Claims:WE CLAIM:
1. A novel process for the preparation of Selinexor of Formula-(I),

Formula-(I)
comprising the steps of:
a) reacting the compound of Formula-(II);

Formula-(II)
with Sodium hydrosulfide hydrate in the presence of metal halides in a solvent to produce compound of Formula-(III).

Formula-(III)
b) reacting the compound of Formula-(III) with dimethylformamide dimethyl acetal or diethyl acetal in a suitable solvent to produce compound of Formula-(IX);

Formula-(IX)
c) reacting the compound of Formula-(IX) in presence of hydrazine hydrate and an acid in a suitable solvent to produce compound of Formula-(IV);

Formula-(IV)
d) reacting the compound of Formula-(IV) with compound of Formula-(X)

Formula-(X)
in the presence of catalyst and a base in a suitable solvent to produce compound of Formula-(XI)

Formula-(XI)
e) hydrolysing the compound of Formula-(XI) in the presence of a base and a suitable solvent to produce compound of Formula-(VII)

Formula-(VII)
f) reacting the compound of Formula (VII) with 2-Hydrazinopyrazine in the presence of coupling agent and an acid in a suitable solvent to produce Selinexor of Formula (I).

2. The process as claimed in claim 1, wherein the metal halides used in step-a) is selected from Magnesium chloride (MgCl2) or Magnesium chloride hexahydrate; and the solvent used in step-a), Step-b) and Step-c) is selected from dichloromethane, dimethylformamide, dimethylsulfoxide, acetonitrile or mixture thereof or ether/cyclic ether containing solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane, and acid used in Step c) is selected from Acetic acid, trifluoroacetic acid, hydrochloric acid, para-toluenesulfonic acid, trifluoromethanesulphonic acid, methanesulphonic acid and mixtures thereof.

3. The process as claimed in claim 1, wherein the catalyst used in step-d is selected from 1,4-diazabicyclo[2.2.2]octane (DABCO) 1,8-diazabicyclo-(5.4.0)undecene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN); and the solvent used in step d) is ether containing solvents such as 1,4-dioxane, tetrahydrofuran, cyclopentyl methyl ether (CPME) and mixtures thereof, base used in step-d is selected from diisopropylethylamine (DIPEA), triethylamine, diisopropylamine, triisopropylamine and mixtures thereof.

4. The process as claimed in claim 1, wherein the base used in step e) is selected from Lithium hydroxide, sodium hydroxide, and potassium hydroxide, metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate and mixtures thereof; and solvent used in step e) is ether solvent such as 1,4-dioxane, tetrahydrofuran, cyclopentyl methyl ether (CPME) and mixtures thereof.

5. The process as claimed in claim 1, wherein the coupling agent used in step f) is selected from 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCHCl), N,N-dicyclohexylcarbodiimide (DCC), N,N-diisopropyl- carbodiimide and 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo- [4,5-b]pyridinium-3-oxide-hexafluorophosphate (HATU), and the solvent used in step f) is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or polar aprotic solvents such as dimethyl formamide, acetonitrile, or ether containing solvents such as tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether and mixtures thereof.
6. Novel intermediate compounds of Formula-(XIII) and Formula-(X).

Formula-(XIII)

Formula-(X).

7. A novel process for the preparation of intermediate compound of Formula (X), comprising the steps of:
a) reacting Propiolic Acid of Formula-(XII);

Formula-(XII)
with 1-Heptanol in the presence of an acid in a suitable solvent to produce compound of Formula-(XIII);

Formula-(XIII)
b) reacting the compound of Formula-(XIII) with metal halide in a solvent to produce compound of Formula-(X).

Formula-(X)

8. The process as claimed in claim 7, wherein an acid used in step a) is selected from p-Toluenesulfonic acid, , pyridinium para toluenesulfonate (PPTS), trifluoromethanesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, sulphuric acid, boron trifluoride diethyl etherate, and solvent used in step-a) is aromatic solvent such as toluene, xylene or chlorinated solvents such as dichloromethane, dichloroethane; and metal halide used in step-b is selected from sodium iodide and sodium bromide, lithium iodide and lithium bromide, and solvent used in step b) is acetic acid toluene, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, hexamethylphosphoramide (HMPA).
9. A process for the purification of Selinexor of Formula-(I), comprising the steps of:
a) dissolving crude Selinexor in suitable solvent at 70 to 75oC;
b) adding oxalic acid to the reaction mixture obtained in step-a) and stirring the reaction mass for 2 to 3hrs;
c) cooling the reaction mass to room temperature;
d) separating the Selinexor oxalate compound by filtration;
e) treating the Selinexor oxalate with an aqueous base in a suitable solvent;
f) isolating pure Selinexor of Formula (I).

10. The process as claimed in claim 9, wherein the suitable solvent used in step-a) is selected from aprotic polar solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile, propionitrile, dichloromethane or mixture thereof preferably acetonitrile; carbonyl containing solvents such as acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester containing solvents such as ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof or ether/cyclic ether containing solvents such as tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane solvent.

11. The process as claimed in claim 9, wherein the base used in step e) is an inorganic bases such as ammonium hydroxide, sodium carbonate, potassium carbonate, caesium carbonate, or organic bases such as triethylamine, diisopropylethylamine, diisopropylamine. And the solvent used for step e) is selected from dimethylformamide, dimethylsulfoxide, acetonitrile, propionitrile mixture thereof; or ester containing solvents such as ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or ether/cyclic ether containing solvents such as tetrahydrofuran, 2-methyltetrahydrofuran Etc or 1,4-dioxane.

12. A process for the preparation of N,N′-Dimethylpropyleneurea (DMPU) solvate of Selinexor of Formula (XV), comprising the steps of:
a) dissolving Selinexor in a Dimethylpropylene urea solvent at room temperature,
b) adding DM water to obtained reaction mixture in step-a) and stirring the reaction mass at the same temperature,
c) isolating the Selinexor DMPU solvate from the reaction mixture obtained in step-b).

13. Selinexor oxalate of formula-(XIV).

Formula-(XIV)

14. The compound as claimed in claim 13, wherein the Selinexor oxalate of formula-(XIV) can be used for purification of Selinexor.
, Description:FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of Selinexor of Formula-I.

Formula (I)

BACKGROUND OF THE INVENTION
Selinexor is chemically known as (2Z)‐3‐{3‐[3,5‐Bis(trifluoromethyl)phenyl]‐1H‐1,2,4‐triazol‐1‐yl}‐N'‐(pyrazin‐2‐yl)prop‐2-¬enehydrazide of Formula (I).
Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export/SINE.TM. 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 60 mg+dexamethasone or at 100 mg+dexamethasone.
US 8999996 discloses a process for the preparation of Selinexor of Formula (I) by the reaction of 3,5-bis(trifluoromethyl)benzonitrile of Formula (II) with Sodium hydrosulfide in the presence of magnesium chloride in DMF solvent to produce 3,5-bis(trifluoromethyl)benzothioamide of formula (III) which is treated with hydrazine hydrate and formic acid in DMF solvent to produce 3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole of Formula (IV). Further, the compound of Formula (IV) is reacted with (Z)-isopropyl-3-iodoacrylate of Formula-(V) in the presence of DABCO in DMF solvent to produce a compound of Formula (VI), which further undergoes hydrolysis in the presence of LiOH in THF solvent to produce (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid of Formula-(VII). Compound of formula-(VII) thus obtained is further reacted with 2-Hydrazinopyrazine in the presence of propanephosphonic acid anhydride (T3P) and DIPEA in DCM and Ethyl acetate solvents followed by purification using preparative TLC to produce Selinexor of Formula-(I).
The synthetic procedure is illustrated in Scheme-I as below:

US 8999996 also discloses a process for the preparation of compound of formula-(V), which is separately prepared by the esterification of propiolic acid with isopropyl alcohol in the presence of borontrifluoride diethyletherate to afford 1-Methylethyl 2-propynoate of formula-(VIII), followed by the iodination of compound of formula-(VIII) with sodium iodide facilitated by acetic acid.
The synthetic procedure is illustrated in Scheme-Ia as below:

The prior art processes suffer from the following disadvantages:
1. Conversion of compound of formula-(III) to compound of formula-(IV) (1,2,4-triazole formation) is sluggish even at 90 °C leaving significant amount of starting material (thiobenzamide) unreacted affecting both yield and purity of compound of formula-(IV). Hence, activation of thiobanzamide is desirable in order to drive the reaction to completion to isolate pure compound of formula-(IV) in high yields.
2. Choice of isopropyl functionality in compound of formula-(VIII) is not favourable because of its low boiling point and hence its manufacture on an industrial scale is not feasible. Hence, replacement of isopropyl group with a higher alkyl chain is desirable so as to manufacture it conveniently.
WO 2020223678 A1 discloses a process for the preparation of Selinexor of Formula (I) by the reaction of compound of Formula (IV) with (Z)-isopropyl 3-iodoacrylate of Formula-(V) in the presence of DABCO and DIPEA in 2-MeTHF solvent to produce compound of Formula (VI), which further undergoes in-situ hydrolysis in the presence of KOH in isopropyl alcohol to produce (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid of Formula-(VII). Compound of formula-(VII) thus obtained is further reacted with 2-Hydrazinopyrazine in the presence of propanephosphonic acid anhydride (T3P) and DIPEA in 2-MeTHF solvent to produce Selinexor of Formula-(I).
The synthetic procedure is illustrated in Scheme-II as below:

Disadvantage of the above prior art processes is a compatible solvent may be identified which can effect both conversions to get compound of formula-(VI) and formula-(VII) respectively rather than choosing two different solvents such as 2-methyltetrahydrofuran and isopropyl alcohol.

US 8513230 discloses a process for the preparation of intermediate compound of formula-(VI) by the reaction of 3,5-bis(trifluoromethyl)benzonitrile of Formula (II) with Sodium hydrosulfide in the presence of magnesium chloride in DMF solvent to produce 3,5-bis(trifluoromethyl)benzothioamide of formula (III) in the presence of Hydrazine hydrate and formic acid in DMF solvent to produce 3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole of Formula (IV). Further, the compound of Formula (IV) is treated with Isopropyl propiolate of Formula-(VIII) in the presence of Triethylamine in DCM solvent to produce compound of Formula (VI).
The synthetic procedure is illustrated in Scheme-III as below:

Disadvantage of the above the prior art processes is conversion of compound of formula-(IV) to compound of formula-(VI) employing isopropyl propiolate afforded disappointingly poor yields (22.26%).

Hence, there exists a need to have simple, easy to handle and cost-effective process for the preparation of Selinexor (I) with high chemical purity and higher yields.
US 10519139 discloses Crystalline Form-A, Form-B, Form-C and Form-D (Acetonitrile solvate) of Selinexor.
US 10993943 discloses Crystalline Forms T1 to T7 of Selinexor.
US 11034675 discloses crystalline Form-Alpha, Form-Beta, Form-Gamma, Form-Delta, Form-Epsilon, Form-Zeta, Form-Eta, Form-Theta, Form-lota, Form-Kappa, Form-Lambda, Form-Mu, Form-Nu, Form-Xi and amorphous form of Selinexor.
WO 2020191140 A1 discloses Selinexor co-crystal and its preparation.
EP 3808742 A1 discloses an anhydrous and non-solvated crystalline form of Selinexor.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple and cost effective process for the preparation of Selinexor of Formula (I) with high purity and good yield on a commercial scale.

SUMMARY OF THE INVENTION
The present invention provides a novel process for the preparation of Selinexor of Formula (I), comprising the steps of:

Formula (I)

a) reacting a compound of Formula (II);

Formula (II)
with Sodium hydrosulfide hydrate in the presence of metal halides in a solvent to produce compound of Formula (III).

Formula (III)
b) reacting the compound of Formula (III) with dimethylformamide dimethyl acetal or diethyl acetal in a suitable solvent to produce compound of Formula (IX);

Formula (IX)
c) reacting the compound of Formula (IX) in presence of a hydrazine hydrate and an acid in a suitable solvent to produce compound of Formula (IV);

Formula (IV)
d) reacting the compound of Formula (IV) with compound of Formula (X)

Formula (X)
in the presence of catalyst and a base in a suitable solvent to produce compound of Formula (XI)

Formula (XI)
e) hydrolysing the compound of Formula (XI) in the presence of a base and a suitable solvent to produce compound of Formula (VII)

Formula (VII)
f) reacting the compound of Formula (VII) with 2-Hydrazinopyrazine in the presence of coupling reagent in a suitable solvent to produce Selinexor of Formula (I).
Another aspect of present invention is that it provides a process for the preparation of intermediate compound of Formula (X), comprising the steps of:
a) reacting propiolic acid of Formula (XII)

Formula (XII)
with 1-Heptanol in the presence of an acid in a suitable solvent to produce compound of Formula (XIII).

Formula (XIII)
b) reacting the compound of Formula (XIII) with metal halide in a solvent to produce compound of Formula (X).
Another aspect of present invention is that it provides a process for the purification of Selinexor of Formula (I), comprising the steps of:
a) dissolving crude Selinexor in a suitable solvent at 70-75 oC.
b) adding oxalic acid to the reaction mixture obtained in step-a) and stirring the reaction mass for 2 to 3hrs.
c) cooling the reaction mass at room temperature,
d) separating the Selinexor oxalate compound by filtration;
e) treating the Selinexor oxalate with an aqueous base in a suitable solvent;
f) isolating pure Selinexor of Formula (I).
Another aspect of present invention is that it provides a process for the preparation of Dimethylpropylene urea (DMPU) solvate of Selinexor of Formula (XV), comprising the steps of:
a) dissolving Selinexor in a Dimethylpropylene urea solvent at room temperature;
b) adding DM water to obtained reaction mixture in step-a) and stirring the reaction mass at the same temperature.
c) isolating the Selinexor DMPU solvate from the reaction mixture obtained in step-b).

Description of the drawings:
Figure 1: Illustrates the XRPD diagram of crystalline Form-N1 of Selinexor oxalate of Formula-(XIV).;
Figure 2: Illustrates the DSC chart of crystalline Form-N1 of Selinexor oxalate of Formula-(XIV);
Figure 3: Illustrates the XRPD diagram of crystalline Form-N2 of Selinexor Dimethylpropylene urea solvate of Formula-(XV);
Figure 4: Illustrates the DSC chart of crystalline Form-N2 of Selinexor Dimethylpropylene urea solvate of Formula-(XV).

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel process for the preparation of Selinexor of Formula (I), comprising the steps of:
a) reacting a compound of Formula (II) with Sodium hydrosulfide hydrate in the presence of metal halides in a solvent to produce compound of Formula (III);
b) reacting the compound of Formula (III) with dimethylformamide dimethyl acetal or diethyl acetal in a suitable solvent to produce compound of Formula (IX);
c) reacting the compound of Formula (IX) in presence of a hydrazine hydrate and an acid in a suitable solvent to produce compound of Formula (IV);
d) reacting the compound of Formula (IV) with compound of Formula (X) in
the presence of catalyst and a base in a suitable solvent to produce
compound of Formula (XI);
e) hydrolysing the compound of Formula (XI) in the presence of a base and a suitable solvent to produce compound of Formula (VII)
f) reacting the compound of Formula (VII) with 2-Hydrazinopyrazine in the presence of coupling reagent in a suitable solvent to produce Selinexor of Formula (I).
The metal halides used in step a) is selected from Magnesium Chloride (MgCl2), Magnesium chloride hexahydrate or mixtures thereof.
The solvent used in step a) is an organic solvent, for example an aprotic polar solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane/dichloroethane or mixtures thereof; ether/cyclic ether containing solvents such as tetrahydrofuran, 2-methyltetrahydrofuran Etc or 1,4-dioxane.
The reaction may be performed usually from 0 °C to a boiling point of used solvent for 30 min to 48 hours and then compound of formula (III) can be obtained by a usual procedure. The obtained compound (III) can be used in the next reaction directly without isolation.
The solvent used in step b) is an organic solvent, for example an aprotic polar solvent comprises dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane/dichloroethane or mixtures thereof preferably dimethylformamide; or ether/cyclic ether containing solvents such as tetrahydrofuran, 2-methyltetrahydrofuran Etc or 1,4-dioxane.
The reaction may be performed from 0 °C to 60 °C for 30 min to 48 hours and then compound of formula (IX) can be obtained by a usual procedure.
An acid used in Step c) is selected from Acetic acid, trifluoroacetic acid, hydrochloric acid, para-toluenesulfonic acid, trifluoromethanesulphonic acid, methanesulphonic acid and mixtures thereof.
Step c) can be performed in a suitable solvent which may be selected from aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof preferably dimethylformamide; alcohol contain solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof; or ether/cyclic ether containing solvents such as tetrahydrofuran, 2-methyltetrahydrofuran Etc or 1,4-dioxane.
The reaction may be performed from -30 °C to 60 °C for 30 min to 48 hours and then compound of formula (IV) can be obtained by a usual procedure.
The catalyst used in step d) is selected from 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo(5.4.0)undecene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN).
The base used in Step d) is selected from Diisopropylethylamine (DIPEA), triethylamine, diisopropylamine, triisopropylamine and mixtures thereof.
Solvent used in step d) is selected from organic solvent, for example ether containing solvents such as 1,4-dioxane, tetrahydrofuran, cyclopentyl methyl ether (CPME) and mixtures thereof.
The reaction may be performed from -30 °C to 60 °C for 30 min to 48 hours and then compound of formula (XI) can be obtained by a usual procedure. The obtained compound (III) can be used in the next reaction directly without isolation.
The base used in step e) is selected from Lithium hydroxide (LiOH), sodium hydroxide, and potassium hydroxide, metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate and mixtures thereof.
Solvent used in step e) is selected from organic solvent, for example ether solvent comprising 1,4-dioxane, tetrahydrofuran, cyclopentyl methyl ether (CPME) and mixtures thereof.
The reaction may be performed usually from 0 °C to a boiling point of used solvent for 30 min to 48 hours and then compound of formula (VII) can be obtained by a usual procedure. The obtained compound (VII) can be used in the next reaction directly without isolation.
The coupling reagent used in step-f) is selected from 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl), N,N-dicyclohexylcarbodiimide (DCC), N,N-diisopropylcarbodiimide, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3 oxide hexafluorophosphate (HATU).
Step f) is performed in a suitable solvent which may be selected from alcohol containing solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or polar aprotic solvents such as dimethyl formamide, acetonitrile, or ether containing solvents such as tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether and mixtures thereof.
The reaction may be performed usually from 0 °C to a boiling point of used solvent for 30 min to 48 hours and then compound of formula (I) can be obtained by a usual procedure.
Another aspect of present invention is that it provides a process for the preparation of intermediate compound of Formula (X), comprising the steps of:
a) reacting propiolic acid of Formula (XII) with 1-Heptanol in the presence of an acid in a suitable solvent to produce compound of Formula (XIII).
b) reacting the compound of Formula (XIII) with metal halide in a solvent to produce compound of Formula (X).
An Acid used in Step-a) is selected from p-Toluenesulfonic acid, pyridinium para toluenesulfonate (PPTS), trifluoromethanesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, sulphuric acid, boron trifluoride diethyl etherate.
Solvent used in step a) is selected from organic solvent, for example aromatic solvents comprising Toluene, Xylene or chlorinated solvents such as dichloromethane, dichloroethane.
The reaction may be performed usually from 0 °C to a boiling point of used solvent for 30 min to 5 hours and then compound of formula (XIII) can be obtained by a usual procedure. The obtained compound (XIII) can be used in the next reaction directly without isolation.
Metal halide used in step b) is selected from Sodium iodide (NaI) and sodium bromide, lithium iodide and lithium bromide.
Solvent used in step-b) is selected from acetic acid, toluene, chloroform, tetrahydrofuran, 1,4-dioxane, dimethylformamide, hexamethylphosphoramide (HMPA).
The reaction may be performed usually from 0 °C to a boiling point of used solvent for 30 min to 48 hours and then compound of formula (X) can be obtained by a usual procedure. The obtained compound (X) can be used in the next reaction directly without isolation.

Another aspect of present invention is that it provides a process for the purification of Selinexor of Formula (I), comprising the steps of:
a) dissolving crude Selinexor in suitable solvent at 70 to 75 oC;
b) adding oxalic acid to the reaction mixture obtained in step-a) and stirring the reaction mass for 2 to 3hrs.
c) cooling the reaction mass to room temperature.
d) isolating Selinexor oxalate compound by filtration.
e) treating the Selinexor oxalate with an aqueous base in a suitable solvent;
f) isolating pure Selinexor of Formula (I).
The solvent used in step a) is selected from aprotic polar solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile, propionitrile, dichloromethane or mixture thereof preferably acetonitrile; carbonyl containing solvents such as acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester containing solvents such as ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof or ether/cyclic ether containing solvents such as tetrahydrofuran, 2-methyltetrahydrofuran Etc or 1,4-dioxane.
The base used in step-e) is selected from inorganic bases such as ammonium hydroxide, sodium carbonate, potassium carbonate, caesium carbonate, or organic bases such as triethylamine, diisopropylethylamine, diisopropylamine Etc.
The solvent used for step-e) is selected from dimethylformamide, dimethylsulfoxide, acetonitrile, propionitrile mixture thereof; or ester containing solvents such as ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or ether/cyclic ether containing solvents such as tetrahydrofuran, 2-methyltetrahydrofuran Etc or 1,4-dioxane.

The crystalline Form of Selinexor oxalate provided by the present invention is characterized in that its X-ray powder diffraction pattern has a 2theta value of 4.41°±0.2°, 8.76°±0.2°, 11.71°±0.2°, 17.58°±0.2°, 18.82°±0.2°, 20.26°±0.2°, 20.75°±0.2°, 22.01°±0.2°,23.22°±0.2°, there is a characteristic peak at 13.16°±0.2°.
Furthermore, the Form of Selinexor oxalate is characterized in that its X-ray powder diffraction pattern is basically the same as that of FIG. 1.
Form-N1 can be characterized by Differential Scanning Calorimetry (DSC) thermogram having endotherm at about 195.84 ±2°C and shown in Figure-2.
Another aspect of present invention is that it provides a process for the preparation of Dimethylpropylene urea (DMPU) solvate of Selinexor of Formula (XV), comprising the steps of:
a) dissolving Selinexor in a N,N′-Dimethylpropyleneurea solvent at room temperature;
b) adding DM water to obtained reaction mixture in step-a) and stirring the reaction mass at the same temperature.
c) isolating the Selinexor DMPU solvate from the reaction mixture obtained in step-b).
Step-a, b and c may be carried out at temperatures ranging from -20 °C to 80 °C to from Selinexor DMPU solvate.

The crystalline Form of Selinexor DMPU solvate provided by the present invention is characterized in that its X-ray powder diffraction pattern has a 2theta value of 6.55±0.2°, 8.87°±0.2°, 10.73°±0.2°, 14.96°±0.2°, 16.31°±0.2°, 16.76°±0.2°, 17.10°±0.2°, 17.79°±0.2°, 18.86°±0.2°, 20.20°±0.2°, 22.30°±0.2°, 23.15°±0.2°, 23.71°±0.2° and 27.35°±0.2°, there is a characteristic peak at 19.68°±0.2°.
Furthermore, the crystalline Form of Selinexor DMPU solvate is characterized in that its X-ray powder diffraction pattern is basically the same as that of FIG. 3.
Further, crystalline Form of Selinexor DMPU solvate can be characterized by Differential Scanning Calorimetry (DSC) thermogram having endotherm at about 136.87 ±2°C and shown in Figure-4.

Advantages of present invention:

1. Improved yields during the conversion of compound of formula-(II) to compound of formula-(IV) (0.9 w/w from compound of formula (II)) are obtained compared to the prior art.
2. Compound of formula-(IV) can be efficiently accessed at temperatures as low as 0-5 °C by suitably activating the compound of formula-(III) as its corresponding thioformamidine derivative (Formula-IX) for 1,2,4-triazole formation.
3. 1,4-dioxane is identified to be the compatible reaction solvent for both N-alkylation of compound of formula-(IV) and for the subsequent heptyl ester hydrolysis of compound of formula-(XI). Consequently, additional isolation at N-alkylation stage can be avoided making the process operationally simple and cost-effective.
4. Purity of Selinexor crude (97.93%) was significantly enhanced to 99.93% via the Selinexor oxalate formation.
5. Incorporation of heptyl group in the compound of formula-(XIII) makes the process of isolation of heptyl propiolate operationally viable (plant feasible process) as it does not evaporate under vacuum during its isolation (because of its high boiling point).

The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.

EXAMPLES:
Example-1: Preparation of 3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole of Formula (IV).
Step-i: Preparation of 3,5-bis(trifluoromethyl)benzothioamide of formula (III).

To a stirred solution of compound of formula-(II) (120 g, 0.50 mol) in DMF (1200 mL, 10 V), charged sodium hydrosulphide hydrate (44.58 g, 0.60 mol) and magnesium chloride hexahydrate (112.2 g, 0.552 mol) at 0-5 °C. The resulting reaction mass was stirred at the same temperature for 30 min. Progress of the reaction was monitored by in-process HPLC analysis. After consumption of compound of formula-(II), reaction mass was used as such for the next reaction without any further isolation of compound of formula-(III).
HPLC Results: Compound of formula-(II): 0.23%
Compound of formula-(III): 98.81%
Step-ii: Preparation of compound of Formula (IX).

After the consumption of compound of formula-(II), reaction mass containing compound of formula-(III) was charged with dimethylformamide dimethylacetal (107.63 g, 0.903 mol) at 0-5 °C for 15 minutes. Subsequently, reaction mass was stirred at the same temperature for 60-90 minutes. Progress of the reaction was monitored by in-process HPLC analysis. After consumption of compound of formula-(III) (Judged by HPLC), the resulting reaction mass was used for the next reaction without any further isolation of compound of formula-(IX).
HPLC Results: Compound of formula-(III): 1.68%
Compound of formula-(IX): 96.14%
Step-iii: Preparation of 3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole of Formula (IV).

After the consumption of compound of formula-(III), reaction mass containing compound of formula-(IX) was sequentially charged with acetic acid (600 mL, 5 V) and hydrazine hydrate (37.66 g, 0.75 mol) at 0-5 °C. Reaction mass was stirred at the same temperature for 120 minutes. Progress of the reaction was monitored by in-process HPLC analysis. After completion of reaction (judged by HPLC), compound of formula-(IV) was precipitated by the addition of DM Water (7.2 Lt). The resulting precipitate was further allowed to stir at 27.5±2.5 °C for 60-90 minutes. The product was filtered, washed with 1200 mL of DM water and dried under vacuum for 20 minutes. 158.64 g of crude thus obtained was charged with 600 mL of toluene and 600 mL of n-heptane for leaching. The resulting mass was heated to 80-85 °C and stirred at the same temperature for 20 minutes. Subsequently, reaction mass was cooled to 25-30 °C and stirred for 120 min. The reaction mass containing solids of compound of formula-(IV) was filtered and washed with 360 mL of n-heptane. Wet sample was dried under vacuum for 5-6 h at 60-65 °C to afford compound of formula-(IV) (101.96 g, 72.29% yield). HPLC Purity: 99.61%; Mass: m/z-280.21 (M-H).
1H NMR (400 MHz, DMSO-d6): bs, 1 H), 8.79 (s, 1 H), bs, 2 H), 8.17 (s, 1 H).
13C NMR(100 MHz, DMSO-d6):
qJ=32.9HzqJ=271.1 Hz).

Example-2: Preparation of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid of Formula-(VII).
Step-i: Preparation of compound of formula (XI).

DABCO (21.55 g, 0.19 mol) and DIPEA (45.53 g, 0.35 mol) were sequentially added to the mixture of 1,4 dioxane (270 mL) and compound of formula-(IV) (90.0 g, 0.32 mol) at 25-30 °C and cooled to 15-20 °C. Subsequently, 1,4-dioxane solution of compound of formula-(X) (104.3 g, 0.35 mol dissolved in 180 mL of 1,4-dioxane) was added to the reaction mass at 15-20 °C. The resulting reaction mass was stirred at the same temperature for 3-4 h. Progress of the reaction was monitored by in-process HPLC analysis. After consumption of compound of formula-(IV) (judged by HPLC), the resulting reaction mass was used for the next reaction without any further isolation of compound of formula-(XI).
HPLC Results: Compound of formula-(IV): 0.05%
Step-ii: Preparation of compound of Formula (VII).

After the consumption of compound of formula-(IV), reaction mass containing compound of formula-(XI) was treated with aqueous lithium hydroxide solution (53.71 g dissolved in 450 mL DM water) at 25-30 °C for 3-4 h. Progress of the reaction was monitored by in-process HPLC analysis. After completion of reaction, reaction mass was acidified by the addition of dilute hydrochloric acid (274 mL, 5 N) until reaction mass attains a pH of 1.5-2.5. The resulting precipitate was stirred for 30 minutes at 27.5±2.5 °C. The resulting precipitate was filtered, washed with 450 mL of DM water and dried under vacuum. 155.50 g of crude thus obtained was charged with 1800 mL of acetonitrile for leaching. The resulting mass was heated to 80-85 °C and stirred at the same temperature for 20 minutes. Subsequently, reaction mass was cooled to 25-30 °C and stirred for 120 min. The reaction mass containing solids of compound of formula-(VII) was filtered and washed with 270 mL of acetonitrile. Wet sample was dried under vacuum for 5-6 h at 60-65 °C to afford compound of formula-(VII) (89.56 g, 79.63% yield).
HPLC Purity: 99.93%
Trans isomer of compound of formula-(VII): 0.04%.
Mass: m/z-352.08 (M+H).
1H NMR (400 MHz, DMSO-d6): bssbssdJHzdJz
13C NMR (100 MHz, DMSO-d6):
qJzqJz

Example-3: Preparation of Selinexor of Formula (I).

2-Hydrazinopyrazine (25.86 g, 0.234 mol) was added to mixture of compound of formula-(VII) (75.0 g, 0.213 mol) and methanol (750 mL, 10 V) at 25-30 °C. The resulting heterogeneous mass was cooled to 0-5 °C. EDC HCl (53.21 g, 0.277 mol) was introduced into the reaction mass at the same temperature and the resulting reaction mass was stirred for 2-3 h at 0-5 °C. Progress of the reaction was monitored by in-process HPLC analysis. After completion of reaction, Selinexor was precipitated by the addition of DM Water (2.25 Lt, 30 V). The resulting precipitate was stirred for 60-90 minutes at 27.5±2.5 °C. The product was filtered, washed with 375 mL of DM water and dried under vacuum. 132.46 g of wet selinexor thus obtained was dried under vacuum at 60-65 °C for 5h. The resulting 85.3 g of crude selinexor was charged with 1125 mL of acetonitrile for leaching. The resulting mass was heated to 70-75 °C and stirred at the same temperature for 20 minutes. Subsequently, reaction mass was cooled to 25-30 °C and stirred for 120 min. The reaction mass containing selinexor solids was filtered and washed with 225 mL of acetonitrile. Wet sample was dried under vacuum for 5-6 h at 60-65 °C to afford selinexor (70.52 g, 74.49% yield) as a cream coloured powder.
HPLC Purity: 99.99%
Trans isomer of Selinexor: Not detected.
Mass m/z-444.11 (M+H)
1H NMR (400 MHz, DMSO-d6):
sssbssd, 1H, J= 1.2 Hz), 8.07-8.08 (m, 1 H), 7.931-7.938 (d, 1H, 2.8 Hz), 7.33-7.36 (d, 1 H, 10.4 Hz), 6.08-6.10 (d, 1 H, 10.8 Hz).
13C NMR (100 MHz, DMSO-d6):
qJzqJz

Example-4: Purification of Selinexor (I).

Selinexor (40.0 g) was dissolved in methanol (1.6 Lt, 40 V) and treated with Norit-CGP grade charcoal (4.0 g, 0.1 W) for 10-15 min at 27.5±2.5 °C. Subsequently the resulting slurry was filtered over Hyflo, washed with 200 mL of methanol. Filtrate containing dissolved selinexor was transferred into appropriate flask and precipitated by the addition of DM Water (2.0 Lt, 50 V). The resulting precipitate of Selinexor was stirred for 60-90 minutes at 27.5±2.5 °C. The resulting slurry was filtered and washed with 800 mL of DM water. 43.82 g of wet Selinexor was dried at 60-65 °C under vacuum for 5-6 h to afford Selinexor as an off-white to white coloured powder (36.46 g, 91.15% yield).
HPLC Purity: 99.96%
Trans isomer of selinexor: 0.02%.
Mass m/z-444.11 (M+H)
1H NMR (400 MHz, DMSO-d6):
dJzsdJzbssd, 1H, J= 1.6 Hz), 8.06-8.07 (dd, 1H, J=2.8, 1.6 Hz), 7.92-7.93 (d, 1H, 2.8 Hz), 7.51-7.53 (d, 1 H, 10.4 Hz), 6.07-6.10 (d, 1 H, 10.4 Hz).
13C NMR(100 MHz, DMSO-d6):
qJzqJz

Example-5: Preparation of Selinexor oxalate of Formula-(XIV).

Acetonitrile (750 mL) was charged to Selinexor crude (30.0 g. 0.067 mol) in an appropriate flask at 25-30 °C. Temperature of the reaction mass was raised to 80-85 °C for the dissolution of Selinexor crude in acetonitrile. A solution of oxalic acid dihydrate (9.38 g in 150 mL acetonitrile, 0.074 mol) was added to the above reaction mass at 80-85 °C over a period of 20 minutes. The resulting heterogeneous mass was maintained at the same temperature for 40 min and cooled to 25-30 °C and maintained for 1h at the same temperature. Subsequently, reaction mass was filtered, washed with 60 mL of acetonitrile. 32.6 g of wet compound thus obtained was dried under vacuum at 60-65 °C to get 30.5 g of Selinexor oxalate of formula-(XIV) (84.5% yield).
Selinexor Crude purity:
Selinexor: 97.93%; Trans isomer of Selinexor: 0.30%
Selinexor oxalate purity:
Selinexor-Oxalate: 99.93%; Trans isomer of Selinexor oxalate: 0.05%
Melting point of Selinexor Oxalate By DSC: 193.67 °C-195.34 °C
1H NMR (400 MHz, DMSO-d6):
Broadpeaksssbss, 1H),d, 1H, J= 1.6 Hz), 8.08-8.07 (dd, 1H, J=2.4, 1.2 Hz), 7.937-7.931 (d, 1H, 2.4 Hz), 7.539-7.512 (d, 1 H, 10.8 Hz), 6.107-6.081 (d, 1 H, 10.4 Hz).
13C NMR(100 MHz, DMSO-d6):


Example-6: Purification of Selinexor of Formula-(I) via the dissociation of
Selinexor oxalate of formula-(XIV).

Selinexor oxalate of formula-XIV (2.0 g, 4.09 mmol) in a mixture of methanol (100 mL) and DM water (100 ml) was treated with aqueous ammonia (10 ml) at 0-5 °C for 1 h. Precipitated out Selinexor free base was filtered and washed with 20 ml of DM water and dried under vacuum. 2.4 g wet Selinexor free base thus obtained was dried under vacuum at 60-65 °C to get 1.24 g of Selinexor free base of formula-(I) (68.5% yield). HPLC purity: 99.943%;
Trans isomer of selinexor: 0.02%

Example-7: Preparation of compound of Formula-(XIII).

Propiolic acid (66.3 g, 0.946 mol) was added to mixture of 1-heptanol (100.0 g, 0.86 mol) and toluene (1000 mL) at 25-30 °C. PTSA (16.4 g, 0.086 mol) was added to above reaction mass and the temperature of the reaction mass was raised to 105.0±5.0 °C. The resulting reaction mass was stirred at the same temperature for 3-4 h. Progress of the reaction was monitored by in-process GC analysis. After completion of reaction, reaction mass was cooled to 25-30 °C and quenched with 1000 mL of DM water. Separated toluene layer was washed sequentially with aqueous 5% sodium bicarbonate solution (1000 ml) and DM water (1000 ml). Evaporation of toluene layer under reduced pressure afforded a light brown colored syrupy residue of formula-(XIII) (136.6 g) which was used for next step without any further purification.
1H NMR (400 MHz, DMSO-d6): stJzmmtJz
13C NMR (100 MHz, DMSO-d6):


Example-8: Preparation of compound of Formula-(X).

Sodium iodide (141.9 g, 0.946 mol) was added to mixture of compound of formula-(XIII) (136.0 g) and acetic acid (500 mL) at 25-30 °C. Temperature of the reaction mass was raised to 65-70 °C and maintained at the same temperature for 2-3 h. The progress of the reaction was monitored by in-process GC analysis. After completion of the reaction, reaction mass was cooled to 25-30 °C and charged with 7.5% aqueous sodium bisulphite (2000 mL). Subsequently the reaction mass was extracted with ethyl acetate (2×1000 mL). Combined organic layers were sequentially washed with 5% aqueous sodium bicarbonate solution (2×2000 mL) and 20% aqueous sodium chloride (2000 mL). Evaporation of separated ethyl acetate layer yielded an oily mass of compound of formula-(X) (228.4 g, 89.63% from propiolic acid) which was characterized and used for the formation of compound of formula-(XI).
GC purity: 97.55%
1H NMR (400 MHz, DMSO-d6): dzdztzmmtz
13C NMR (100 MHz, DMSO-d6):

Mass by GCMS: 296.0

Example-9: Preparation of compound of Formula-(XV)-DMPU solvate of Selinexor.

Selinexor free base (2.0 g) obtained from recrystallization in acetonitrile was dissolved in 10 ml of dimethylpropylene urea (DMPU) at 25-30 °C. 50 mL of DM water was added to the above reaction mass and the resulting white precipitate was stirred for 2 h at 25-30 °C. Following the maintenance, reaction mass was filtered and washed with DM water (30 mL). 3.8 g wet material thus obtained was dried under vacuum at 60-65 °C to get 1.88 g of Selinexor DMPU solvate of formula-XV.
HPLC Purity: 97.92%
Melting point by DSC: 135.71 °C-136.87 °C.
1H NMR (400 MHz, DMSO-d6):
sssbssd, 1H, J= 1.6 Hz), 8.07-8.08 (dd, 1H, J=2.8, 1.6 Hz), 7.92-7.93 (d, 1H, 2.8 Hz), 7.51-7.54 (d, 1 H, 10.4 Hz), 6.07-6.10 (d, 1 H, 10.4 Hz), 3.198-3.168 (t, 2H, J=5.6 Hz), 2.758 (s, 3H), 1.902-1.843 (m, 1H).