DESC:The following specification particularly describes the invention and the manner in which it is to be performed.

IMPROVED PROCESSES FOR THE PREPEARATION OF SELINEXOR

INTRODUCTION
Aspects of the present application relate to improved processes for preparation of Selinexor and intermediates thereof.
The drug compound having the adopted name “Selinexor” has chemical name: (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol- 1 -yl)-N'-(pyrazin-2-yl)acrylohydrazide as below.

Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE™ compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. Over 1,200 patients have been treated with Selinexor in company and investigator-sponsored Phase 1 and Phase 2 clinical trials in advanced hematologic malignancies and solid tumors. Karyopharm has initiated four later-phase clinical trials of selinexor, including one in older patients with acute myeloid leukemia (SOPRA), one in patients with Richter's transformation (SIRRT), one in patients with diffuse large B-cell lymphoma (SADAL) and a single-arm trial of selinexor and lose-dose dexamethasone in patients with multiple myeloma (STORM). Patients may receive a twice-weekly combination of Selinexor in combination with low dose dexamethasone. Randomized 1:1, Selinexor will be dosed either at 60mg + dexamethasone or at 100 mg + dexamethasone.
US 8999996 B2 discloses Selinexor and a pharmaceutically acceptable salt thereof, pharmaceutical compositions and use for treating disorders associated with CRM1 activity. Further, it discloses preparative methods for the preparation of compounds disclosed therein including Selinexor by reacting (Z)-3-(3- (3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-l-yl)acrylic acid in 1:1 CH2Cl2: AcOEt with 2-Hydrazinopyrazine at -40 °C followed by addition of T3P[Propylphosphonic anhydride] (50%) and DIPEA. After 30 minutes, the reaction mixture was concentrated and the crude oil was purified by preparative TLC using 5% MeOH in CH2Cl2 as mobile phase (under ammonia atmosphere) to afford 40 mg of Selinexor with purity: 95.78%.
Prior art process for the preparation of Selinexor suffers from disadvantages interms of process such as the use of lengthy procedures to practice and resulting in low yields, which may not be viable at industrial scale. Synthetic product obtained therein has very low purity and contains significant amounts of unreacted starting materials and trans-isomer of Selinexor, which are further purified by time consuming and expensive chromatographic separations leading to loss of yield. Hence, there remains a need for improved process for the preparation of Selinexor which is industrially viable and reproducible. Particularly, it is desirable to have a process avoiding purification steps still meeting desired pharmaceutical quality.

SUMMARY
In an aspect, the present application provides an improved process for the preparation of Selinexor, comprising the steps of:
a) N-alkylation of triazole compound of formula (II) to obtain the N-alkylated ester of formula (IV), wherein X may be hydrogen, Y may be a leaving group such as a halogen or a sulphonate group (or) X and Y may together form a triple bond between carbons atoms to which there are linked and R may be an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl group;

b) optionally purifying the N-alkylated ester of formula (IV);
c) hydrolysis of the N-alkylated ester of formula (IV) of step a) or step b) to corresponding N-alkylated acid of formula (IVa);

d) purifying the N-alkylated acid of formula (IVa) through formation of its addition salt of formula (VI), wherein B is a base;

e) converting the addition salt of formula (VI) or N-alkylated acid of formula (IVa) to Selinexor of formula (I), wherein Z may be hydrogen or a protecting group.
f) optionally, removing the protecting group to obtain Selinexor.

In another aspect, the present application provides a process for the preparation of Selinexor or a salt thereof, comprising the steps of:
a) N-alkylation of triazole compound of formula (II) to obtain the N-alkylated ester of formula (IV), wherein X may be hydrogen and Y may be a leaving group such as a halogen or a sulphonate group (or) X and Y together form a triple bond between carbons atoms to which there are linked, R may be an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl group;

b) optionally purifying the N-alkylated ester of formula (IV) of step a);
c) reacting the N-alkylated ester of step a) or step b) with 2-Hydrazinopyrazine derivative of formula V, wherein Z may be hydrogen or protecting group to obtain Selinexor of formula I.

d) Optionally, removing the protecting group to obtain Selinexor.
e) purifying the Selinexor obtained in step c) or d).

In another aspect, the present application provides an addition salt of N-alkylated acid of formula VI.

In another aspect, the present application provides a process for the preparation of Selinexor comprising the step of preparing an addition salt of N-alkylated acid of formula VI.

In another aspect, the present application provides a pharmaceutical composition comprising Selinexor obtained according any of the aspects of this application and atleast one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form-Alpha of Selinexor prepared by the method of Example No 4.
According to National Institute of Standards and Technology (NIST), for silica powder, one of the PXRD peak position is at 28.44°(2?). Silica powder was spiked to Form-Alpha of Selinexor in order to obtain accurate PXRD peak positions. In Figures 1, peak at 28.44° (2?) corresponds to silica powder.

DETAILED DESCRIPTION
Aspects of the present application provide improved processes for the preparation of Selinexor and intermediates thereof.
In an aspect, the present application provides an improved process for the preparation of Selinexor, comprising the steps of:
a) N-alkylation of triazole compound of formula (II) to obtain the N-alkylated ester of formula (IV), wherein X may be hydrogen, Y may be a leaving group such as a halogen or a sulphonate group (or) X and Y may together form a triple bond between carbons atoms to which there are linked and R may be an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl group;

b) optionally purifying the N-alkylated ester of formula (IV);
c) hydrolysis of the N-alkylated ester of formula (IV) of step a) or step b) to corresponding N-alkylated acid of formula (IVa);

d) purifying the N-alkylated acid of formula (IVa) through formation of its addition salt of formula (VI), wherein B is a base;

e) converting the addition salt of formula (IV) or N-alkylated acid of formula (IVa) to Selinexor of formula (I), wherein Z may be hydrogen or a protecting group.
f) optionally, removing the protecting group to obtain Selinexor.

The individual steps of the process are described herein below.
Starting materials, triazole compound of formula (II) and ester compound of formula (III) are either commercially available or may be prepared by the procedures known in art or the procedures described and exemplified in present application.
The starting materials can be purified by techniques known in art like column chromatography, fractional distillation, acid-base treatment, slurring or re-crystallization, before using.
In an embodiment, step a) may be carried out by N-alkylation of triazole compound of formula (II) with an ester compound of formula (III) to obtain the N-alkylated ester of formula (IV), wherein X may be hydrogen, Y may be a leaving group such as a halogen or a sulphonate group (or) X and Y may together form a triple bond between carbons atoms to which there are linked and R may be an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl group.

In an embodiment, N-alkylation of triazole compound of formula (II) may be carried out in the presence of a base. Base may be selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), 1,4-diazabicyclo(2.2.2)octane (DABCO), N,N-dicyclohexylmethylamine, 2,6-di-tert-butyl-4-methylpyridine, quinuclidine, 1,2,2,6,6-pentamethylpiperidine (PMP), 7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD), triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, triethylamine, diisopropyl amine or the like.
In an embodiment, N-alkylation of triazole compound of formula (II) may be carried out in the presence of a suitable solvent. Suitable solvent may include, but not limited to ether solvent such as tetrahydrofuran, dioxane; ketone solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone; ester solvent such as ethyl acetate, isopropyl acetate; alcohol solvent such as methanol, ethanol, isopropyl alcohol, butanol; nitrile solvent such as acetonitrile; halogenated hydrocarbons such as dichloromethane; water and the like.
In an embodiment, N-alkylation of triazole compound of formula (II) may be carried out at suitable temperature at about -30°C to reflux temperature of the solvent used. In preferred embodiment, N-alkylation may be carried out at about -0°C to 50°C.
In an embodiment, N-alkylation of triazole compound of formula (II) may be carried out for sufficient time to complete alkylation of triazole compound. In preferred embodiment, N-alkylation may be carried out for atleast 30 minutes or more.
In an embodiment, step b) of this aspect may be carried out by optionally purifying N-alkylated ester of formula (IV) before proceeding to next step. In an embodiment N-alkylated ester may be purified by methods known in the art such as chromatographic separations, fractional distillation, acid - base treatment, recrystallization, slurry or procedures described or exemplified in the present application.
In an embodiment, N-alkylated ester of formula (IV) may be purified by chromatographic separations, recrystallizing or slurrying in a solvent or mixture of solvents.
In an embodiment, N-alkylated ester of formula (IV) may be purified by recrystallizing or slurrying in a solvent or mixture of solvents. In embodiments, the recrystallization or slurrying of N-alkylated ester may be repeated to attain desired quality of the product. In an embodiment, the recrystallization or slurrying of N-alkylated ester may be repeated to obtain substantially single isomer i.e., cis-isomer of N-alkylated ester of formula (IV). It is evident from the exemplification of the present application, that the unwanted trans-isomer of the N-alkylated ester of formula (IV) has been well controlled with this purification method.
In an embodiment, N-alkylated ester of formula (IV) may be purified by slurrying it in a solvent or mixture of solvents at suitable temperature and for sufficient time to obtain the product with desired quality. In an embodiment, N-alkylated ester of formula (IV) may be slurried in the solvent at temperature of about -50°C to about 0°C. In an embodiment, N-alkylated ester of formula (IV) may be slurried in the solvent for atleast 10 minutes or more.
Solvent may include, but not limited to hydrocarbons such as hexane, cyclohexane, pentane, cyclopentane, toluene, xylene, or the like.
In a preferred embodiment, N-alkylated ester of formula (IV) may be purified by slurrying in a solvent system comprising atleast one hydrocarbon solvent such as hexane, heptane or the like.
N-alkylated ester of formula (IV) or its addition salt recovered by the processes of application can be subjected to drying at suitable temperatures, such as about 30°-100°C and suitable pressures, using drying equipment known in the art, such as air dryer, vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying can be carried out at temperatures and times sufficient to achieve desired quality of product.
Step c) of this aspect may be carried out by hydrolyzing the N-alkylated ester of formula (IV) to corresponding N-alkylated acid of formula (IVa) under suitable conditions. Hydrolysis of N-alkylated ester may be carried out according any method known in the art for ester hydrolysis or by following procedures described or exemplified in the present application.

In an embodiment, N-alkylated ester may be hydrolyzed under acidic, basic or neutral conditions to obtain N-alkylated acid of formula (IVa). In preferred embodiment, the N-alkylated ester may be hydrolyzed using suitable acid or base.
Suitable acid may be selected from group comprising of inorganic or organic acid such as concentrated or diluted Hydrochloric acid, Sulphuric acid, phosphoric acid, formic acid, acetic acid, alkyl sulphonic acids or the like.
Suitable base may be selected from group comprising of hydroxides, carbonates, bicarbonates or alkoxides of alkali or alkali earth metal such as Lithium, Sodium, Potassium, Cesium, Calcium, Magnesium or the like.
Step d) of this aspect may be carried out by purification of N-alkylated acid of formula (IVa) through the formation of its addition salt of formula (VI)
Alternatively, N-alkylated acid may be purified by chromatographic separations, recrystallizing or slurrying in a solvent or mixture of solvents.
Inventors of the present application have identified, that the purity of N-alkylated acid of formula (IVa) was surprisingly enhanced to significant extent through acid-base treatment such as through formation of its salt and it is evidential as per the exemplification of the present application.
In an embodiment, N-alkylated acid of formula (IVa) may be purified comprising the steps of
I. converting the N-alkylated acid of formula (IVa) to its addition salt of N-alkylated acid of formula (VI), wherein B is a base.
II. neutralizing this addition salt to obtain pure N-alkylated acid of formula IVa;

In an embodiment, N-alkylated acid of formula (IVa) may be treated with a base to obtain an addition salt thereof under suitable conditions. Base may be a inorganic or organic base selected from the group comprising of hydroxides, carbonates, alkoxides, bicarbonates of alkali metals, alkaline earth metals, non-toxic metals, ammonium for example the sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium trimethylammonium, triethanolammonium, Pyridinium, substituted Pyridinium salts; mono-, di- and trisubstituted amines such as, Dicyclohexylamine(DCHA), tert-Butyl amine, diethyl amine, dibutylamine, Morpholine, 3-diemthylamino-1-propylamine, diisopropyl amine, N-tert-butylbenzylamine, N-benzylmethylamine, a-Methyl benzyl amine, (s)-a-methyl benzylamine, benzyl amine, dibenzylamine, cyclohexyl amine, tert-octylamine. Tris(hydroxymethyl)aminomethane, 2-Amino-2-methyl-1 - propanol, 2-Amino-2-methyl-1,3-propanediol, 2,2'-(Propane-1,3-diyldiimino)bis[2-(hydroxymethyl) propane-1,3-diol], 2-[Bis(2-hydroxyethyl)imino]-2-(hydroxymethyl)-1,3-propane diol, 2-Aminoethanol, (2R,3R,4R,5S)-6-Methylaminohexane-1, 2,3,4, 5-pentol, 2,2',2"-Nitrilotriethanol or the like.
In an embodiment, N-alkylated acid may be treated with the base in the presence of a solvent or mixture of solvents. In an embodiment, the mixture of N-alkylated acid of formula (IVa) and the solvent may be either homogenous or heterogeneous. Solvent that are disclosed in any aspect of the present application may be used for the purification of N-alkylated acid of formula (IVa).
In an embodiment, N-alkylated acid of formula (IVa) may be treated with the base for sufficient time and suitable temperature to complete formation of its addition salt.
In an embodiment, base may be treated with N-alkylated acid by adding the base for sufficient time either gradually in a single lot or periodically in multiple lots. Base may be treated directly or in diluted state in a solvent.
In an embodiment, base may be treated with N-alkylated acid at suitable temperature of about 0°C to reflux temperature of the reaction mixture. In preferred embodiment, base treatment may be carried out at 0°C to 60°C.
In an embodiment, the addition salt of N-alkylated acid of formula (VI) may be isolated by any methods known in the art or by following the procedures described or exemplified in the present application. In embodiments, the addition salt of N-alkylated acid may be isolated by cooling crystallization, anti-solvent addition or evaporation of the solvent or combinations thereof.
In an embodiment, the addition salt of N-alkylated acid may be neutralized before proceeding to next step (or) the addition salt of N-alkylated acid of formula (VI) may be directly used in the next step for the preparation of Selinexor of formula I.
In an embodiment, the addition salt of N-alkylated acid of formula (VI) may be neutralized with an acid to obtain pure N-alkylated acid. Acid may be selected from the group comprising of inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, Perchloric acid, formic acid, acetic acid, alkyl or aryl sulphonic acid or the like. Acid may be used in concentrated or in diluted state such as aqueous or alcoholic solutions.
In an embodiment, addition salt of N-alkylated acid of formula (VI) may be treated with the acid optionally in the presence of a solvent or mixture of solvents. In an embodiment, the mixture of addition salt of N-alkylated acid of formula (VI) and the solvent may be either homogenous or heterogeneous.
In an embodiment, addition salt of N-alkylated acid of formula (VI) may be treated with the acid for sufficient time and suitable temperature to complete liberation of pure N-alkylated acid of formula (IVa).
In an embodiment, acid may be treated with addition salt of formula (VI) by adding the acid for sufficient time either gradually in a single lot or periodically in multiple lots.
In an embodiment, acid may be treated with addition salt at suitable temperature of about 0°C to reflux temperature of the reaction mixture. In preferred embodiment, base treatment may be carried out at 0°C to 60°C.
In an embodiment, the N-alkylated acid of formula (IVa) may be isolated by any methods known in the art or by following the procedures described or exemplified in the present application. In embodiments, N-alkylated acid may be isolated by cooling crystallization, anti-solvent addition or evaporation of the solvent or combinations thereof.
In an embodiment, the N-alkylated acid of formula (IVa) or its addition salt of formula (VI) may be recovered employing any of the techniques known to a person skilled in art. Techniques for the recovering pure N-alkylate acid may include, but not limited to: decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing with a solvent.
The N-alkylate acid of formula (IVa) or its addition salt of formula (VI) recovered by the processes of application can be subjected to drying at suitable temperatures, such as about 30°-100°C and suitable pressures, using drying equipment known in the art, such as air dryer, vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying can be carried out at temperatures and times sufficient to achieve desired quality of product.
Step e) of this aspect may be carried out by converting the addition salt of formula (IV) or N-alkylated acid of formula (IVa) to Selinexor of formula (I).
In an embodiment, N-alkylated acid of formula (IVa) may be reacted with 2-Hydrazinopyrazine derivative of formula V, wherein Z may be hydrogen or protecting group.

In an embodiment, step e) of this aspect may be carried out by reacting the addition salt thereof of formula (VI) with 2-Hydrazinopyrazine derivative of formula V optionally in the presence of a base according any methods known in the art or procedures described or exemplified in the present application.
In an embodiment, step e) of this aspect may be carried out by reacting N-alkylated acid of formula (IVa) with 2-Hydrazinopyrazine derivative of formula V, wherein the N-alkylated acid is either in isolated state or generated insitu without its isolation. In embodiments, the N-alkylated acid of formula (IVa) is generated insitu either by hydrolysis of corresponding ester of formula (IV) or by neutralization of corresponding addition salt of formula (VI). In embodiments, hydrolysis of the ester or neutralization of addition salt may be carried out according to the methods known in the art or procedures described or exemplified in the present application.
In an embodiment, N-alkylated acid of formula (IVa) may be reacted with 2-Hydrazinopyrazine derivative of formula V in the presence of a catalyst.
Catalyst that may be used for the reaction of N-alkylated ester of formula (IV) or N-alkylated acid of formula (IVa) with 2-Hydrazinopyrazine derivative of formula V may be selected from the group comprising of pyridine, dimethyl aminopyridine, , triethyl amine, diisopropyl ethyl amine, metal alkoxides such as sodiummethoxide, organoaluminium reagents such as trialkyl or triaryl aluminium, 1-hydroxy benzotriazole (HOBT), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) OR ITS HCl salt, Carbonyldiimidazole (CDI), dicylohexylcarbodiimide, Propane Phosphonic Acid Anhydride (T3P),HOBT + EDC, dicyclohexylcarbodiimide(DCC or the like.
Step f) of this aspect may be carried out by optionally removing the protecting the group to obtain Selinexor of formula (I), wherein Z may be hydrogen. Removal of protecting group may be carried out according to methods known in the art for deprotection of nitrogen or according to the procedures described or exemplified in the present application.
Selinexor obtained according to the present aspect may be optionally purified by according to the suitable methods known in the art which include, but not limited to chromatographic separations, recrystallizing or slurrying in a solvent or mixture of solvents, acid-base treatment i.e., through salt formation or the like. Suitable acid that may be used is selected from any of the acceptable organic or inorganic acids known in the art and suitable for the formation of acid-addition salt or any acid disclosed in any aspect of the instant application.
Selinexor of formula (I) or its addition salt recovered by the processes of application can be subjected to drying at suitable temperatures, such as about 30°-100°C and suitable pressures, using drying equipment known in the art, such as air dryer, vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying can be carried out at temperatures and times sufficient to achieve desired quality of product.

In another aspect, the present application provides a process for the preparation of Selinexor or a salt thereof, comprising the steps of:
a) N-alkylation of triazole compound of formula (II) to obtain the N-alkylated ester of formula (IV), wherein X may be hydrogen and Y may be a leaving group such as a halogen or a sulphonate group (or) X and Y together form a triple bond between carbons atoms to which there are linked, R may be an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl group;

b) optionally purifying the N-alkylated ester of formula (IV) of step a);
c) reacting the N-alkylated ester of step a) or step b) with 2-Hydrazinopyrazine derivative of formula V, wherein Z may be hydrogen or protecting group to obtain Selinexor of formula I.

d) Optionally, removing the protecting group to obtain Selinexor.
e) purifying the Selinexor obtained in step c) or d).

Starting materials, triazole compound of formula (II) and ester compound of formula (III) are either commercially available or may be prepared by the procedures known in art or the procedures described and exemplified in present application.
The starting materials can be purified by techniques known in art like column chromatography, fractional distillation, acid-base treatment, slurring or re-crystallization, before using.
Process of this aspect is advantageous interms of reduced number of steps for the preparation of Selinexor of formula (I). The process of this aspect avoids the step of hydrolysis of N-alkylated ester of formula (IV) and converting it directly to Selinexor of formula (I) as against the process known in the prior art.
Step a) of this aspect may be carried out by N-alkylation of triazole compound of formula (II) to obtain the N-alkylated ester of formula (IV). N-alkylation may be carried out according to any of the procedures described in any of the previous aspect or exemplified in the present application.
In embodiments, N-alkylated ester of formula (IV) may be purified using methods such as recrystallization or slurrying in a suitable solvent or mixture of solvents, chromatographic separation or acid-base treatment i.e., through salt formation and neutralization.
Step b) of this aspect may be carried out by optionally purifying the N-alkylated ester of formula (IV) according to any of the methods known in the art or procedures as described in previous aspect or exemplified in the present application. In an embodiment, purification of N-alkylated ester of formula (IV) may be carried out through the formation of its addition salt according to methods described in any aspect of the instant application.
In an alternate embodiment, the N-alkylated ester of formula (IV) may be optionally purified by slurrying in a solvent or mixture of solvents at suitable temperature and sufficient time. Solvent that may be used include, but not limited to an alcohol such as methanol, ethanol, isopropyl alcohol; an ester such as ethyl acetate, isopropyl acetate; an ketone such as acetone, methyl isobutyl ketone; hydrocarbons such as hexane, cyclohexane, pentane, cyclopentane, toluene, xylene; water or the mixtures thereof.
In an embodiment, N-alkylated ester of formula (IV) may be purified by slurrying in a solvent or mixture of solvents for sufficient time till the desired content of either of the Cis or trans isomer is obtained. In an embodiment, slurrying is carried out for sufficient time to obtain substantially pure Cis-isomer of N-alkylated ester of formula (IV). In an embodiment, N-alkylated ester of formula (IV) may be purified by slurrying at suitable temperature of about -50°C and above.
N-alkylated ester of formula (IV) or its addition salt recovered by the processes of application can be subjected to drying at suitable temperatures, such as about 30°-100°C and suitable pressures, using drying equipment known in the art, such as air dryer, vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying can be carried out at temperatures and times sufficient to achieve desired quality of product.
Step c) of this aspect may be carried out by reacting the N-alkylated ester of formula (IV) with 2-Hydrazinopyrazine derivative of formula V to obtain Selinexor of formula (I), wherein Z may be hydrogen or protecting group.
In an embodiment, N-alkylated ester of formula (IV) may be reacted with 2-Hydrazinopyrazine derivative of formula V, to obtain Selinexor of formula I optionally in the presence of a solvent. Any of the solvents disclosed in any aspect of the instant application may be used.
N-alkylated ester of formula (IV) may be reacted with 2-Hydrazinopyrazine derivative of formula V using any of the methods or conditions known in the art or procedures described or exemplified in this specification.
In an embodiment, N-alkylated ester of formula (IV) may be reacted with 2-Hydrazinopyrazine derivative of formula V by heating the reaction mixture. In an embodiment, the reaction mixture may be heated to about 50°C to reflux temperature of the reaction mixture.
In an embodiment, N-alkylated ester of formula (IV) may be reacted with 2-Hydrazinopyrazine derivative of formula V for sufficient time to complete the formation of Selinexor of formula (I).
In an embodiment, N-alkylated ester of formula (IV) may be reacted with 2-Hydrazinopyrazine derivative of formula V in the presence of a catalyst. Catalyst may be selected from the group comprising of pyridine, dimethyl aminopyridine, , triethyl amine, diisopropyl ethyl amine, metal alkoxides such as sodiummethoxide, organoaluminium reagents such as trialkyl or triaryl aluminium, 1-hydroxy benzotriazole (HOBT), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) OR ITS HCl salt, Carbonyldiimidazole (CDI), dicylohexylcarbodiimide, Propane Phosphonic Acid Anhydride (T3P) or the like.
Step d) of this aspect may be carried out by optionally removing the protecting the group to obtain Selinexor of formula (I), wherein Z may be hydrogen. Removal of protecting group may be carried out according to methods known in the art for deprotection of nitrogen or according to the procedures described or exemplified in the present application.
Step e) of this aspect may be carried out by purifying Selinexor obtained in step c) of d) according to the suitable methods known in the art which include, but not limited to chromatographic separations, recrystallizing or slurrying in a solvent or mixture of solvents, acid-base treatment i.e., through salt formation or the like. Suitable acid that may be used is selected from any of the acceptable organic or inorganic acids known in the art and suitable for the formation of acid-addition salt or any acid disclosed in any aspect of the instant application.
In an embodiment, Selinexor may be purified through the formation of its acid addition salt.
In an embodiment, formation of acid addition salt of Selinexor may be obtained according to the methods known in the art or procedures described or exemplified in the instant application. In embodiments, Selinexor may be combined with a suitable acid optionally in the presence of a solvent or mixture of solvents to provide its acid addition salt.
The acid addition salt of Selinexor may be optionally isolated or converted into free Selinexor insitu without its isolation. In an embodiment, the salt of Selinexor may be combined with a suitable base to obtain free Selinexor.
In alternate embodiment, the salt of Selinexor may be isolated and then neutralized with a base to obtain Selinexor. Selinexor obtained by this method may be substantially pure Cis-isomer of Selinexor with enhanced chemical purity.
Selinexor of formula (I) or its addition salt recovered by the processes of application can be subjected to drying at suitable temperatures, such as about 30°-100°C and suitable pressures, using drying equipment known in the art, such as air dryer, vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying can be carried out at temperatures and times sufficient to achieve desired quality of product.

In another aspect, the present application provides an addition salt of N-alkylated acid of formula VI.
In an embodiment, a addition salt of N-alkylated acid of formula VI may be a salt with a base selected from inorganic or organic base comprising hydroxides, carbonates, alkoxides, bicarbonates of alkali metals, alkaline earth metals, non-toxic metals, ammonium for example sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium trimethylammonium, triethanolammonium, Pyridinium, substituted Pyridinium salts; mono-, di- and trisubstituted amines such as, Dicyclohexylamine(DCHA), tert-Butyl amine, diethyl amine, dibutylamine, Morpholine, 3-diemthylamino-1-propylamine, diisopropyl amine, N-tert-butylbenzylamine, N-benzylmethylamine, a-Methyl benzyl amine, (s)-a-methyl benzylamine, benzyl amine, dibenzylamine, cyclohexyl amine, tert-octylamine. Tris(hydroxymethyl)aminomethane, 2-Amino-2-methyl-1 - propanol, 2-Amino-2-methyl-1,3-propanediol, 2,2'-(Propane-1,3-diyldiimino)bis[2-(hydroxymethyl) propane-1,3-diol], 2-[Bis(2-hydroxyethyl)imino]-2-(hydroxymethyl)-1,3-propane diol, 2-Aminoethanol, (2R,3R,4R,5S)-6-Methylaminohexane-1, 2,3,4, 5-pentol, 2,2',2"-Nitrilotriethanol or the like.

In another aspect, the present application provides a process for the preparation of Selinexor comprising the step of preparing an addition salt of N-alkylated acid of formula VI.
In an embodiment, the process of preparing Selinexor using an addition salt of N-alkylated acid of formula VI obtained according to procedures described or exemplified in any aspect of the present application.
In embodiments, the addition salt of N-alkylated acid may be neutralized to obtain corresponding free acid of formula (IVa) before proceeding to next step (or) the addition salt of N-alkylated acid of formula (VI) may be directly used for the preparation of Selinexor. Neutralization of addition salt of N-alkylated acid may be carried out according to procedures described or exemplified in any aspect of the present application to obtain corresponding free acid of formula (IVa).

In another aspect, the present application provides N-alkylated acid of formula IVa or N-alkylated ester of formula IV having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
In another aspect, the present application provides N-alkylated acid of formula IVa or N-alkylated ester of formula IV with corresponding trans-isomer content of not more than 0.1 % by HPLC or not more than 0.05% by HPLC.

In another aspect, the present application provides a pharmaceutical composition comprising Selinexor obtained according any of the aspects of this application and atleast one pharmaceutically acceptable excipient.
In another aspect, the present application provides Selinexor or its pharmaceutical composition comprising Selinexor having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
In another aspect, the present application provides Selinexor or its pharmaceutical composition comprising trans-isomer of Selinexor or (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid of not more than 0.1% by HPLC or not more than 0.05% by HPLC.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
Definitions
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
The term “solvent” when used in the present application is a solvent that does not react with the reactants or reagent s under conditions that cause the chemical reaction indicated to take place.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol,2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called“aromatic.” Examples of “C5-C8aliphatic or aromatic hydrocarbons” include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.

EXAMPLES
Example-1: Preparation of isopropyl (Z)-3-(3-(3,5-bis(trifluoromethyl) phenyl)-1H-1,2,4-triazol-1-yl)acrylate

3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole (250 g) was dissolved in tetrahydrofuran (2 l) under nitrogen atmosphere at 27°C and cooled to -5°C. 1,4-diazabicyclo[2.2.2]octane (DABCO, 199.5 g) was added to the reaction mixture at -5°C and stirred at the same temperature for 40 minutes. Isopropyl (Z)-3-iodoacrylate (234.8 g in 500 mL of tetrahydrofuran) was added drop wise to the reaction mixture in 1 hour 10 minutes at -5°C and stirred at the same temperature for 2 hours. After the completion of the reaction, the reaction mixture was added to ice cold water (2 l) and separated the organic layer. The aqueous layer was extracted with ethyl acetate (2 x 1 l). The combined organic layer was washed with brine solution (1 l) and dried over sodium sulphate. The dried solution was evaporated completely under vacuum at 40°C to obtain crude product with HPLC purity of 93.53% The crude product was triturated with hexane (700 mL) and stirred for 20 minutes at -30°C and filtered the solid. Trituration of crude product with hexane was repeated for three times and dried under vacuum to obtain the title compound with HPLC purity of 97.46% and trans-isomer content of 0.66%. Yield: 297 g
Example-2: Preparation of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid.

To a mixture of tetrahydrofuran (300 mL) and water (300 mL), Isopropyl (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate (30 g) was added and cooled to 0°C. Lithium hydroxide monohydrate (16.03 g) under cooling condition at 0°C was added to the reaction mixture and stirred the reaction mixture at same temperature for 7 hours. After completion of the reaction, 2 N HCl (180 mL) was added to adjust the pH of the reaction mixture to 2 and extracted it with ethyl acetate (300 mL). Organic layer was dried over sodium sulphate and evaporated under vacuum at 40°C. The crude compound was stirred with hexane (150 mL) and filtered the solid. Dried the compound dried under vacuum at 40°C for 0.5 hour to obtain the title compound with HPLC purity of 97.25% with trans-isomer content of 3 %. Yield: 24 g
Example-3: Purification of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid.
A mixture of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (24 g) and acetone (240 mL) was stirred for complete dissolution at 30°C. Dicyclohexyl amine (15 mL) was added drop wise for 20 minutes under stirring at the same temperature. Acetone (50 mL) was added to the reaction mixture and stirred for 2 hours at 27°C. Filtered the solid and washed with hot acetone (150 mL) and dried in vacuum drier at 30°C for 1hour to obtain the Dicyclohexyl amine salt of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid. To the above salt, dichloromethane (150 mL) and water (100 mL) was added and stirred for complete dissolution at 30°C and adjusted the pH of the solution with 2 N sulphuric acid (100 mL) to 2. Filtered the reaction mixture and washed the product with water (100 mL) and then with hexane (150 mL). The solid was dried under vacuum at 40°C for 0.5 hour to obtain title compound with HPLC purity 99.98% with no detectable content of trans-isomer. Yield: 17 g
Example-4: Preparation of Selinexor

(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (10
g) was combined with a mixture of acetonitrile (100 mL) and ethyl acetate (50 mL) then added the 2-hydrazinylpyrazine (3.76 g) and stirred for 5 min. Reaction mixture was cooled to 0°C and diisopropyl ethyl amine (16.63 ml) and then Propylphosphonic anhydride (T3P, 33.31 mL) was added at 0°C and stirred the reaction mixture for 2.5 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with cold water (100 mL) and extracted the product with ethyl acetate (2 x 150 mL). The combined organic layer was dried over sodium sulphate and evaporated the solvent under vacuum at 40°C to obtain the crude product as yellow syrup. The obtained crude product was combined with dichloromethane (100 mL) and filtered the solid and washed with dichloromethane (2 x 50 mL). The solid was dried under vacuum at 40°C to obtain the title compound with purity by HPLC of 99.86%. Yield: 7 g.
,CLAIMS:1. A process for the preparation of Selinexor, comprising the steps of:
a) N-alkylation of triazole compound of formula (II) to obtain the N-alkylated ester of formula (IV), wherein X may be hydrogen, Y may be a leaving group such as a halogen or a sulphonate group (or) X and Y may together form a triple bond between carbons atoms to which there are linked and R may be an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl group;

b) optionally purifying the N-alkylated ester of formula (IV);
c) hydrolysis of the N-alkylated ester of formula (IV) of step a) or step b) to corresponding N-alkylated acid of formula (IVa);

d) purifying the N-alkylated acid of formula (IVa) through formation of its addition salt of formula (VI), wherein B is a base;

e) converting the addition salt of formula (VI) or N-alkylated acid of formula (IVa) to Selinexor of formula (I), wherein Z may be hydrogen or a protecting group.
f) optionally, removing the protecting group to obtain Selinexor.
2. A process of claim 1, N-alkylation of triazole compound of formula (II) of step a) is carried out in the presence of a base.
3. A process of claim 2, wherein base is selected from the group comprising of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), 1,4-diazabicyclo(2.2.2)octane (DABCO), N,N-dicyclohexylmethylamine, 2,6-di-tert-butyl-4-methylpyridine, quinuclidine, 1,2,2,6,6-pentamethylpiperidine (PMP), 7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD), triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, triethylamine and diisopropyl amine.
4. A process of claim 1, wherein the base B of step d) is an organic base selected from the group comprising of Dicyclohexylamine(DCHA), tert-Butyl amine, diethyl amine, dibutylamine, Morpholine, 3-diemthylamino-1-propylamine, diisopropyl amine, N-tert-butylbenzylamine, N-benzylmethylamine, a-Methyl benzyl amine, (s)-a-methyl benzylamine, benzyl amine, dibenzylamine, cyclohexyl amine, tert-octylamine. Tris(hydroxymethyl)aminomethane, 2-Amino-2-methyl-1 - propanol, 2-Amino-2-methyl-1,3-propanediol,2,2'-(Propane-1,3-diyldiimino)bis[2-(hydroxyl methyl)propane-1,3-diol], 2-[Bis(2-hydroxyethyl)imino]-2-(hydroxymethyl)-1,3-propanediol, 2-Aminoethanol, (2R,3R,4R,5S)-6-Methylaminohexane-1, 2,3,4, 5-pentol, 2,2',2"-Nitrilotriethanol, ammonium trimethylammonium and triethanolammonium.
5. A process for the preparation of Selinexor or a salt thereof, comprising the steps of:
a) N-alkylation of triazole compound of formula (II) to obtain the N-alkylated ester of formula (IV), wherein X may be hydrogen and Y may be a leaving group such as a halogen or a sulphonate group (or) X and Y together form a triple bond between carbons atoms to which there are linked, R may be an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl group;

b) optionally purifying the N-alkylated ester of formula (IV) of step a);
c) reacting the N-alkylated ester of step a) or step b) with 2-Hydrazinopyrazine derivative of formula V, wherein Z may be hydrogen or protecting group to obtain Selinexor of formula I.

d) Optionally, removing the protecting group to obtain Selinexor.
e) purifying the Selinexor obtained in step c) or d).
6. An addition salt of N-alkylated acid of formula VI.
7. Addition salt of claim 6, wherein N-alkylated acid of formula VI forms a salt with a base.
8. Addition salt of claim 7, wherein the base is selected from the group comprising of Dicyclohexylamine(DCHA), tert-Butyl amine, diethyl amine, dibutylamine, Morpholine, 3-diemthylamino-1-propylamine, diisopropyl amine, N-tert-butylbenzylamine, N-benzylmethylamine, a-Methyl benzyl amine, (s)-a-methyl benzylamine, benzyl amine, dibenzylamine, cyclohexyl amine, tert-octylamine. Tris(hydroxymethyl)aminomethane, 2-Amino-2-methyl-1 - propanol, 2-Amino-2-methyl-1,3-propanediol, 2,2'-(Propane-1,3-diyldiimino)bis[2-(hydroxymethyl) propane-1,3-diol], 2-[Bis(2-hydroxyethyl)imino]-2-(hydroxymethyl)-1,3-propane diol, 2-Aminoethanol and (2R,3R,4R,5S)-6-Methylaminohexane-1, 2,3,4, 5-pentol, 2,2',2"-Nitrilotriethanol.

9. A process for the preparation of Selinexor comprising the step of preparing an addition salt of N-alkylated acid of formula VI.
10. A process of claim 9, further comprising the step of neutralizing addition salt of N-alkylated acid to obtain corresponding free acid of formula (IVa).