DESC:“PREPARATION OF 3'-AMINO-2'-HYDROXY-[1,1'-BIPHENYL]-3-CARBOXYLIC ACID”

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid with high yield and purity.

BACKGROUND OF THE INVENTION

3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid as a key intermediate for the preparation of a thrombopoietin receptor agonist, this intermediate is also used in the preparation of Eltrombopag Olamine, which is treated thrombocytopenia in patients with chronic ITP, Hepatitis C Infection and Severe Aplastic Anemia.

3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid, is represented by structural Formula (I).

3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid of formula (I), which is a key intermediate for the preparation of Eltrombopag Olamine.

US 7,160,870 discloses a process for the preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I), according to the following Scheme 1:
The above process is schematically shown as below:

Scheme 1
EP 2799425 discloses another a process for the preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I), according to the following Scheme 2:
The above process is schematically shown as below:

Scheme 2
The prior art processes are not suitable for commercially in industrial scalable and provide the compound of formula (I) with very low overall yield.
So, our inventors have developed a process for the preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I). The present invention is providing industrial applicable process with high purity and good yield.
OBJECT OF THE INVENTION

The present invention relates to a process for the preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I) with high yield and purity.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I), comprising the steps of;

a) compound of formula (II) is treating with N-bromosuccinimide in presence of Azobisisobutyronitrile (AIBN) to obtain the compound of formula (III),

b) optionally, isolating compound of formula (III) from mixture of suitable solvents,

c) compound of formula (III) is methylating with dimethyl sulphate to obtain compound of formula (IV),

d) optionally, isolating compound of formula (IV) from suitable solvent,
e) compound of formula (IV) is condensing with compound of formula (V) in presence of palladium catalyst to obtain compound of formula (VI),

f) optionally, compound of formula (VI) is recrystallization from suitable solvents,
g) compound of formula (VI) is hydrolysing with acid to obtain compound of formula (VII),

h) optionally, compound of formula (VII) is recrystallization from suitable solvents,
i) compound of formula (VII) is reducing with palladium catalyst in presence of ether solvent to obtain compound of formula (I),

j) isolating compound of formula (I) from mixture of suitable solvents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I) with high yield and purity.

The present invention provides a process for the preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I), comprising the steps of:

a) compound of formula (II) is treating with N-bromosuccinimide in presence of Azobisisobutyronitrile (AIBN) to obtain the compound of formula (III),

b) optionally, isolating compound of formula (III) from mixture of suitable solvents,
c) compound of formula (III) is methylating with dimethyl sulphate to obtain compound of formula (IV),

d) optionally, isolating compound of formula (IV) from suitable solvent,
e) compound of formula (IV) is condensing with compound of formula (V) in presence of palladium catalyst to obtain compound of formula (VI),

f) optionally, compound of formula (VI) is recrystallization from suitable solvent,
g) compound of formula (VI) is hydrolysing with acid to obtain compound of formula (VII),

h) optionally, compound of formula (VII) is recrystallization from suitable solvent,
i) compound of formula (VII) is reducing with palladium catalyst in presence of ether solvent to obtain compound of formula (I),

j) isolating compound of formula (I) from mixture of suitable solvents.

In an embodiment of the present invention, compound of formula (II) is treating with N-bromosuccinimide in presence of azobisisobutyronitrile (AIBN), the reaction is carried out at -5 to 10°C for 8-10 hours and followed by pH adjustment with conc. hydrochloric acid to obtain the compound of formula (III), optionally, isolating compound of formula (III) from mixture of suitable solvents. Compound of formula (III) is methylating with dimethyl sulphate, the reaction is carried out at 20 to 40 °C for 1 to 4 hours to obtain compound of formula (IV) and optionally, isolating compound of formula (IV) from suitable solvent. Compound of formula (IV) is condensing with compound of formula (V) in presence of palladium catalyst, reaction is carried out at 70 to 100°C for 3 to 6 hours and followed by pH adjustment with conc. hydrochloric acid (i.e. 0.5 to 3.0) to obtain compound of formula (VI), optionally, compound of formula (VI) is recrystallization from suitable solvent. Compound of formula (VI) is hydrolysing with acid, the reaction is carried out at 90 to 120 °C for 50 to 60 hours to obtain compound of formula (VII) and optionally, compound of formula (VII) is recrystallization from suitable solvents. Compound of formula (VII) is reducing with palladium catalyst in presence of ether solvent, the reaction is carried out at 45 to 75°C for 4 to 6 hours to obtain compound of formula (I) and isolating compound of formula (I) from mixture of suitable solvents.

The process for preparing Eltrombopag olamine comprising the process for preparing compound of Formula (I).

According to an embodiment of the present invention provides 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I) having HPLC purity = 99.5%.

According to an embodiment of the present invention. wherein the suitable solvent is selected 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, heptane and xylene; 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; water; cyclohexane and or mixtures thereof.

According to an embodiment of the present invention, wherein the palladium catalyst is selected from palladium catalyst selected from Palladium on charcoal (Pd/C), Pd(OAc)2, tetrakis(triphenylphosphine) palladium (0) (Pd(PPh3)4), trans-Benzyl(chloro) bis(triphenyl phosphine) palladium(II).

According to an embodiment of the present invention, wherein the acid is selected from hydrochloric acid, hydrobromic acid, acetic acid, sulphuric acid or mixtures thereof.

According to an embodiment of the present invention, wherein the ether solvent is selected from tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dioxane or mixture thereof.

According to an embodiment of the present invention, the reaction is carried out by using base is selected from triethylamine, tert-butylamine, pyridine, diazabicycloundecane (DBU); sodium methoxide, potassium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate or potassium hydrogen carbonate. According to a more preferred embodiment the base is tert-butylamine, potassium carbonate, triethylamine, sodium hydroxide or potassium hydroxide or mixtures thereof or other suitable bases.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES

Example-1:
Preparation of 2-bromo-6-nitrophenol (III):
2-Nitrophenol (100gm), dichloromethane(500ml) and azobisisobutyronitrile (10 gm) were charged into flask, cooled to 0-5°C and add tertiary butyl amine (52.5gm), stir the reaction mass 20-30min, followed by lot wise addition of N-bromosuccinamide (128gm) into the reaction mass at 0-5° and stir for 9 hours, after completion of the reaction. The resultant mixture was quenched with water (500ml), adjust pH with conc. hydrochloric acid and stir the mass for 10 min, separate the two layers. Extract the product from aqueous layer with dichloromethane (300ml) and wash the total the organic layer with water (300ml), separate the two layers. Take the organic layer (MDC Layer) and concentrate the mass under reduced pressure at below 40°C. The resultant product was charge into cyclohexane (300ml), heat the mass to 45-50°C and stir for 10-15min, cool the mass 10-15°C, Filter the obtained material and wash with cyclohexane (30ml) to obtained crude product. The obtained crude charge into methanol (100ml), heat the mass to 45-50°C and stir for 10-15min. Filter the material, suck dry the material, unload the material to obtained yellow colour material of 2-Bromo-6-nitrophenol.

Yield: 69 % (108gm)
Purity: 96.8%

Example-2:
Preparation of 1-bromo-2-methoxy-3-nitrobenzene (IV):
2-Bromo-6-nitro phenol (50gm), acetone (250ml) and di methyl sulphate (72.2gm) were charged into RB flask at 25-30°C and added potassium carbonate (63gm). The reaction mass maintained at 25-30°C for 2 hours, distil out the acetone at below 50°C and charge water (300ml). The reaction mass maintained at 25-30°C for 60min, filter the material and wash with water (100ml). The obtained product charge into cyclohexane (150ml) at 25-30°C and stir for 20 min. The resultant mass further cooled to 10-15°C, filter the material and wash with water (100ml). The obtained dry the material at 35-40°C to obtained the 1-Bromo-2-methoxy -3-nitrobenzene.
Yield: 85% (45 gm)
Purity: 99.6 %
Example-3:
Preparation of 2’-methoxy-3’-nitrobiphenyl-3- carboxylic acid (VI)
1-Bromo-2-methoxy-3-nitrobenzene (40gm), 3-carboxy phenyl boronic acid (34.2gm), 1,4-dioxane (240ml), sodium carbonate (36.5gm), tetrakis (triphenyl phosphine) palladium (0) (0.80gm) and water (200ml) were into RB flask. The reaction mass temperature raised to 80-90°C, stir for 5 hours at same temperature and cool the reaction mass at 25-30°C. The resultant reaction mass wash with 1,4-dioxane (25ml), distil out the reaction mass at below 80°C, under vacuum. The obtained reaction mass charge into water (80ml) at 60-65°C, then cool the mass to 25-30°C and pH adjustment 1.0-2.0 with conc. hydrochloric acid, stir for 60min. The resultant material filtered and wash with purified water (80ml). The obtained wet crude material charge into isopropyl alcohol (200ml), heat the mass to 50-55°C and stir for 15-20min, then cool to 0-5°C. The resultant solid material wash isopropyl alcohol (20ml), unload the material and dry the material 55-60°C to obtained the brown colour material of 2’-methoxy-3’-nitrobiphenyl-3- carboxylic acid.

Yield: 85.4% (40 gr)
Purity: 99.75 %

Example-4:
Preparation of 2'-hydroxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid (VII)
2'-Methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid (35gm), 48% hydro bromic acid solution in water (205ml) and acetic acid (410ml) were into RB flask at 25-30°C. The reaction mass was heated to 100-110°C, maintain for 60 hours and cool the mass to 25-30°C. The reaction mass add into water (410ml) and stir for 30min. The resultant material filtered and wash with water (200ml), unload the wet material. The obtained wet material charge into dimethyl formamide (140ml), heat the mass to 60-65°C and stir for 10-15min. The obtained mass charge into water (420ml) at 60-65°C and cooled at 0-5°C. The resultant material filtered and wash the material with water (35ml). The obtained material dry at 50-55°C to obtained the yellow color material of 2'-hydroxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid.
Yield: 85.1% (28 gm)
Purity: 99.52%.

Example-5:
Preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I):
2'-Hydroxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid (25.0gm), 5% palladium carbon (1.25gm) and tetrahydrofuran (175ml) was stirred under hydrogen gas pressure (4-5 kg/cm2), at 50-55°C for 5 hours and cool the reaction mass to 25-30°C. The resultant reaction mass filtered through hyflow bed under nitrogen gas atmosphere and wash with tetrahydrofuran (25ml). The resultant material charge into isopropyl alcohol (63ml) and ethyl acetate (63ml) at 75°C and stir for 30min, cool to 25-30°C. The obtained material filtered and wash with isopropyl alcohol (12.5ml). The resultant mass charge into isopropyl alcohol (63ml) and ethyl acetate (63ml), heat the mass to 75°C and stir for 30min. The obtained mass was cooled to 25-30°C and maintained for 30min. The resultant wet solid filtered and wash with isopropyl alcohol (12.5ml), dry the material 55-60°C to obtained brown colour of the 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid.
Yield: 82% (18 gm)
Purity: 99.5%.
,CLAIMS:
WE CLAIM:
1. A process for the preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I), comprising the steps of:

a) compound of formula (II) is treating with N-bromosuccinimide in presence of Azobisisobutyronitrile (AIBN) to obtain the compound of formula (III),

b) optionally, isolating compound of formula (III) from mixture of suitable solvents,
c) compound of formula (III) is methylating with dimethyl sulphate to obtain compound of formula (IV),

d) optionally, isolating compound of formula (IV) from suitable solvent,
e) compound of formula (IV) is condensing with compound of formula (V) in presence of palladium catalyst to obtain compound of formula (VI),

f) optionally, compound of formula (VI) is recrystallization from suitable solvent,
g) compound of formula (VI) is hydrolysing with acid to obtain compound of formula (VII),

h) optionally, compound of formula (VII) is recrystallization from suitable solvent,
i) compound of formula (VII) is reducing with palladium catalyst in presence of ether solvent to obtain compound of formula (I),

j) isolating compound of formula (I) from mixture of suitable solvents.
2. The process as claimed in claim 1, wherein the suitable solvent is selected 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, heptane and xylene; 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; water; cyclohexane and or mixtures thereof.
3. The process as claimed in claim 1, wherein the palladium catalyst is selected from palladium catalyst selected from Palladium on charcoal (Pd/C), Pd(OAc)2, tetrakis(triphenylphosphine) palladium (0) (Pd(PPh3)4), trans-Benzyl(chloro) bis(triphenyl phosphine) palladium(II).
4. The process as claimed in claim 1, wherein the acid is selected from hydrochloric acid, hydrobromic acid, acetic acid, sulphuric acid or mixtures thereof.
5. The process as claimed in claim 1, wherein the ether solvent is selected from tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dioxane or mixture thereof.