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

FIELD OF THE INVENTION

The present invention relates to a synthesis of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid.

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 8,367,710 discloses a process for the preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I), according to the following Scheme 1:
Scheme 1
The prior art process is not suitable for commercially in industrial scalable and provide the compound of formula (I) with low purity, yield and formation of unwanted impurities, which comprises the use of purified by silica gel column chromatography. By removing of impurities very difficult and its impact on final API product. Obviously, such a process is not recommendable or feasible in large scale production.
So, our inventors have developed a process for the preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I) provide high yield, high chemical purity with reducing time cycle and better controlling impurities, not requiring the use of silica gel flash column chromatography purification.
OBJECT OF THE INVENTION

The present invention relates to a synthesis of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I).

SUMMARY OF THE INVENTION

The present invention relates to a synthesis of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid.

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 (III) is reducing with palladium catalyst to obtain compound of formula (II), and

b) compound of formula (II) is hydrolysing with hydroiodic acid (HI) to obtain compound of formula (I).

In yet another aspect of the present invention, a process for the preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I) by hydrolysing compound of formula (II) with hydroiodic acid (HI).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a synthesis 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 (III) is reducing with palladium catalyst to obtain compound of formula (II), and

b) compound of formula (II) is hydrolysing with hydroiodic acid (HI) to obtain compound of formula (I).

In yet another aspect of the present invention, a process for the preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I) by hydrolysing compound of formula (II) with hydroiodic acid (HI).

According to embodiment of the present invention, compound of formula (II) is reducing with palladium catalyst to obtain compound of formula (II), reaction is carried out at 50-55°C for 13-15 hours and compound of formula (II) is hydrolysing with hydroiodic acid (HI), reaction is carried out at 105-115°C for 38 hours and followed by pH adjustment with potassium carbonate to obtain compound of formula (I).

In yet another aspect of the present invention, a process for the preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I) is obtained from compound of formula (II) is hydrolysing with hydroiodic acid (HI) to produce compound of formula (I).

According to embodiment of the present invention, compound of formula (II) is hydrolysing with hydroiodic acid (HI), reaction is carried out at 105-115°C for 38 hours and followed by pH adjustment with potassium carbonate to obtain compound of formula (I).

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 palladium catalyst 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 above reaction is carried out in presence of solvent and it is selected from 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.

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

EXAMPLES

Example-1:
Preparation of 3'-amino-2'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (II):
2'-Methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid (III) (100.0gm), 5% palladium carbon (3.0gm) and Methanol (1000ml) was stirred under hydrogen gas pressure (4-5 kg/cm2) at 50-55°C for 13-15 hours and cool the reaction mass to 25-30°C. The resultant reaction mass filtered through high-low bed under nitrogen gas atmosphere and wash with Methanol (50ml). Distilled out solvent completely followed by isopropyl alcohol (300ml) charge into the resultant material and 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 (30ml), dry the material 40-45°C to obtained brown colour of the 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid.
Yield: 90% (80.5 gm)
Purity: 99.21%.

Example-2:
Preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I):
3'-Amino-2'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (II) (100gm) and 55-58% hydroiodic acid solution were into RB flask at 25-30°C. The reaction mass was heated to 105-115°C, maintain for 38hours and cool the mass to 25-30°C and stir for 30min. The resultant material filtered and wash with water (50ml), unload the wet material. The obtained wet material charge into Purified water (500ml) and mass pH with 10% Potassium carbonate solution followed by water leaching’s(800ml) and finally obtained material charged in Isopropyl alcohol (700ml), heat the mass to 75-80°C and cooled at 25-35°C. The resultant material filtered and wash the material with IPA (50ml). The obtained material dry at 50-55°C to obtained of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid.
Yield: 91% (86 gm)
Purity: 99.50%.

Example-3:
Preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I):
3'-Amino-2'-methoxy-[1,1'-biphenyl]-3-carboxylic acid (II) (100gm) and 55-58% hydroiodic acid solution were into RB flask at 25-30°C. The reaction mass was heated to 105-115°C, maintain for 38hours and cool the mass to 25-30°C and stir for 30min. The resultant material filtered and wash with water (50ml), unload the wet material. The obtained wet material charge into Purified water (500ml) and mass pH with 10% Potassium carbonate solution followed by water leaching’s (800ml) and finally obtained material charged in ethyl acetate (600ml), heat the mass to 75-80°C and cooled at 25-35°C. The resultant material filtered and wash the material with ethyl acetate (60ml). The obtained material dry at 50-55°C to obtained of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid.
Yield: 90% (85.5 gm)
Purity: 99.50%.
,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 (III) is reducing with palladium catalyst to obtain compound of formula (II), and

b) compound of formula (II) is hydrolysing with hydroiodic acid (HI) to obtain compound of formula (I).

2. The process as claimed in claim 1, wherein the palladium catalyst 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).

3. A process for the preparation of 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (I) by hydrolysing compound of formula (II) with hydroiodic acid (HI).