DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

A PROCESS FOR THE PREPARATION OF APALUTAMIDE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD, 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of compound of Formula – II and its conversion to apalutamide of Formula – I or pharmaceutically acceptable salts thereof.
, .

BACKGROUND OF THE INVENTION

Apalutamide is chemically known as (4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro [3.4]oct-5-yl]-2-fluoro-N-methylbenzamide). Apalutamide is approved under the brand name Erleada® for the treatment of patients with metastatic or non-metastatic castration-sensitive or castration-resistant prostate cancer.

Apalutamide (I) is disclosed first time in US 8445507. This patent discloses a process for the preparation of Apalutamide comprises reacting the 2-cyano-3-trifluoromethyl-5-aminopyridine of Formula – III with thiophosgene in water to obtain 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile of Formula – II followed by coupling with a compound of Formula – IVa to obtain Apalutamide. The process is depicted in the below as scheme-I:
Scheme-I

The major disadvantages associated with the process disclosed in US 8445507 is the use of highly toxic reagent thiophosgene, which is poisonous in nature and it generates high amount of poisonous phosgene gas and it is difficult to control, specifically at an industrial scale. Thus requires more labor and extreme care to use, which makes the process commercially not viable.

The inventors of the present invention found an improved process to prepare Apalutamide [Formula – I], which is industrially feasible, can avoid the use of potentially hazardous, toxic reagents. The present invention directed towards a process for the preparation of Apalutamide [Formula – I] with high purity and high yield.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide an improved process for the preparation of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile [Formula – II] and its conversion to Apalutamide [Formula – I] or pharmaceutically acceptable salts thereof.
, .

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides an improved process for the preparation of Apalutamide of formula – I,
,
which comprises the steps of:
a) reacting 2-cyano-3-trifluoromethyl-5-aminopyridine [Formula – III] with a source of isothiocyanate of formula P–NCS to obtain a compound of Formula – IIa;
, ,
wherein, P is selected from a hydrogen or any protecting group;
b) optionally converting the compound of Formula – IIa to a compound of Formula – IIb;
,
c) heating the compound of Formula – IIb to obtain 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile of Formula – II;
,
d) reacting the compound of Formula – II with a compound of Formula – IV to obtain Apalutamide [Formula – I] or pharmaceutically acceptable salts thereof,
,
wherein, R is selected from –CN, –COOR1;
R1 is selected from H, C1-8 alkyl.

In another embodiment, the present invention provides a process for the preparation of source of isothiocyanate of formula P–NCS, comprises reacting a suitable salt of thiocyanate with a compound of Formula P–X,
wherein P is selected from a hydrogen or any protecting group;
X represents fluoro, chloro, bromo, iodo.

In another preferred embodiment, the present invention provides an improved process for the preparation of Apalutamide of Formula – I or pharmaceutically acceptable salts thereof,
,
which comprises:
a) reacting 2-cyano-3-trifluoromethyl-5-aminopyridine of Formula – III with thiocarbonyldiimidazole to obtain a compound of Formula – II;
, ,
b) reacting the compound of Formula – II with a compound of Formula – IV to obtain Apalutamide of Formula – I or pharmaceutically acceptable salts thereof,
,
wherein, R is selected from –CN, COOR1;
R1 is selected from H, C1-8 alkyl.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Apalutamide of Formula – I or pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts of the compounds of this invention include those derived from a suitable inorganic and organic acid and base. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and quaternary ammonium salts. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counter ions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

The term "protecting group," defined as P, as used herein refers to any chemical group introduced into a molecule by chemical modification of a functional group in a subsequent chemical reaction. P represents H, R’–CO–, R’–CO–O–, R’–SO2–; wherein R’ is selected from the group comprising alkyl, alkoxy, haloalkyl, aryl, aralkyl, aryloxy. Non-limiting examples of protecting groups comprise acetyl, benzoyl, substituted benzoyl, benzyl, ß-methoxyethoxymethyl ether, dimethoxytrityl, methoxymethyl ether, methoxytrityl, p-methoxybenzyl ether, pivaloyl, tetrahydropyranyl, trityl, and trimethylsilyl.

The term "alkyl" used herein the specification represents C1-8 alkyl and is selected from the group comprising of methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.

The term "alkoxy" used herein the specification represents C1-8 alkoxy and is selected from the group comprising of methoxy, ethoxy, butoxy and tert-butoxy.
The term "haloalkyl" used herein the specification represents any alkyl radical having one or more hydrogen atoms replaced by a halogen atom and is selected from the group comprising of trifluoromethyl, difluoromethyl and trichloromethyl.

The term "aryl" used herein the specification represents aryl refers to any functional group or substituent derived from an aromatic ring and is selected from the group comprising phenyl, naphthyl; optionally substituted with chloro, bromo, fluoro, iodo, methoxy or nitro.

The term "aralkyl" used herein the specification represents an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group) and is selected from the group comprising of benzyl or substituted benzyl, wherein the substituents are selected from nitro, methoxy and aryl.

Step a) of the aforementioned process comprises, 2-cyano-3-trifluoromethyl-5-aminopyridine of Formula – III with a source of isothiocyanate of Formula P–NCS is carried out in the presence of a solvent to obtain a compound of Formula – IIa.

The solvent used in above reaction system comprises water, alcohols, nitriles, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof. The alcohols comprises C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol; nitrile solvent selected from acetonitrile, propionitrile; halogenated hydrocarbons selected from methylene chloride, ethylene chloride, chloroform; hydrocarbons selected from hexane, cyclohexane, toluene, xylene; amides selected from dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone; sulfoxides selected from but are not limited to dimethyl sulfoxide; nitriles selected from acetonitrile, propionitrile; esters comprises, ethyl acetate and butyl acetate; ethers selected from diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran; ketones selected from acetone, methyl ethyl ketone, methyl isopropyl ketone and mixtures thereof.

The above reaction is carried out at a temperature ranging from about 25°C to reflux temperature.

After completion of the reaction, the resultant compound of Formula – IIa may be isolated from the reaction mass or may be directly proceed for the next step. Preferably, compound of Formula – IIa is isolated as solid, which process includes saturating the reaction mass by adding suitable anti solvent such as water to precipitate the compound of Formula – IIa.

Step b) of the aforementioned process comprises the optional deprotection of compound of Formula – IIa is carried out in the presence of a base and a solvent to obtain a compound of Formula – IIb.

The base used herein for deprotection comprises alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; and organic bases selected from the group consisting of triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine; guanidine bases such as 1,1,3,3-Tetramethylguanidine (TMG) and mixtures thereof.

The source of base can be added either as solution in water or it may be added as solid to the solution of reaction mixture.

The solvent system used in the above deprotection is as defined above.

The deprotection is carried out at a temperature ranging from about 25°C to reflux temperature.

The compound of Formula – IIb obtained from step b) reaction mass may be isolated by known techniques, for example one or more solvent extractions, washings and the like.

In an embodiment, the compound of Formula – IIb may be isolated by evaporating the reaction solvent under vacuum followed by extracting the product in to water immiscible organic solvent such as ethyl acetate, methylene chloride and removing the water immiscible organic solvent to obtain compound of Formula – IIb as residue, which is optionally treated with a suitable hydrocarbon solvent such as hexane, heptanes, cyclohexane, methyl cyclohexane and mixtures thereof to obtain compound of Formula – IIb as solid compound.

Step c) of the aforementioned process comprises heating the compound of Formula – IIb in a solvent to obtain 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile of Formula – II.

The heating is carried out at a temperature ranging from about 25°C to about reflux temperature.

The solvent used in the step c) comprises a high boiling point solvents comprises aromatic hydrocarbons such as toluene, chlorobenzene, bromo benzene, ethyl benzene, xylenes, cumene or trimethylbenzenes and mixture thereof.

After completion of the reaction, the step c) reaction mass may be subjected to evaporation under vacuum to obtain the compound of Formula – II as a residue, which is optionally purified using a suitable hydrocarbon solvent to obtain a solid compound of Formula – II.

Step d) of the aforementioned process comprises reacting 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile of Formula – II with a compound of Formula – IV to obtain Apalutamide of Formula – I or pharmaceutically acceptable salts thereof.

The starting material of source of isothiocyanate of Formula P–NCS prepared by a process comprising reacting a suitable salt of thiocyanate with a compound of Formula P–X in a solvent.

The suitable salt of thiocyanate comprising of ammonium thiocyanate, lithium thiocyanate, sodium thiocyanate, potassium thiocyanate, cesium thiocyanate, magnesium thiocyanate, calcium thiocyanate, barium thiocyanate, cobalt thiocyanate, lead thiocyanate, mercury thiocyanate.

The compound of Formula P–X comprising of hydrogen chloride, hydrogen bromide, acetyl chloride, acetyl bromide, acetyl iodide, acryloyl chloride, adipoyl chloride, anisoyl chloride, p-methoxy benzoyl chloride, p-methoxy benzoyl bromide, p-nitro benzoyl chloride, p-nitro benzoyl bromide, benzoyl chloride, benzoyl bromide, benzoyl iodide, benzyl chloroformate, tert-butyl chloroformate, methanesulfonyl chloride, ethanesulfonyl chloride, bromodifluoroacetylchloride, butyryl chloride, trichloroacetyl chloride and trifluoroacetyl chloride.

The above reaction is carried out at a temperature ranging from about 25 °C to reflux temperature.

After completion of the reaction, the resultant compound of Formula P-NCS can be isolated from the reaction mass as solid by methods known in the art or the product containing existing solution may be used for the subsequent processing steps without isolating the compound; preferably the compound of Formula P-NCS is converted directly to the next step without further workup.

Reaction of aforementioned 2-cyano-3-trifluoromethyl-5-aminopyridine of Formula – III with thiocarbonyldiimidazole is carried out in the presence of a base and a solvent to obtain a compound of Formula – II.

The base used herein comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, triethylamine, N,N-diisopropyl ethyl amine and mixtures thereof.

The solvent used herein comprises halogenated hydrocarbons, ethers, amides, nitriles and mixtures thereof. The halogenated hydrocarbons comprise methylene chloride, ethylene chloride, chloroform and mixtures thereof; ethers comprise dimethyl ether, diethyl ether, methyl ethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 1,4-dioxane and mixtures thereof; amides comprise dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and mixtures thereof; nitriles comprise acetonitrile, propionitrile; water and mixtures thereof.

The above reaction is carried out at a temperature ranging from about 0°C to reflux temperature.

The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE-1:
Preparation of 3-(trifluoromethyl)-5-isothiocyanatopyridine-2-carbonitrile (Formula II)
5-Amino-3-(trifluoromethyl) pyridine-2-carbonitrile (100 grams, 0.534 mol) and 1,1-thiocarbonyl diimidazole (142.85 grams, 0.801 mol) were added to methylene chloride (200 ml) at 20 – 30 °C. The reaction mass was cooled to 10 – 15 °C and triethylamine (108.15 grams, 1.068 mol) was added, stirred for 10 minutes at 10 – 15 °C. The temperature was raised to 20 – 30 °C and maintained for 16 hours. Methylene chloride (300 ml) was charged to the reaction mass and then cooled to -10 to 0 °C. Pre-cooled aqueous hydrochloride solution (260 ml concentrated hydrochloric acid in 740 ml water) was added to the reaction mass at -10 to 0 °C and stirred for 25 minutes. Methylene chloride layer was separated wand distilled out completely at below 30 °C to obtain brown color residue. n-hexane (500 ml) was added to the obtained residue at 20 – 30 °C and stirred for 30 minutes. n-hexane was distilled out completely at below 30 °C and dried to obtain 3-(trifluoromethyl)-5-isothiocyanatopyridine-2-carbonitrile.

EXAMPLE-2:
Preparation of Apalutamide (Formula I)
4-(1-cyano cyclobutyl amino)-2-fluoro-N-methyl benzamide (5.0 grams, 0.02 mol) and 3-(trifluoromethyl)-5-isothiocyanatopyridine-2-carbonitrile (13.9 grams, 0.06 mol) were charged in to dimethyl formamide (25 ml) and n-butyl acetate (25 ml) at 20 – 30 °C. The temperature of reaction mass was raised to 100 – 105 °C and maintained for 24 hours. Concentrated hydrochloric acid (5 ml) and water (5 ml) were added to the reaction mass and maintained for 1 hour at 85-90°C. The solvent was distilled out completely to obtain residue, water (50 ml) was added to the obtained residue at 20 – 30 °C for 10 minutes and decanted the aqueous layer from the gummy solid. Isopropyl alcohol (60 ml) was charged to the gummy solid, heated to 70 °C and stirred for 1 hour. The reaction mass was cooled to 20 – 30 °C and stirred for 2 hours. The reaction mass was filtered, washed with isopropyl alcohol (20 ml) and dried at 65 °C to obtain Apalutamide solid. The obtained solid was charged in to ethyl acetate (50 ml) and the temperature raised to 60 °C, stirred for 1 hour. n-hexane (100 ml) was slowly added for 30 minutes and the reaction mass was cooled to 25 °C and stirred for 3 hours. The reaction mass was filtered, washed with mixture of ethyl acetate (10 ml) and n-hexane (20 ml) and dried at 65 °C to obtain Apalutamide.
,CLAIMS:CLAIMS
We claim,
1. A process for the preparation of Apalutamide of formula – I,

which comprises the steps of:
a) reacting 2-cyano-3-trifluoromethyl-5-aminopyridine of formula – III with a source of isothiocyanate of formula P–NCS to obtain a compound of formula – IIa;
, ,
wherein, P is selected from a hydrogen or any protecting group;
b) optionally converting the compound of formula – IIa to a compound of formula – IIb;
,
c) heating the compound of formula – IIb to obtain 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile of formula – II;
,
d) reacting the compound of formula – II with a compound of formula – IV to obtain Apalutamide of formula – I,
,
wherein, R is selected from –CN, –COOR1;
R1 is selected from H, C1-8 alkyl.

2. The process according to claim 1, wherein the source of isothiocyanate of Formula P–NCS is prepared by a process comprising reacting a suitable salt of thiocyanate with a compound of Formula P–X in a solvent.

3. The process according to claims 1 and 2, wherein suitable salt of thiocyanate comprising of ammonium thiocyanate, lithium thiocyanate, sodium thiocyanate, potassium thiocyanate, cesium thiocyanate, magnesium thiocyanate, calcium thiocyanate, barium thiocyanate, cobalt thiocyanate, lead thiocyanate, mercury thiocyanate.

4. The process according to claims 1 and 2, wherein the compound of Formula P–X comprising of hydrogen chloride, hydrogen bromide, acetyl chloride, acetyl bromide, acetyl iodide, acryloyl chloride, adipoyl chloride, anisoyl chloride, p-methoxy benzoyl chloride, p-methoxy benzoyl bromide, p-nitro benzoyl chloride, p-nitro benzoyl bromide, benzoyl chloride, benzoyl bromide, benzoyl iodide, benzyl chloroformate, tert-butyl chloroformate, methanesulfonyl chloride, ethanesulfonyl chloride, bromodifluoroacetylchloride, butyryl chloride, trichloroacetyl chloride and trifluoroacetyl chloride.

5. The process according to claim 1, wherein step (a), step (b) are carried out in the presence of a solvent comprises halogenated hydrocarbons, ethers, amides, nitriles and mixtures thereof. The halogenated hydrocarbons comprise methylene chloride, ethylene chloride, chloroform and mixtures thereof; ethers comprise dimethyl ether, diethyl ether, methyl ethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 1,4-dioxane and mixtures thereof; amides comprise dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and mixtures thereof; nitriles comprise acetonitrile, propionitrile; water and mixtures thereof.

6. The process according to claim 1, wherein step (b) is the deprotection carried out in the presence of a base comprises alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; and organic bases selected from the group consisting of triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine; guanidine bases such as 1,1,3,3-Tetramethylguanidine (TMG) and mixtures thereof.

7. The process according to claim 1, wherein step c) is carried out at a temperature ranging from about 25°C to reflux temperature.

8. The process according to claim 1, wherein step c) is carried out in the presence of a high boiling point solvents comprises aromatic hydrocarbons such as toluene, chlorobenzene, bromo benzene, ethyl benzene, xylenes, cumene or trimethylbenzenes and mixture thereof.