reaction may be carried out at a temperature ranging from 5 about 0?C to about reflux temperature of the solvent.
In one embodiment, the in step b) the reduction is carried out using reducing agent.
In one embodiment, the reduction of compound of formula IV was carried out using reducing agent selected from the group consisting of hydrides such as sodium hydride, sodium borohydride, lithium borohydride, sodium bis (2-10 methoxyethoxy)aluminium hydride (vitride) and the like.
In one embodiment, the reduction of compound of formula V is carried out in using vitride.
In one embodiment, the reaction may be carried out in presence of a solvent.
In one embodiment, the solvent includes but is not limited to hydrocarbons such as 15 toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl 20 acetate, n-propyl acetate, tert-butyl acetate and the like; nitriles such as acetonitrile, benzonitrile and the like; amides such as dimethylformamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof.
In one embodiment, the compound of formula IV may be recrystallized in a solvent or mixture of solvents. 25
In one embodiment, the compound of formula IV may be purified by acid-base purification method.
In one embodiment, the compound of formula IV may be purified in a solvent.
In one embodiment, the compound of formula may be purified by solvent-anti solvent method. 30
6
In one embodiment, in step c) the compound of formula IV is oxidised to the compound of formula III using oxidising agents selected from the group consisting of chromium based oxidising agents such as pyridinium chlorochromate, pyridine-trioxochromium, sulfonium species such as dimethylsulfoxide-oxalyl chloride, dimethylsulfoxide-carbodiimide; sulfur trioxide pyridine complex, sodium 5 tungstate, hydrogen peroxide, sodium hypochlorite, potassium hypochlorite and the like.
In one embodiment, the reaction may be carried out in presence of a base.
In one embodiment, base may be organic base or inorganic base.
In one embodiment, the organic base is selected from the group consisting of 10 methylamine, dimethylamine, dipropylamine, tripropylamine, tributylamine, N,N-dimethylcyclohexylamine trimethylamine, ethylamine, propylamine, butylamine, dibutylamine, triethylamine, diisopropylethylamine, cyclopropyl amine, aniline, N,N-dimethyl aniline, N-methylpiperidine, N-methyl morpholine, N-tert-butyl benzyl amine, N-benzylmethylamine and piperidine. 15
In one embodiment, the inorganic base selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide and the like; carbonates such as sodium carbonate, potassium carbonate and the like; and bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like.
In one embodiment, the reaction may be carried at temperature ranging from about 20 -100?C to about reflux temperature of the solvent.
In one embodiment, the reaction may be carried out in presence of a solvent.
In one embodiment, the solvent includes but is not limited to hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, 25 dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; nitriles such as acetonitrile, benzonitrile and the like; amides such as dimethylformamide, dimethyl acetamide 30 and the like; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof.
7
In one embodiment, the compound of formula III may be recrystallized in a solvent or mixture of solvents.
In one embodiment, the compound of formula III may be recrystallized using solvent-anti solvent method.
In one embodiment, the compound of formula III may be purified in a solvent. 5
In one embodiment, in step d) the compound of formula III is coupled with diethyl benzyl phosphonate to obtain 1,3-dimethoxy-5-[(E)-2-phenylethenyl]-2-(propan-2-yl)benzene, the compound of formula II wherein the reaction is carried out in presence of a base. The base may be selected from the group consisting of potassium 10 hexamethyldisilazide (KHMDS), sodium hexamethyldisilazide (NaHMDS), sodium amide, potassium tertiary butoxide, n-Butyllithium (n-BuLi) and Lithium diisopropylamide (LDA). In one embodiment, the coupling may be carried out in presence of a solvent. The solvent may be as discussed supra. 15
In one embodiment, in step d) the compound of formula III is coupled with diethyl benzyl phosphonate to obtain 1,3-dimethoxy-5-[(E)-2-phenylethenyl]-2-(propan-2-yl)benzene, the compound of formula II using butyl lithium.
In one embodiment, in step e) demethylation of compound of formula II may be carried out using a dealkylating agent. 20
In one embodiment, the dealkylating agent is selected from the group consisting of pyridinium hydrobromide, boron tribromide, aluminium trichloride, sodium sulphide and the like. In one embodiment, the reaction may be carried out at a temperature of about -90?C to about 200?C. 25
In one embodiment, the reaction may be carried out in presence of a catalyst.
In one embodiment, the catalyst may be selected from the group consisting of tetrabutyl ammonium bromide, tetra butyl ammonium iodide, Tetrabutyl ammonium chloride, Tetrabutyl ammonium fluoride and the like.
In one embodiment, the reaction may be carried out in presence of a solvent. 30
8
In one embodiment, the solvent includes but is not limited to hydrocarbons such as
toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers
such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether,
dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the
5 like; halogenated hydrocarbons such as dichloromethane, dichloroethane,
chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl
acetate, n-propyl acetate, tert-butyl acetate and the like; nitriles such as acetonitrile,
benzonitrile and the like; amides such as dimethylformamide, dimethyl acetamide
and the like; sulfoxides such as dimethyl sulfoxide; water, sulfolane or mixtures
10 thereof.
In one embodiment, the present invention provides a process for the preparation of
benvitimod comprising:
I;
15 a) converting methyl 3, 5-dimethoxybenzoate, a compound of formula VI to
methyl 3, 5-dimethoxy-4-(propan-2-y l) benzoate, a compound of formula V in
presence of isopropyl alcohol and sulfuric acid
VI; V;
20 b) reducing the compound of formula V to 3, 5-dimethoxy-4-(propan-2-yl) phenyl]
methanol, a compound of formula IV, wherein the reduction is carried out in using
of sodium bis (2-methoxyethoxy)aluminium hydride (vitride)
9
IV;
c) oxidation of compound of formula IV to obtain 3, 5-dimethoxy-4-(propan-2-yl)
benzaldehyde, a compound of formula III, wherein the oxidation is carried out using
dimethyl sulfoxide and oxalyl chloride
5
III;
d) coupling the compound of formula III with diethyl benzyl phosphonate to obtain
1, 3-dimethoxy-5-[I-2-phenylethenyl]-2-(propan-2-yl) benzene, a compound of
formula II in presence of NaHMDS
10
II; and
e) demethylation of compound of formula II to obtain benvitimod, the compound
of formula I.
In one embodiment, the present invention provides a process for the preparation of
15 benvitimod, a compound of formula I, comprising:
a) converting methyl 3, 5-dimethoxybenzoate, a compound of formula VI to
3, 5-dimethoxy-4-(propan-2-y l) benzoic acid, a compound of formula VII;
b) reducing the compound of formula VII to 3, 5-dimethoxy-4-(propan-2-yl)
phenyl] methanol, a compound of formula IV;
20 c) oxidation of compound of formula IV to obtain 3, 5-dimethoxy-4-(propan-2-yl)
benzaldehyde, a compound of formula III;
d) coupling the compound of formula III with diethyl benzyl phosphonate to obtain
1, 3-dimethoxy-5-[(E)-2-phenylethenyl]-2-(propan-2-yl) benzene, a compound of
formula II; and
25 e) demethylation of compound of formula II to obtain benvitimod, the compound
of formula I.
10
In one embodiment, benvitimod, the compound of formula I may be recrystallized in a suitable solvent.
In one embodiment, the solvent includes but is not limited to hydrocarbons such as toluene, xylene, chlorobenzene, heptane, n-hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, 5 dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; nitriles such as acetonitrile, benzonitrile and the like; amides such as dimethylformamide, dimethyl acetamide 10 and the like; sulfoxides such as dimethyl sulfoxide; water or mixtures thereof.
In one embodiment, the present invention provides amorphous benvitimod.
In one embodiment, the present invention provides a process for the preparation of crystalline benvitimod comprising:
a) dissolving benvitimod in a solvent or mixture of solvents; 15
b) optionally, cooling the solution in step a)
c) isolating the crystalline benvitimod.
In one embodiment, the solvent is as discussed supra.
In one embodiment, the present invention provides a process for the preparation of crystalline benvitimod comprising: 20
a) suspending benvitimod in a solvent or mixture of solvent to obtain a slurry;
b) stirring the slurry in step a); and
c) isolating crystalline benvitimod.
In one embodiment, the present invention provides process for the preparation of crystalline benvitimod comprising: 25
a) dissolving benvitimod in a solvent or mixture of solvents;
b) optionally, removing the solution in step a);
c) adding a second solvent to the above step a) or b); and
d) isolating the crystalline benvitimod.
In one embodiment, the present invention provides a process for the preparation of 30 benvitimod comprising:
11
a) dissolving benvitimod in a hydrocarbon solvent;
b) stirring the solution in step a);
c) cooling the solution in step b) and
d) isolating the crystalline benvitimod.
In one embodiment, the isolation is carried by filtration or centrifugation. 5
In one embodiment, the present invention provides crystalline benvitimod isolated from a solvent selected from the group of esters, ethers, ketones, nitriles, amides, hydrocarbons, chlorinated solvents, alcohols, water or mixture thereof.
In one embodiment, the present invention provides crystalline benvitimod isolated from a hydrocarbon solvent. 10
In one embodiment, the present invention provides crystalline benvitimod characterized by X-ray Diffraction (XRD) spectrum in accordance with Figure 1.
In one embodiment, the present invention provides crystalline benvitimod characterized by X-ray Diffraction (XRD) spectrum in accordance with Figure 1 wherein the process comprises isolating the crystalline benvitimod from n-hexane. 15
In one embodiment, the present invention provides stable crystalline benvitimod characterized by X-ray Diffraction (XRD) spectrum in accordance with Figure 1 which has no detectable quantity of any other polymorphic form on storage.
In one embodiment, the present invention provides crystalline benvitimod characterized by X-ray Diffraction (XRD) spectrum in accordance with Figure 2. 20
In one embodiment, the present invention provides crystalline benvitimod characterized by X-ray Diffraction (XRD) spectrum in accordance with Figure 2 wherein the process comprises isolating the crystalline benvitimod from toluene.
In one embodiment, the present invention provides stable crystalline benvitimod characterized by X-ray Diffraction (XRD) spectrum in accordance with Figure 2 25 which has no detectable quantity of any other polymorphic form on storage.
As used herein, the term “stable” refers to crystalline benvitimod in accordance with Figure 1 or Figure 2 which retains its original polymorphic form without undergoing polymorphic conversion over time.
In one embodiment, the present invention provides benvitimod wherein the content 30 of undesired Z isomer of benvitimod is less than 0.5%, as measured by HPLC.
12
In one embodiment, the present invention provides benvitimod wherein the content of undesired Z isomer of benvitimod is less than 0.01%, as measured by HPLC.
In one embodiment, the present invention provides benvitimod free of Z isomer of benvitimod, as measured by HPLC.
In one embodiment, the present invention provides benvitimod having a purity of 5 at least 90% purity, as measured by HPLC.
In one embodiment, the present invention provides benvitimod having a purity of at least 95% purity, as measured by HPLC.
In one embodiment, the present invention provides benvitimod having a purity of 100%, as measured by HPLC. 10
In one embodiment, the present invention provides preparation of an amorphous solid dispersion of benvitimod or salt thereof together with at least one pharmaceutically acceptable carrier, the process comprising:
(a) providing a solution or mixture of benvitimod or salt thereof together with at least one pharmaceutically acceptable carrier in a solvent; and 15
(b) obtaining the amorphous solid dispersion of benvitimod or salt thereof together with at least one pharmaceutically acceptable carrier from the solution or mixture of step (a).
In one embodiment, the present invention provides a benvitimod premix comprising benvitimod, and premixing agents which process comprises: 20
(i) providing an intimate mixture comprising the solvent system, benvitimod and premixing agents and optionally, water;
(ii) removing any solvent present from the mixture;
(iii) dissolving in another solvent; and
(iv) precipitating the premix of benvitimod 25
wherein the benvitimod used is amorphous or crystalline.
In one embodiment, the present invention provides pharmaceutical compositions comprising benvitimod obtained by processes herein described, having a D90 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 30
13
microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.
In one embodiment, the present invention provides pharmaceutical compositions comprising benvitimod obtained by the processes herein described, having a D50 particle size of less than about 250 microns, preferably less than about 150 microns, 5 more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.
The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to 10 bring the solid state benvitimod into any of the foregoing desired particle size range.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.
15
20
14
Examples
Ex 1: Preparation of methyl 3, 5-dimethoxy-4-(propan-2-yl) benzoate (compound of formula V)
Methyl-3, 5-dimethoxybenzoate (100 gm, compound VI) was added to 80% sulfuric acid at a temperature of 25-30?C to obtain a reaction mass. The reaction mass was 5 heated to 60-65?C and isopropyl alcohol (32.15 gm) was added slowly to the reaction mass. The reaction mass was stirred for 5 hrs at a temperature of 60-65?C. On completion of reaction, the reaction mass was cooled to 25-30?C and water was added to the reaction mass at a temperature of 25-30?C. The reaction mass was stirred for 120 min and the precipitated solid was filtered and dried. The solid was 10 taken in methanol (500 ml) to obtain a reaction mass and to this sulfuric acid (20 ml) was added. The reaction mass was heated to reflux at 60-65?C for 5 hrs. On completion of the reaction, the reaction mass was cooled to 25-30?C and stirred for 2 hrs. The precipitated solid was filtered and washed with methanol. The solid was dried at 40-45?C for 12 hr under vacuum to afford 100 gm of methyl 3,5-15 dimethoxy-4-(propan-2-yl)benzoate (purity 98.32%).
Ex 2: Preparation of [3, 5-dimethoxy-4-(propan-2-yl)phenyl]methanol (compound of formula IV)
A solution of methyl 3,5-dimethoxy-4-(propan-2-yl)benzoate (170 gm) in 20 tetrahydrofuran (THF) 1700 ml was added slowly to Vitride (288.50 gm, 70% solution in THF) at 25-30oC. The reaction mass was stirred for 2 hr. On completion of the reaction, ammonium chloride solution was added to the reaction mass followed by ethyl acetate. This was filtered through hiflow bed. The organic layer was distilled off to get a residue which was crystallized from a mixture of methanol 25 -water. The precipitated solid was filtered and dried under vacuum at 40-45?C for 12 hrs to afford 138 gm of [3,5-dimethoxy-4-(propan-2-yl)phenyl]methanol (98.50%).
Ex 3: Preparation of 3, 5-dimethoxy-4-(propan-2-yl)benzaldehyde (compound 30 of formula III)
15
Pyridinium chlorochromate (PCC) (221.14 gm) was added to a solution of [3,5-dimethoxy-4-(propan-2-yl)phenyl]methanol (180 gm) in dichloromethane at 25-30°C. On completion of the reaction, the reaction mass was filtered through hyflow bed. The filtrate was washed with 15% hydrochloric acid. The organic layer was distilled off to get a residue which was recrystallized from a mixture of methanol-5 water to afford 146 gm of 3,5-dimethoxy-4-(propan-2-yl)benzaldehyde (purity 99.59%).
Ex 4: Preparation of 3,5-dimethoxy-4-(propan-2-yl)benzaldehyde (compound of formula III) 10
A mixture of dimethyl sulfoxide (5.55gm) and methylene chloride (120mL) under nitrogen atmosphere was cooled to about -78°C and oxalyl chloride (7.25g, 0.0571mol) was added. The reaction mixture was stirred for about 20-30 min. A solution of [3, 5-dimethoxy-4-(propan-2-yl)phenyl]methanol (10gm) in methylene chloride was slowly added to the reaction mixture at about -78°C. After completion 15 of addition, the reaction mixture was stirred for about 30 min and triethyl amine (14.4gm) was added drop wise at about -78°C. After completion of reaction, the temperature of the reaction mixture was raised to 25-30°C about room temperature and water was added to the reaction mixture. The reaction mixture was stirred for about 30 min. The organic layer was washed with 5% aqueous hydrochloric acid 20 and water, dried over sodium sulphate and concentrated under vacuum at about 35°C to about 40°C to get crude product which was crystallized from methanol to get 9.1 gm of pure compound.
Ex 5: Preparation of 1,3-dimethoxy-5-[(E)-2-phenylethenyl]-2-(propan-2-yl)benzene (compound of formula II) 25
NaHMDS (1M solution in THF) solution was added slowly to a solution of diethyl benzylphosphonate (109.59 gm) at 25-30°C for 30 min. After completion of addition 3,5-dimethoxy-4-(propan-2-yl)benzaldehyde (91 gm) was added to the reaction mixture at 25-30°C. The reaction mass was stirred for 2 hrs at 25-30°C. After completion of the reaction, water was added to the reaction mass. The organic 30 layer was distilled under vacuum to get a residue which was crystallized from a
16
mixture of methanol-water to obtain 110 gm of 1,3-dimethoxy-5-[(E)-2-phenylethenyl]-2-(propan-2-yl)benzene (purity 99.70%, Z- isomer 0.05%)
Ex 6: Preparation of 1, 3-dimethoxy-5-[(E)-2-phenylethenyl]-2-(propan-2-yl)benzene (compound of formula II) 5
Potassium tertiary butoxide (2.15 gm) was added slowly to a solution of diethyl benzyl phosphonate (2.41 gm) and 3,5-dimethoxy-4-(propan-2-yl)benzaldehyde (2.0 gm ) in tetrahydrofuran at 0-5?C After completion of addition the reaction mass was stirred for 2 hrs at a temperature of about 35 to about 45?C. After completion of the reaction, water was added to the reaction mass. The organic layer was 10 distilled under vacuum to get a residue which was crystallized from a mixture of methanol-water to obtain 1,3-dimethoxy-5-[(E)-2-phenylethenyl]-2-(propan-2-yl)benzene(2.3 gm, purity 99.80% Z-isomer not detected).
Ex 7: Preparation of benvitimod (5-[(E)-2-phenylethenyl]-2-(propan-2-yl) 15 benzene-1, 3-diol) (compound of formula I)
Pyridine hydrobromide (14.32gm) and tetrabutyl ammonium iodide (0.05gm) was added to a solution of 1,3-dimethoxy-5-[(E)-2-phenylethenyl]-2-(propan-2-yl)benzene (5.0 gm) in sulfolane (10 ml). The reaction mass was heated to 160-170 °C for 12 hr. After completion of the reaction mass water was added to the reaction 20 mass and the product was extracted with ethyl acetate. The organic layer was distilled to get a brown colour residue which was crystallized from n-hexane to obtain benvitimod (4 gm, purity 99.80%).
Pos. [°2Th.]
d-spacing [Å]
Rel. Int. [%]
Pos. [°2Th.]
d-spacing [Å]
Rel.Int. [%]
5.79
15.24
31.33
22.97
3.87
8.87
11.53
7.66
100.00
23.54
3.77
6.78
12.10
7.31
9.07
23.90
3.72
21.74
12.49
7.08
34.31
24.33
3.65
5.21
13.48
6.56
2.30
25.09
3.54
2.51
14.13
6.26
30.18
25.44
3.50
5.70
15.99
5.54
82.37
25.67
3.46
6.27
16.85
5.26
8.45
26.52
3.36
1.82
17.29
5.12
7.34
27.17
3.28
11.82
17.51
5.06
5.61
27.83
3.20
3.60
17
19.04
4.65
56.04
28.43
3.13
27.67
20.07
4.42
13.47
28.69
3.11
5.87
20.75
4.27
16.30
29.36
3.04
1.65
22.24
3.99
7.03
30.78
2.90
5.59
22.63
3.92
4.06
32.10
2.78
1.88
Ex 8: Preparation of benvitimod (5-[(E)-2-phenylethenyl]-2-(propan-2-yl) benzene-1,3-diol) (compound of formula I)
Pyridine hydrobromide (14.32 gm) was added to a solution of 1,3-dimethoxy-5-[(E)-2-phenylethenyl]-2-(propan-2-yl)benzene (5.0 gm) in N-methyl 5 pyrrolidinone(2.5 ml). The reaction mass was heated to 160-170?C for 5 hrs. After completion of the reaction, 2N hydrochloric acid was added to the reaction mass and the product was extracted with ethyl acetate. The organic layer was distilled to get a brown colour residue which was crystallized from toluene to obtain benvitimod (4 gm, purity 99.90%). 10
Pos. [°2Th.]
d-spacing [Å]
Rel. Int. [%]
Pos. [°2Th.]
d-spacing [Å]
Rel.Int. [%]
6.18
14.29
0.47
24.97
3.56
0.99
11.03
8.02
0.29
25.55
3.48
8.05
12.21
7.24
58.07
26.03
3.42
1.43
13.58
6.51
2.07
27.27
3.26
9.11
14.60
6.06
0.62
27.50
3.24
5.29
16.19
5.47
100.00
28.10
3.17
1.50
16.71
5.30
1.19
29.46
3.03
3.49
17.41
5.09
0.56
31.08
2.87
6.05
18.45
4.80
2.04
31.85
2.80
0.94
20.16
4.40
10.22
32.91
2.72
2.15
20.47
4.33
2.44
33.51
2.67
0.34
21.08
4.21
17.37
36.45
2.46
1.39
21.94
4.05
1.34
36.93
2.43
2.21
22.77
3.90
14.32
38.04
2.36
0.15
24.45
3.64
30.12
39.15
2.30
0.56
Ex 9: Preparation of benvitimod (5-[(E)-2-phenylethenyl]-2-(propan-2-yl) benzene-1,3-diol)
BBr3 (4 mL, 1 M in dichloromethane) in dry dichloromethane (10 ml) was added drop wise into 1,3-dimethoxy-5-[(E)-2-phenylethenyl]-2-(propan-2-yl)benzene in 15 dry dichloromethane (5 mL) at -78° C., and left at 15-30?C overnight. The mixture
18
was then poured on ice and the organic layer was separated and aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride and dried over sodium sulfate. The organic layer was evaporated under vacuum to get a residue which was purified using column chromatography using (2% ethyl acetate in hexane) to obtain benvitimod (2gm, purity 99.03%. m.p 5 :140-142ºC).
Ex 10: Preparation of benvitimod (5-[(E)-2-phenylethenyl]-2-(propan-2-yl) benzene-1,3-diol)
Pyridine hydrobromide (19.83gm) and) was added to 1,3-dimethoxy-5-[(E)-2-10 phenylethenyl]-2-(propan-2-yl)benzene (5 gm). The reaction mass was heated to 180-190?C for 5 hrs. After completion of the reaction, water was added to the reaction mass and the product was extracted with ethyl acetate. The organic layer was distilled to get a brown colour residue which was crystallized from n-hexane to obtain benvitimod (4 gm, purity, 99.30%). ,CLAIMS:WE CLAIM
1. A process for the preparation of benvitimod, a compound of formula I, comprising:

I
a) converting methyl 3, 5-dimethoxybenzoate, a compound of formula VI to
methyl 3, 5-dimethoxy-4-(propan-2-y l) benzoate, a compound of formula V

VI V;
b) reducing the compound of formula V to 3, 5-dimethoxy-4-(propan-2-yl) phenyl] methanol, a compound of formula IV

IV;
c) oxidation of compound of formula IV to obtain 3, 5-dimethoxy-4-(propan-2-yl) benzaldehyde, a compound of formula III

III;
d) coupling the compound of formula III with diethyl benzyl phosphonate to obtain
1, 3-dimethoxy-5-[I-2-phenylethenyl]-2-(propan-2-yl) benzene, a compound of formula II

II; and
e) demethylation of compound of formula II to obtain benvitimod, the compound of formula I.
2. The process as claimed in claim 1, wherein step a) is carried out in presence of mineral acid.
3. The process as claimed in claim 2, wherein the mineral acid selected from the group consisting of sulfuric acid, hydrochloric acid, acetic acid and polyphosphoric acid.
4. The process as claimed in claim 1, wherein step b) is carried out using a reducing agent.
5. The process as claimed in claim 4, wherein the reducing agent is selected from the group consisting of hydrides such as sodium hydride, sodium borohydride, lithium borohydride, sodium bis (2-methoxyethoxy)aluminium hydride (vitride).
6. The process as claimed in claim 1, wherein in step c) the oxidising agent is selected from the group consisting of chromium based oxidising agents selected from the group consisting of pyridinium chlorochromate, pyridine-trioxochromium or sulfonium species selected from the group consisting of dimethylsulfoxide-oxalyl chloride, dimethylsulfoxide-carbodiimide, sulfur trioxide pyridine complex or sodium tungstate, hydrogen peroxide, sodium hypochlorite, and potassium hypochlorite.
7. The process as claimed in claim 6, wherein the reaction is carried out in presence of a base.
8. The process as claimed in claim 7, wherein the base is selected from the group consisting of potassium hexamethyldisilazide (KHMDS), sodium hexamethyldisilazide (NaHMDS), sodium amide, potassium tertiary butoxide, n-Butyllithium (n-BuLi) and Lithium diisopropylamide (LDA).
9. The process as claimed in claim 1, wherein in step (e) the demethylation is carried out using a dealkylating agent.
10. The process as claimed in claim 9, wherein the dealkylating agent is selected from the group consisting of pyridinium hydrobromide, boron tribromide, aluminium trichloride and sodium sulphide.