DESC:RELATED APPLICATIONS:
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. 201921029656 filed on Jul. 23, 2019 and Indian Provisional Patent Application No. 201921041788 filed on Oct. 15, 2019.
FIELD OF THE INVENTION
The present application provides a process of preparation of an amorphous form of Glasdegib Maleate. The Present invention also provides a process of preparation of compound of Formula II and converting it to Glasdegib Maleate.

Formula II
BACKGROUND OF THE INVENTION
Glasdegib Maleate, has a chemical name 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea maleate. Glasdegib Maleate is represented by the following chemical structure according to Formula (I).

Formula I
Glasdegib Maleate is an inhibitor of the Hedgehog pathway. Glasdegib binds to and inhibits Smoothened, a trans membrane protein involved in hedgehog signal transduction.
US 8,148,401 disclose Glasdegib and its hydrochloride salt and a process for the preparation thereof. US2018/0086731 discloses Glasdegib Maleate and a process of preparation of thereof; further US ’731 patent discloses Form I of Glasdegib Maleate.
Considering importance of Glasdegib Maleate in the pharmaceutical field, the invention provides a process for the preparation Glasdegib Maleate which is robust and of commercially viable.
SUMMARY OF THE INVENTION
An aspect of the invention related to the preparation of an amorphous form of Glasdegib Maleate which comprises providing a solution of Glasdegib Maleate in one or more of suitable solvent or mixture thereof followed by removal of solvent.
Another aspect of the present invention is to provide process for the preparation of solid dispersion of Glasdegib Maleate, comprising comprises mixing Glasdegib Maleate with a polymer in a suitable organic solvent and obtaining solid dispersion of Glasdegib Maleate by removal of solvent
Yet another aspect is to provide a process of preparation of (1R, 5S)-2-[(S)-2-Phenylethyl]-6-oxa-2-azabicyclo-[3.2.1]-octan-7-one, a compound of Formula (II), comprising the step of:

Formula II
a. reacting compound of Formula (III) with R-phenylethylamine to obtain compound of Formula (IV) in presence of suitable base and optionally in presence of suitable solvent;

III IV
Wherein, R is a leaving group such as, but not limited to halogen, tosylate, mesylate;
b. reacting the compound of Formula (IV) with glyoxylic acid to obtain the mixture of diastereomers, a compound of Formula (V);

V
c. crystallising the salt of desired isomer from mixture of diastereomer of compound of Formula (V) by treating it with (1R)-(endo,anti)]-(+)-3-Bromocamphor-8-sulfonic acid in presence of suitable solvent to obtain a compound of Formula (VI); and

VI
d. neutralising the compound of Formula (VI) in presence of suitable base to obtain compound of Formula (II).
Another aspect is to provide converting compound of Formula (II) to Glasdegib Maleate.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 shows the X-ray powder diffractogram ("PXRD") pattern of amorphous form of Glasdegib Maleate.
DETAILED DESCRIPTION OF THE INVENTION
Provided herein is an amorphous form of Glasdegib Maleate prepared by a process, comprising the steps of:
a) providing a solution of Glasdegib Maleate in a solvent or a mixture of two or more solvents;
b) removing solvent from the solution of Glasdegib Maleate obtained in step a); and
c) isolating amorphous form of Glasdegib Maleate.
Providing a solution in step (a) includes direct use of a reaction mixture containing Glasdegib Maleate that is obtained in the course of its synthesis or dissolving Glasdegib Maleate in a suitable solvent or a mixture of solvents.
The suitable techniques in step b) used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, rotary vacuum paddle dryer, agitated nutsche filter drying, pressure nutsche filter drying, freeze -drying or any other suitable technique known in the art. The drying may be carried at normal pressure or under reduced pressure.
The isolation of amorphous form of Glasdegib Maleate can be carried out by employing any of the techniques known in the art. Techniques for the isolation of amorphous form of Glasdegib Maleate include, but not limited to: decantation, trituration followed by filtration by gravity or suction, evaporation of the solvent, concentrating the solution centrifugation, and the like, and optionally washing with a solvent.
Also, provided herein is a process for preparing amorphous form of Glasdegib Maleate, by dissolving the Glasdegib Maleate in a suitable solvent in which it is soluble followed by adding the solution containing Glasdegib Maleate in to an anti-solvent in which Glasdegib Maleate is insoluble or vice-versa.
Provided herein a process for preparing an solid dispersion comprising Glasdegib Maleate and one or more pharmaceutically acceptable carriers, the process comprising
a) providing a solution comprising Glasdegib Maleate and one or more pharmaceutically acceptable excipients;
b) removing solvent from the solution obtained in step (a); and
c) isolating an solid dispersion comprising Glasdegib Maleate and one or more pharmaceutically acceptable excipient.
Providing a solution in step (a) includes direct use of a reaction mixture containing Glasdegib Maleate that is obtained in the course of its synthesis or dissolving Glasdegib Maleate and pharmaceutically acceptable carrier in a suitable solvent or a mixture of solvents.
The pharmaceutically acceptable excipients in step (a) include, but are not limited to: water soluble polymers and enteric polymers or mixtures thereof. Suitable water soluble polymer may include hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, copovidone, ß-cyclodextrin, graft copolymer of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g. Soluplus®) and the like and mixtures thereof. Suitable enteric polymer include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate and the like and mixtures thereof. Additionally, water insoluble polymers may be used for hot melt extrusion such as cellulose acetate, ethylcellulose, croscarmellose sodium, crospovidone and the like and mixtures thereof.
Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze drying, filtration or any other technique known in the art. The solid dispersion can also prepared by technique like hot-melt extrusion, the hot-melt extrusion is preferably carried out in the absence of solvent.
The suitable solvent and anti-solvent that can be used include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, 2-butanol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile and the like; water, dimethyl formamide, dimethylacetamide and dimethylsulfoxide, and any mixtures of two or more thereof.
Still further, provided herein is a pharmaceutical composition, comprising a therapeutically effective amount of a solid form of Glasdegib Maleate obtained according to present application, and at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient thereof.
The at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient” can readily be selected by one of ordinary skill in the art and will be determined by the desired mode of administration.
Provided herein a method of the treatment of newly-diagnosed acute myeloid leukemia (AML) comprising administering a pharmaceutical composition comprising, Glasdegib Maleate or polymorphic forms thereof prepared by the processes of the present application and one or more pharmaceutically acceptable excipient.
The X-ray powder diffraction (XRPD) spectrum according to the present invention was measured on a PANalytical X'Pert PRO X- Ray Diffractometer. The parameters of the X-ray powder diffraction method of the present invention were as follows:
X-ray Reflection: Cu, Ka
Ka1 (Å): 1.54060; Ka2 (Å): 1.54443
Ka2 / Ka1 intensity ratio: 0.50
Voltage: 45 (kV), Current: 40 (mA)
Scan range: from 2.5084 degree to 40.0 degree.
Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
An aspect is to provide a process of preparation of (1R, 5S)-2-[(S)-2-Phenylethyl]-6-oxa-2-azabicyclo-[3.2.1]-octan-7-one, a compound of Formula II, comprising the step of:

Formula II
In an embodiment of the present invention, the step (a) reaction between Formula (III) and R-phenylethylamine to obtain compound of Formula (IV) is carried out optionally in an inert organic solvent including but not limited to solvent like ethers such as diethyl ether, isopropyl ether, tetrahydrofuran (THF), dioxane; nitriles such as acetonitrile (ACN); other solvent such as dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) and the like or mixture thereof; more preferably tetrahydrofuran. The reaction may be carried out in presence of suitable base. Suitable base may be selected from the organic base like triethyl amine (TEA), di-isopropyl ethyl amine (DIPEA), pyridine, ammonia or inorganic base such as sodium carbonate (Na2CO3), potassium carbonate (K2CO3), sodium hydroxide (NaOH), potassium hydroxide (KOH); more preferably triethyl amine. The reaction may be carried out at a temperature of about 0oC to about boiling point of the solvent used. Specifically, the reaction step (a) may be carried out at 70 ± 5 °C.
In one embodiment, compound of Formula (IV) may be isolated and purified if required from the reaction mixture by any known technique in the art or the compound can be subjected to next reaction without isolation and/or purification.
In an embodiment of the present invention, the step (b) reaction between Formula (IV) and glyoxylic acid to obtain compound of Formula (V) is carried out in an inert organic solvent including but not limited to solvent such as ethers such as diethyl ether, isopropyl ether, tetrahydrofuran (THF), dioxane,; nitriles such as acetonitrile (ACN); other solvent such as dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) and the like or mixture thereof; more preferably tetrahydrofuran. The reaction may be carried out at a temperature of about 0oC to about boiling point of the solvent used. Specifically, the reaction step (b) may be carried out at 65 ± 5 °C.
In one embodiment, compound of Formula (V) may be isolated and purified if required from the reaction mixture by any known technique in the art or the compound can be subjected to next reaction without isolation and/or purification.
In an embodiment of the present invention, the step (c) crystallisation of salt of desired isomer from mixture of diastereomer of compound of Formula (V) by treating it with (1R)-(endo,anti)]-(+)-3-Bromocamphor-8-sulfonic acid to obtain a compound of Formula (VI) is carried out in an inert organic solvent including but not limited to solvent such as alcohols such as methanol, ethanol, propanol and butanol; esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate and the like or mixture thereof; more preferably ethyl acetate. The reaction may be carried out at a temperature of about 0oC to about boiling point of the solvent used. Specifically, the reaction step (c) may be carried out at ambient temperature.
In one embodiment, the compound of Formula (VI) may be isolated and further crystallised if required from the reaction mixture by any known technique in the art or the compound can be subjected to next reaction without isolation and/or purification.
In an embodiment of the present invention, the step (d) neutralisation of compound of Formula (VI) to obtain compound of Formula (II) is carried out in an suitable base including but not limited to base such as ammonia, sodium carbonate (Na2CO3), potassium carbonate (K2CO3), sodium hydroxide (NaOH), potassium hydroxide (KOH), pyridine; more preferably ammonia. The reaction may be carried out at ambient temperature.
In one embodiment, compound of Formula (II) may be isolated and purified if required from the reaction mixture by any known technique in the art OR the compound can be subjected to next reaction without isolation and/or purification.
Still further, provided herein is a pharmaceutical composition, comprising a therapeutically effective amount of a solid form of Glasdegib Maleate obtained according to present application, and at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient thereof.
The at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient” can readily be selected by one of ordinary skill in the art and will be determined by the desired mode of administration.
Provided herein a method of the treatment of newly-diagnosed acute myeloid leukemia (AML) comprising administering a pharmaceutical composition comprising, Glasdegib Maleate or polymorphic forms thereof prepared by the processes of the present application and one or more pharmaceutically acceptable excipient.
In an embodiment, the process for the preparation according to present invention is represented schematically in Scheme-1 as shown below.
Scheme-1
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Examples
Example 1: Preparation of amorphous Glasdegib Maleate
Glasdegib maleate Form-I (1.0 g) was dissolved in methanol (10.0 mL) at 60°C, removed the solid particles by filtration and filtrate mL was distilled out under vacuum and degased the residual mass to give Glasdegib maleate Amorphous (1.0g).
Example 2: Preparation of amorphous Glasdegib Maleate
Glasdegib maleate (1.0 g) was dissolved in mixture of DMF (1.0ml) and methanol (5.0ml) under heating followed by spray drying.
Example 3: Preparation of solid dispersion of Glasdegib Maleate
Glasdegib Maleate (4 g) and HPMCAS (4 g) dissolved in methanol and the clear solution was subjected to spray drying.
Example 4: Preparation of solid dispersion of Glasdegib Maleate
Glasdegib Maleate and Povidone were mixed and extruded using twin-screw extruder at elevated zone temperatures ranging from about 70°C to about 200°C.
Example-5: Preparation of 1R, 5S)-2-[(S)-2-Phenylethyl]-6-oxa-2-azabicyclo-[3.2.1]-octan-7-one (compound of Formula II)
To a mixture of 3-buten-1-ol (100g) and p-toluenesulfonyl chloride (251.12g) in tetrahydrofuran (300 mL), triethylamine (168.38 g) was added dropwise over a period of 60±5 min. The reaction mixture was stirred at 27 ± 3°C. After completion of reaction, reaction mass was filtered. To the obtained filtrate triethylamine (168.38 g) was added, followed by dropwise addition of (R)-alpha-methylbenzylamine (201.64 g) over 60 ± 5 min. The reaction mixture was stirred at 70±3°C. After completion of reaction, the reaction mass was cooled to room temperature. To the obtained reaction mass sodium hydroxide solution was added. The reaction mass was stirred, settled and the organic layer separated. The aqueous phase was extracted with di-isopropyl ether. The combined organic phases were concentrated under reduced pressure upto 400 ml. The obtained solution was diluted with tetrahydrofuran (300 mL) followed by dropwise addition of glyoxylic acid (50% w/w aqueous solution, 308.0 g). The reaction was stirred at 65 ± 3°C, cooled to 27 ± 3°C and further stirred. After completion of reaction, water and brine were added to reaction mass and the mixture was basified to pH 8-9 with sodium hydroxide. Ethyl acetate was added to obtained reaction mass and the organic layer separated followed by treatment with saturated sodium bicarbonate, water, and brine. Organic layer was distilled out completely under vacuum. The obtained oil was dissolved in ethyl acetate (500 mL) and a solution of [(1R)-Bromocamphor-8-sulfonic acid in ethyl acetate (241.63 g,) was added. The mixture was stirred for 120 min. at 27 ± 3°C. The precipitated solids were collected by filtration and washed with Ethyl acetate. To obtained wet cake dichloromethane (500 mL), water (500 mL) and liquid ammonia (120 mL) were added and stirred at 27 ± 3°C. The organic layer was separated washed with 10% ammonium hydroxide, water, and brine. Solvent was distilled out completely under vacuum below 60°C to obtain compound of Formula II. (Yield: 16%) ,CLAIMS:We claim:
1. An amorphous form of Glasdegib Maleate.
2. A process for the preparation of amorphous form of Glasdegib Maleate comprises;
a. providing a solution of Glasdegib Maleate in a solvent or a mixture of two or more solvents;
b. removing solvent from the solution of Glasdegib Maleate obtained in step a); and
c. isolating amorphous form of Glasdegib Maleate.
3. An amorphous solid dispersion comprising Glasdegib Maleate and pharmaceutically acceptable carrier.
4. A process for preparing a solid dispersion comprising Glasdegib Maleate and pharmaceutically acceptable carrier comprises;
a. providing a solution comprising Glasdegib Maleate and pharmaceutically acceptable excipient;
b. removing solvent from the solution obtained in step (a); and
c. isolating an solid dispersion comprising Glasdegib Maleate and one or more pharmaceutically acceptable excipient.
5. The solid dispersion as claimed in claim 3, wherein the carrier is selected from the group of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, copovidone, ß-cyclodextrin, graft copolymer of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate, ethylcellulose, croscarmellose sodium, crospovidone and mixtures thereof.
6. The process as claimed in claim 2 and 4, wherein the solvent is selected from the group of methanol, ethanol, isopropyl alcohol, dichloro methane, dimethyl formamide, dimethyl sulfoxide and acetone or mixture thereof.
7. A process of preparation of (1R, 5S)-2-[(S)-2-Phenylethyl]-6-oxa-2-azabicyclo-[3.2.1]-octan-7-one, a compound of Formula II, comprising the step of:

Formula II
a. reacting compound of Formula III with R-phenylethylamine to obtain compound of Formula IV in presence of suitable base and optionally in presence of suitable solvent;

III IV
wherein, R is any leaving group such as, but not limited to halogen, tosylate, mesylate;
b. reacting the compound of Formula IV with glyoxylic acid to obtain the mixture of diastereomers, a compound of Formula V;

V
c. crystallising the salt of desired isomer from mixture of diastereomer of compound of Formula V by treating it with (1R)-(endo,anti)]-(+)-3-Bromocamphor-8-sulfonic acid in presence of suitable solvent to obtain a compound of Formula VI; and

VI
d. neutralising the compound of Formula VI in presence of suitable base to obtain compound of Formula II.
8. The process as claimed in claim 7, where in suitable base used in step a) is selected from the group of triethyl amine, di-isopropyl ethyl amine, pyridine, and ammonia.
9. The process as claimed in claim 7, where in suitable solvent used in step c) is selected from the group of methanol, ethanol, propanol, butanol, ethyl acetate, isopropyl acetate and butyl acetate.
10. The process as claimed in claim 7, where in suitable base used in step d) is selected from the group of ammonia, sodium carbonate, potassium carbonate, sodium hydroxide , potassium hydroxide and pyridine.