Description:FIELD OF THE INVENTION:
The present invention relates to 5-(4-aminophenyl)-2-{carboxy[(2,6-difluorophenyl) methyl] amino}-4-[(dimethylamino)methyl] thiophene-3-carboxylic acid derivative, and more particularly to a process for preparation of ethyl 5-(4-aminophenyl)-2-{[(2,6-difluorophenyl) methyl] (ethoxycarbonyl) amino}-4-[(dimethylamino)methyl] thiophene-3-carboxylate and salts thereof.

BACKGROUND OF THE INVENTION:
Ethyl 5-(4-aminophenyl)-2-{[(2,6-difluorophenyl) methyl] (ethoxycarbonyl) amino} -4-[(dimethylamino) methyl] thiophene-3-carboxylate of formula I, is an important key intermediate used in the preparation of Relugolix.

Relugolix is a thienopyrimidine compound developed by Takeda and belongs to a class of drugs called gonadotropin-releasing hormone (GnRH) receptor antagonists. It is used for the treatment of advanced prostrate cancer.
Relugolix works by binding to GnRH receptors in the pituitary gland that reduces the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This decreases the amount of testosterone produced and helps to slow or stop the spread of the cancer cells that rely on this hormone for their growth.
Compound of formula (I) is the key intermediate of Relugolix. Cost effective synthesis of pure compound of formula (I) is very important to achieve the ICH purity of Relugolix.
CN113717149 to Weiven and others discloses preparation of formula (I) as shown in scheme 1 below.

Scheme 1
The reaction includes reduction of nitro compound followed by tert-butyloxycarbonyl (BOC) protection of amino group. The BOC protected compound is then subjected to bromination. In the final stage, the brominated compound is treated with dimethylamine followed by BOC deprotection. However, the yield of bromination is 8-10%. Instead of selective alkyl bromination; N-bromination, N-BOC cleavage and bromination on benzene was observed in the reaction. The raw material was consumed completely. However, LC-MS of the reaction mass showed formation of N-bromo and bromobenzene impurities (collectively known as “Bromo Impurities”). Bromination stage did not yield the desired product more than 8-10% even after N-BOC protection.
Due to the above-mentioned technical difficulties of the processes cited in prior art, there is a need for improved process for preparation of compound (I) that avoids formation of impurities in bromination stage and make it cost effective.

SUMMARY OF THE INVENTION:
The present invention describes a process for preparation of compound of formula (I) that includes a plurality of steps. The process includes a first step of hydrogenation of compound of formula (VI) using metal catalyst. The second step includes N-protection of compound of formula (V) with phthalic anhydride to form compound of formula (IV). In the third step, bromination of compound of formula (IV) using suitable brominating agents to form compound (III) is performed. Next, in the fourth step, dimethylamination of compound (III) by treating with dimethylamine to form compound of formula (II) is carried out. In the next step i.e., the fifth step, deprotection of formula (II) is performed using suitable amine solution to form compound of formula (I). The last step i.e., the sixth step includes optionally converting compound of formula (I) to acid addition salt.
DESCRIPTION OF THE INVENTION:
References in the specification to "one embodiment" or "an embodiment" means that a particular feature, structure, characteristic, or function described in connection with the embodiment is included in at least one embodiment of the invention. The appearances of the phrase “in one embodiment” in various places in the specification are not necessarily all referring to the same embodiment.
References in the specification to “preferred embodiment” means that a particular feature, structure, characteristic, or function described in detail thereby omitting known constructions and functions for clear description of the present invention.
The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed and obviously many modifications and variations are possible in light of the above teaching.
While working on the prior art processes for the preparation of compound (I), it was found that there is formation of various bromo impurities in the process due to multiple bromination. The inventors of the present invention have developed a process that provides higher yield of compound (I) without bromo impurity formation. The process is cost effective with selective bromination even at higher scale production.
The process for preparation of compound of formula (I) includes several steps.
a) A first step including hydrogenation of compound of formula (VI) at a predefined temperature and predefined pressure in a predefined solvent and in presence of a metal catalyst to form compound of formula (V).

b) A second step including N-protection of compound of formula (V) by reacting with phthalic anhydride in a predefined solvent at a predefined temperature to form compound of formula (IV).

c) A third step of brominating compound of formula (IV) by reacting with a predefined brominating agent at a predefined temperature in a predefined solvent in presence of a catalyst to form compound of formula (III).

d) A fourth step of performing dimethylamination of compound of formula (III) by reacting with dimethylamine at a predefined temperature in a predefined solvent to form compound of formula (II).

e) A fifth step of deprotecting compound of formula (II) by reacting with a predefined alkali in a predefined solvent to form compound of formula (I).
The process optionally includes a sixth step of converting the compound of formula (I) to acid addition salt.

The schematic representation of the process of the present invention is shown below.

The multiple bromination is avoided by taking away proton on nitrogen by phthalamide protection that was not possible in BOC protection.
In an embodiment of the present invention, the metal catalyst used for hydrogenation in step (a) is selected from Palladium, Platinum and Nickel. The hydrogenation is carried out in alcoholic solvent selected from (1-4C) alcohol such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol and ethyl acetate. The hydrogenation is carried out at predefined temperature of 20-75°C, preferably at 20-30°C and under predefined pressure of 1-10 kg pressure.
In a preferred embodiment, the hydrogenation is carried out in presence of Raney Nickel in ethanol or ethyl acetate at 20-50°C under 1-10Kg pressure.
In an embodiment of the present invention, the solvent used in step (b) is selected from trifluoroacetic acid and acetic acid. In this embodiment, the reaction proceeds at temperature of 80-140°C, preferably at 90-130°C, more preferably at 100-115°C.
In a preferred embodiment, the acid is selected from trifluoroacetic acid and acetic acid, particularly acetic acid.
In an embodiment of the present invention, the predefined brominating agent in step (c) is selected from N-bromosuccinamide, 1,3-Dibromo-5,5-Dimethyl hydantoin (DBDMH), liquid bromine and the like.
In a preferred embodiment, the bromination is carried out in presence of the catalyst selected from Azobisisobutyronitrile (AIBN), hydrogen peroxide and benzoyl peroxide.
The bromination is carried out in the solvent selected from ethyl acetate and halogenated solvents such as Chloroform, dichloromethane, Benzotrifluoride, carbon tetrachloride.
In a preferred embodiment, the brominating agent and the catalyst is added lot wise. This ensures completion of the reaction in lesser time. The bromination is carried out at predefined temperature of 40-80°C, preferably at 70-75°C.
In an embodiment, the dimethylamination in step (d) is carried out in a solvent selected from dimethyl formamide, Ethanol, tetrahydrofuran and dichloromethane.
Step (d) is carried out in presence of combination of Triethylamine and dimethyl amine hydrochloride wherein hydrochloride salt is broken to generate dimethyl amine that is responsible for dimethylamination. The reaction preferably proceeds at room temperature.
In an embodiment, the fifth step (e) of deprotection is carried out in a solvent selected from alcoholic solvent such as methanol, ethanol and isopropyl alcohol (IPA). The deprotection is carried out in presence of predefined alkali selected from monomethylamine or hydrazine hydrate.
In a preferred embodiment, the deprotection is carried out using monomethylamine and in solvent ethanol.
In another embodiment, the salt prepared in step f) is of hydrochloric acid or trifluoracetic acid.
These and other embodiments will be apparent to those of skill in the art and others in view of the following detailed description of some embodiments. It should be understood, however, that this summary, and the detailed description illustrate only some examples of various embodiments and are not intended to be limiting to the invention as claimed. The following examples illustrate the invention but are not limiting thereof.

EXAMPLES:
Example 1
Preparation of ethyl 2-[(2,6-difluorophenyl) methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-aminophenyl) thiophene-3-carboxylate (compound V)
Ethanol (1000 ml) was charged to ethyl 2-[(2,6-difluorophenyl) methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-nitrophenyl) thiophene-3-carboxylate (100 gm) at room temperature. Raney Ni (10 gm) was charged to the mixture and 1 kg hydrogen pressure was applied at room temperature. The mixture was maintained for 6-7 hours and filtered and washed with ethanol (200 ml). The filtrate was distilled under vacuum and ethyl 2-[(2,6-difluorophenyl) methyl-ethoxy carbonyl-amino]-4-methyl-5-(4-aminophenyl) thiophene-3-carboxylate was isolated as oil (93 gm; 98% yield).
HPLC purity: 97.5%

Example 2
Preparation of ethyl 2-[(2,6-difluorophenyl) methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-aminophenyl)thiophene-3-carboxylate (compound V)
Ethanol (280 ml) was charged to ethyl 2-[(2,6-difluorophenyl) methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-nitrophenyl) thiophene-3-carboxylate (40 gm) at 25-30°C. 10 % Pd/C (0.8 gm) was charged to the reaction mixture. 5 kg/cm3 H2 pressure was applied and the reaction mixture was stirred and maintained for 30 min at 25-30°C. The mixture was maintained for 20-22 hours and the mass was filtered. The filtrate was distilled under vacuum and ethyl 2-[(2,6-difluorophenyl) methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-aminophenyl) thiophene-3-carboxylate was isolated as oil (37 gm; 98.5% yield).
(Purity 96.5%)

Example 3
Preparation of ethyl 2-[(2,6-difluorophenyl) methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-aminophenyl)thiophene-3-carboxylate (compound V)
Ethyl acetate (225 ml) was charged to ethyl 2-[(2,6-difluorophenyl) methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-nitrophenyl) thiophene-3-carboxylate (25 gm) at room temperature. Raney Ni (2.5 gm) was charged to the mixture and 5 kg hydrogen pressure was applied at room temperature. The mixture was stirred for 30 minutes and maintained for 20-24 hours. The mass was filtered and the filtrate was distilled under vacuum and ethyl 2-[(2,6-difluorophenyl) methyl-ethoxycarbonyl-amino]-4-methyl-5-(4-aminophenyl) thiophene-3-carboxylate was isolated as oil (22.5 gm; 95.7% yield).
(Purity: 97%)

Example 4
Preparation of ethyl 2-[(2,6-difluorophenyl) methyl](ethoxy carbonyl) amino-5-[4-(1,3-dioxo- 1,3-dihydro -2H-isoindol-2-yl) phenyl]-4-methyl thiophene-3-carboxylate (compound IV)
Acetic acid (300 ml) was charged to Ethyl 2-[(2,6-difluorophenyl) methyl-ethoxy carbonyl-amino]-4-methyl-5- (4-aminophenyl) thiophene-3-carboxylate (100 gm) isolated in example 1. Phthalic anhydride (31.21 gm) was charged to the mixture at room temperature. The mixture was heated to 115-120°C and stirred for 1 hour. After completion of the reaction the mixture was quenched in chilled water (500 ml). The solid was filtered and washed with water (500 ml). Ethyl 2-[(2,6-difluorophenyl) methyl] (ethoxy carbonyl) amino-5-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) phenyl] -4-methylthiophene-3-carboxylate isolated was suck dried and further dried under vacuum at 40-50°C for 5-6 hours.
Dry weight (120 gm, 94% yield)
HPLC Purity: 99.2%

Example 5
Preparation of ethyl 4-(bromomethyl)-2-[(2,6-difluorophenyl) methyl] (ethoxy carbonyl) amino-5-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) phenyl] thiophene -3-carboxylate (Compound III)
Ethyl acetate (1000 ml) was charged to Ethyl 2-[(2,6-difluorophenyl) methyl] (ethoxy carbonyl) amino-5-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) phenyl]-4-methyl thiophene-3-carboxylate (100 gm) at room temperature. The mixture was heated to 70-75°C. First lot of NBS (14.1 gm) AIBN (1.25 gm) was charged to the reaction mixture and the mass was maintained at 70-75°C for 30 minutes.
Second lot of NBS (14.1 gm) AIBN (1.25 gm) was charged to the reaction mixture and the mass was maintained at 70-75°C for 30 minutes.
Third lot of NBS (14.1 gm) AIBN (1.25 gm) was charged to the reaction mixture and the mass was maintained at 70-75°C for 30 minutes.
Fourth lot of NBS (14.1 gm) AIBN (1.25 gm) was charged to the reaction mixture and the mass was maintained at 70-75°C for 30 minutes.
The mixture was heated to the reflux and stirred for 3 hours. The mass was cooled to 30-35°C. The layers were settled and separated. The organic layer was distilled under vacuum at 45-50°C and IPA (500 ml) was charged. The mixture was cooled to room temperature and stirred for 1 hour. The solid was filtered and washed with IPA (50g x 2). The compound ethyl 4-(bromomethyl)-2-[(2,6-difluorophenyl) methyl] (ethoxycarbonyl) amino-5-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) phenyl] thiophene-3-carboxylate obtained was suck dried and further dried under vacuum.
(Dry weight: 93 gm; 82% yield)
HPLC Purity - 98.5%

Example 6
Preparation of ethyl 2-[(2,6-difluorophenyl) methyl](ethoxycarbonyl)amino-4-[(dimethylamino)methyl]-5-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]thiophene-3-carboxylate (Compound II)
Ethyl 4-(bromomethyl)-2-[(2,6-difluorophenyl) methyl] (ethoxycarbonyl) amino-5-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]thiophene-3-carboxylate (100 gm) was charged to dimethyl formamide (500 ml) at 25-30°C and stirred for 10 minutes.
Dimethylamine hydrochloride (36 gm) and triethylamine (60 gm) was charged to the above mixture and stirred for 30 minutes at 25-30°C. The reaction mixture was quenched in chilled water (2000 ml)). The mixture was stirred at 0-5°C for 30 minutes. The solid was filtered and the wet solid was charged to toluene (800 ml) at 25-30°C. The mixture was stirred for 10 minutes, and the layers were separated. The organic layer was distilled under vacuum and n-heptane (200 ml) was charged to the oil obtained. The mixture was stirred for 60 minutes at 25-30°C. The solid was filtered and charged to IPA (70 ml) at 25-30°C. The mixture was stirred for 60 minutes and filtered. The wet cake obtained was washed with IPA (25 ml). The solid was further dried under vacuum at 40-45°C.
Dry weight 70 gm; % yield - 73%
HPLC purity - 97%

Example 7
Preparation of ethyl 5-(4-aminophenyl)-2-[(2,6-difluorophenyl) methyl] (ethoxycarbonyl)amino-4-[(dimethylamino)methyl]thiophene-3-carboxylate dihydrochloride (Compound I)
IPA (400 ml) was charged to ethyl 2-[(2,6-difluorophenyl) methyl] (ethoxycarbonyl)amino-4-[(dimethylamino)methyl]-5-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) phenyl] thiophene-3-carboxylate (100 gm) isolated in example 5 at 25-30°C and stirred for 10 minutes. Monomethylamine (100 ml) was charged slowly to the mixture and the temperature was raised to 40-45°C. The mixture was stirred for 1 hour till the solution becomes clear. The solvent was distilled out under vacuum. dichloromethane (600 ml) was charged at 25-30°C and stirred for 10 minutes. The layers were separated, and the organic layer was kept aside.
Dichloromethane (200 ml) was charged to the aqueous layer and stirred for 10 minutes at 25-30°C. The layers were separated the organic layers were combined.
The organic layer was distilled under vacuum and toluene (400 ml) was charged to the oil obtained. The mixture was cooled and filtered at 0-5°C. 5% Dilute HCl (500 ml) was charged to the filtrate at 25-30°C and stirred for 10 minutes. The layers were settled, separated and the pH of the aqueous layer was adjusted to 8 by using saturated sodium bicarbonate solution. The mixture was stirred for 10 minutes. Toluene (300 ml) was charged at 25-30°C and the mixture was stirred for 10 minutes. The layers were separated and organic layer was passed through sodium sulphate. The solvent was distilled under vacuum 40-45°C and the degassed oil was obtained.
Ethyl acetate (300 ml) was charged to the degassed oil and Dhalcot charcoal (10 gm) was added. The solution was stirred for 30 minutes at 25-30°C. The mixture was filtered over hyflow. The filtrate containing ethyl 5-(4-aminophenyl)-2-[(2,6-difluorophenyl) methyl] (ethoxycarbonyl) amino-4-[(dimethylamino) methyl] thiophene-3-carboxylate was cooled to 5-10°C. IPA HCl (100 ml) was charged and the mixture was stirred for 30 minutes. The solid obtained was filtered and charged to methanol (150 ml) at 25-30°C and temperature was raised to 40-45°C. Ethyl acetate (300 ml) was slowly added to the above mixture.
The mass was cooled gradually to 5-10°C and stirred for 30 minutes. The solid was filtered and dried under vacuum for 7-8 hours.
(Dry weight: 65 gm 71.4% yield)
(HPLC Purity:) - 99.3%
In the context of the present invention, the process of the present invention provides higher yield of compound (I) without bromo impurity formation. The process is cost effective with selective bromination even at higher scale production.
The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.
It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the scope of the present invention.

, Claims:We claim:
1) A process for preparation of compound of formula (I),

comprising:
a) a first step including hydrogenation of compound of formula (VI) at a predefined temperature and predefined pressure in a predefined solvent and in presence of a metal catalyst to form compound of formula (V);

b) a second step including N-protection of compound of formula (V) by reacting with phthalic anhydride in a predefined solvent at a predefined temperature to form compound of formula (IV);

c) a third step of brominating compound of formula (IV) by reacting with a predefined brominating agent at a predefined temperature in a predefined solvent in presence of a catalyst to form compound of formula (III);

d) a fourth step of performing dimethylamination of compound (III) by reacting with dimethyl amine at a predefined temperature in a predefined solvent to form compound of formula (II);

e) a fifth step of deprotecting compound of formula (II) by reacting with a predefined alkali in a predefined solvent to form compound of formula (I); and
f) a sixth step of optionally converting compound of formula (I) to its acid addition salt.

2) The process as claimed in claim 1, wherein metal catalyst for the first step of hydrogenation being selected from Palladium, Platinum and Nickel.
3) The process as claimed in claim 1 and 2, wherein metal catalyst for the first step of hydrogenation being Raney Nickel.
4) The process as claimed in any preceding claims, wherein the first step of hydrogenation being carried out in a predefined solvent selected from ethyl acetate and alcoholic solvent.
5) The process as claimed in claim 4, wherein the alcoholic solvent being selected from (1-4C) alcohol such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol.
6) The process as claimed in any preceding claims, wherein the first step of hydrogenation being carried out at a predefined temperature of 20-75°C and under a predefined pressure of 1-10 kg hydrogen pressure.
7) The process as claimed in claim 6, wherein the first step of hydrogenation being carried out at 20-30°C and under 4-7 kg hydrogen pressure.
8) The process as claimed in claim 1, wherein the predefined solvent for the second step of N-protection being selected from trifluoroacetic acid and acetic acid.
9) The process as claimed in claim 1 and 8, wherein the solvent for the second step of N-protection being acetic acid.
10) The process as claimed in claim 1, wherein the second step of N-protection being carried out at 80-140°C.
11) The process as claimed in claim 1 and 10, wherein the second step of N-protection being carried out at 90-130°C.
12) The process as claimed in claim 1, 10 and 11, wherein the second step of N-protection being carried out at 100-115°C.
13) The process as claimed in claim 1, wherein the brominating agent in the third step of bromination being selected from N-bromosuccinamide, 1,3-Dibromo-5,5-Dimethylhydantoin (DBDMH), liquid bromine.
14) The process as claimed in claim 1 and 13, wherein the brominating agent in the third step of bromination being N-bromosuccinamide.
15) The process as claimed in claim 13 and 14, wherein the third step of bromination being carried out in presence of catalyst selected from Azobisisobutyronitrile (AIBN), hydrogen peroxide and benzoyl peroxide.
16) The process as claimed in claim 15, wherein the third step of bromination being carried out in presence of Azobisisobutyronitrile (AIBN).
17) The process as claimed in claim 1 and 13, wherein the predefined solvent used in the third step of bromination being selected from ethyl acetate and halogenated solvents such as chloroform, dichloromethane, benzotrifluoride, carbon tetrachloride.
18) The process as claimed in claim 1 and 17, wherein the solvent used in the third step of bromination being ethyl acetate.
19) The process as claimed in claim 1 and 17-18, wherein the third step of bromination being carried out at predefined temperature of 40-80°C.
20) The process as claimed in claim 1 and 17-19, wherein the third step of bromination being carried out at 70-75°C.
21) The process as claimed in claim 15, wherein brominating agent and the catalyst in the third step of bromination being added lotwise.
22) The process as claimed in claim 1, wherein the fourth step of dimethylamination being carried out in a predefined solvent selected from dimethyl formamide, Ethanol, Tetrahydrofuran and dichloromethane.
23) The process as claimed in claim 1 and 22, wherein the fourth step of dimethylamination being carried out in dimethyl formamide.
24) The process as claimed in claim 1, wherein the fifth step of deprotection being carried out in presence of predefined alkali selected from monomethylamine or hydrazine hydrate.
25) The process as claimed in claim 1, wherein the fifth step of deprotection being carried out in a predefined solvent selected from alcoholic solvent such as methanol, ethanol and isopropylalcohol (IPA).
26) The process as claimed in claim 25, wherein the fifth step of deprotection being carried out in ethanol.
27) The process as claimed in claim 1, wherein salt of compound of formula (I) being formed by treating the compound obtained in deprotection step with a predefined acid selected from hydrochloric acid or trifluoracetic acid.
28) The process as claimed in any of the above claim,
wherein the process comprises:
a) hydrogenation of compound of formula (VI) using Raney Nickel;
b) N-protection of compound of formula (V) with phthalic anhydride to form compound of formula (IV);
c) bromination of compound of formula (IV) using N-bromosuccinamide to form compound (III);
d) dimethylamination of compound (III) by treating with dimethylamine to form compound of formula (II);
e) deprotection of formula (II) in presence of monomethylamine to form compound of formula (I); and
f) converting compound of formula (I) to hydrochloride salt by treating with Conc. hydrochloric acid.

Dated this 09th day of January 2023.
For AARTI PHARMALABS LIMITED

Mahurkar Anand Gopalkrishna
IN/PA-1862
(Agent for Applicant)