DESC:CRYSTALLINE POLYMORPH AND CO-CRYSTALS OF PIRTOBRUTINIB, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THEREOF

FIELD OF THE INVENTION
The present invention relates to a crystalline form of Pirtobrutinib, co-crystals comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan, processes for their preparation, pharmaceutical formulations, and therapeutic uses thereof. The invention further relates to an improved process for the preparation of Pirtobrutinib and intermediates thereof.

BACKGROUND OF THE INVENTION
Pirtobrutinib is a kinase inhibitor. Pirtobrutinib, chemical name 5-amino-3-{4-[(5-fluoro-2-methoxybenzamido);’l]phenyl}-1-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-4-carboxamide, has the following chemical structure of Formula (I):

Formula (I)
Pirtobrutinib marketed as JAYPIRCA® is a kinase inhibitor currently indicated (in the United States of America) for the treatment of Mantle Cell Lymphoma, and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

International Publication Nos. WO2017/103611A1 and WO2022/056100A1 provides processes for the preparation of Pirtobrutinib.

International Publication No. WO2020/028258A1 provides a process for the preparation of spray-dried dispersion comprising the compound of Formula (I) and a hypromellose acetate succinate (HPMCAS) polymer. It further provides processes for the preparation of Form A of Pirtobrutinib, mixture of Forms A and B of Pirtobrutinib, and Form C of Pirtobrutinib (hemi-1,4-dioxane solvate).

International Publication No. WO2022/240920A1 provides processes for the preparation of cocrystalline form of Pirtobrutinib and a coformer selected from the group consisting of adipic acid and camphoric acid.

Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray powder diffraction (XRPD) pattern, infrared absorption fingerprint, and solid state (13C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

It is desired to have physically stable forms of the compound that are suitable for the therapeutic use and the manufacturing process.

Different crystalline forms (including co-crystals) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different crystalline forms, co-crystals may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different crystalline forms (including co-crystals) may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability.

New crystalline forms (including co-crystals) of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist may have for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional crystalline forms (including co-crystals) of Pirtobrutinib.

The present invention provides a crystalline form of Pirtobrutinib, and co-crystals comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan.

Compared to their other free form(s), the crystalline form and co-crystals of the invention are advantageous as these compounds possess improved dissolution, higher aqueous solubility, and greater solid state physical stability. The specific Pirtobrutinib co-crystals may provide a reduced mass of the dosage form and therefore lower pill burden since the Pirtobrutinib co-crystals may also exhibit higher bulk densities.

The invention further provides improved processes for the preparation of Pirtobrutinib and intermediates thereof in high yield using cost effective reagents. The process according to this invention results in a consistent quality product in reproducible yields. The processes of the invention provide for the quantitative conversion of reagents and decreased formation of by-products, resulting in a high yielding process for preparing Pirtobrutinib.

BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of a crystalline form of Pirtobrutinib, designated Form N.
FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of a crystalline form of Pirtobrutinib, designated Form N.
FIG. 3 shows a thermogravimetric analysis (TGA) graph of a crystalline form of Pirtobrutinib, designated Form N.
FIG. 4 shows an X-ray powder diffraction (XRPD) pattern of a crystalline form of Pirtobrutinib, designated Form S.
FIG. 5 shows a differential scanning calorimetry (DSC) thermogram of a crystalline form of Pirtobrutinib, designated Form S.
FIG 6 shows an X-ray powder diffraction (XRPD) pattern of a co-crystal formed between Pirtobrutinib and glutaric acid.
FIG. 7 shows a differential scanning calorimetry (DSC) pattern of a co-crystal formed between Pirtobrutinib and glutaric acid.
FIG. 8 shows an Infra-Red (IR) diffraction pattern of a co-crystal formed between Pirtobrutinib and glutaric acid.
FIG. 9 shows X-ray powder diffraction (XRPD) pattern of a co-crystal formed between Pirtobrutinib and oxalic acid.
FIG. 10. shows a differential scanning calorimetry (DSC) pattern of a co-crystal formed between Pirtobrutinib and oxalic acid.
FIG. 11 shows an Infra-Red (IR) diffraction pattern of a co-crystal formed between Pirtobrutinib and oxalic acid.
FIG. 12 shows an X-ray powder diffraction (XRPD) pattern of a co-crystal formed between Pirtobrutinib and L-tryptophan.
FIG. 13 shows a differential scanning calorimetry (DSC) pattern of a co-crystal formed between Pirtobrutinib and L-tryptophan.
FIG. 14 shows an Infra-Red (IR) diffraction pattern of a co-crystal formed between Pirtobrutinib and L-tryptophan.

SUMMARY OF THE INVENTION
In general, the present invention relates to a crystalline form of 5-amino-3-{4-[(5-fluoro-2-methoxybenzamido)methyl]phenyl}-1-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-4-carboxamide (Pirtobrutinib of Formula (I)), processes for its preparation, pharmaceutical formulations, and therapeutic uses thereof.

Further, in general, the present invention relates to a co-crystal comprising 5-amino-3-{4-[(5-fluoro-2-methoxybenzamido)methyl]phenyl}-1-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-4-carboxamide (Pirtobrutinib of Formula (I)) and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan, processes for their preparation, pharmaceutical formulations, and therapeutic uses thereof. Under certain circumstances, Pirtobrutinib and the co-crystal former wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan together may form a multi-component single phase crystalline solid or composition, i.e., a co-crystal.

In one aspect, the present invention provides a crystalline form of Pirtobrutinib, which is designated Form N.

In another aspect, the present invention provides a crystalline form of Pirtobrutinib, which is designated Form N, characterized by data selected from one or more of the following:
(i)Form N of compound of Formula I characterized by having an X-ray powder diffraction pattern comprising peaks at 10.2°,11.3°,16.7°, 20.2°, and 25.1° 2? ± 0.2°;
(ii) Also provided herein is Form N of compound of Formula I having a differential scanning calorimetry (DTA) thermogram substantially as set forth in FIG. 2;
(iii) Also provided herein is Form N of compound of Formula I a differential scanning calorimetry (DTA) thermogram having at least a peak at about 193.04 °C;
(iv) a thermogravimetric analysis (TGA) graph substantially as set forth in FIG. 3;

In yet another aspect, the present invention provides a crystalline form of Pirtobrutinib designated Form N, which is isolated, and which contains no more than about 10% of any other crystalline forms of Pirtobrutinib.

In yet another aspect, the present invention provides a process for the preparation of a crystalline form N of Pirtobrutinib, which comprises:
a) heating a mixture of Pirtobrutinib in a solvent to a temperature less than or equal to about 65 °C to form a solution;
b) cooling the solution to a temperature of about 20 °C to 30 °C;
c) adding the solution to water at a temperature of about 0 °C to 5 °C to form a mixture;
d) stirring the mixture at a temperature of about 0 °C to 5 °C for about 4 to 6 hours;
e) isolating the crystalline form of Pirtobrutinib.

In still another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of Pirtobrutinib, which is designated Form N, and at least one pharmaceutically acceptable excipient.

In still another aspect, the present invention provides a pharmaceutical composition prepared by combining a therapeutically effective amount of a crystalline form of Pirtobrutinib, which is designated Form N, and at least one pharmaceutically acceptable excipient.

In still another aspect, the present invention provides a use of a crystalline form of Pirtobrutinib, which is designated Form N, for the preparation of a pharmaceutical composition and/or formulation, wherein the pharmaceutical formulation is a tablet or a capsule.

In still another aspect, the present invention provides a use of a crystalline form of Pirtobrutinib, which is designated Form N, in the preparation of another crystalline form of Pirtobrutinib, or a co-crystal or a salt thereof.

In another aspect, the present invention provides another crystalline form of Pirtobrutinib, which is designated Form S, characterized by data selected from one or more of the following
(i) Also provided herein is Form S of compound of Formula I characterized by having an X-ray powder diffraction pattern comprising peaks at 14.9°, 17.0°, 20.7°, 21.3° and 24.7± 0.2° 2?;

In another aspect, the present invention provides a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan.

In yet another aspect, the present invention provides a co-crystal of the formula (Pirtobrutinib)m: (CCF)n, wherein CCF is a co-crystal former selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan; and m and n, independently, are an integer of 0.5 to 1.5.

In still another aspect, the present invention provides a method of making a co-crystal comprising: grinding, heating, co-subliming, co-melting, or contacting Pirtobrutinib with the co-crystal former under crystallization conditions so as to form the co-crystal in solid phase, wherein the co-crystal former is selected from glutaric acid, oxalic acid, or L-tryptophan.

In still another aspect, the present invention provides a method of making a co-crystal comprising providing a pre-existing co-crystal as a seed to form the co-crystal, wherein the pre-existing co-crystal comprises: (i) Pirtobrutinib and (ii) glutaric acid, oxalic acid, or L-tryptophan; and the co-crystal to be formed comprises: (a) an active ingredient selected from Pirtobrutinib and (b) a co-crystal former selected from glutaric acid, oxalic acid, or L-tryptophan.

In still another aspect, the present invention provides a method of making a co-crystal comprising: treating Pirtobrutinib with glutaric acid, oxalic acid, or L-tryptophan at an elevated temperature to form the co-crystal.

In still another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan, and at least one pharmaceutically acceptable excipient.

In still another aspect, the present invention provides a pharmaceutical composition prepared by combining a therapeutically effective amount of a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan, and at least one pharmaceutically acceptable excipient.

In still another aspect, the present invention provides a use of a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan for the preparation of a pharmaceutical composition and/or formulation, wherein the pharmaceutical formulation is a tablet or a capsule.

In still another aspect, the present invention provides a use of a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan, in the preparation of another crystalline form of Pirtobrutinib, or a co-crystal or a salt thereof.

In still another aspect, the present invention provides a method of treating diseases including mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma cancer, Waldenstrom’s macroglobulinemia, follicular lymphoma, marginal zone lymphoma, multiple sclerosis, arthritis, rheumatoid arthritis which comprises administering to a subject in need thereof a therapeutically effective amount of a crystalline form of Pirtobrutinib, which is designated Form N or Form S or a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan of this invention or a composition of this invention.
In another aspect, the present invention provides a process for the preparation of a compound of Formula (II), an intermediate of Pirtobrutinib,

Formula (II)
which involves
treating a compound of formula (III) and compound of Formula (IV)

Formula (III) Formula (IV)
in the presence of a base and a palladium catalyst,
wherein the base is a phosphate base or a carbonate base selected from potassium carbonate (K2CO3), lithium carbonate, calcium carbonate, tripotassium phosphate (K3PO4), sodium carbonate (Na2CO3), or trisodium phosphate (Na3PO4).

In still another aspect, the present invention provides a process for the preparation of Pirtobrutinib of Formula (I) or a salt thereof,

Formula (I)
which involves:
a) treating a compound of formula (III) and compound of Formula (IV)

Formula (III) Formula (IV)
in the presence of a base and a palladium catalyst, to obtain a compound of Formula (II), wherein the base is a phosphate base or a carbonate base selected from potassium carbonate (K2CO3), lithium carbonate, calcium carbonate, tripotassium phosphate (K3PO4), sodium carbonate (Na2CO3), or trisodium phosphate (Na3PO4); and

Formula (II)
b) converting the compound of Formula (II) to Pirtobrutinib of Formula (I) or a salt thereof.
In still another aspect the invention further provides composition comprising Pirtobrutinib where in Pirtobrutinib has purity greater than 99% by weight and desmethyl impurity of compound of Formula (V) present in an amount less than about 0.2% by weight by area percentage of HPLC.

In one embodiment, the desmethyl impurity compound (V) comprises the structure:

Formula (V)
In still another aspect the invention further provides composition comprising Pirtobrutinib where in Pirtobrutinib has purity greater than 99% by weight and (R) isomer of Pirtobrutinib compound of Formula (VI) present in an amount less than about 0.2% by weight by area percentage of HPLC.In one embodiment, compound (VI) comprises the structure:

Formula (VI)
In another general aspect there is provided a process for the preparation of substantially pure Pirtobrutinib.

DETAILED DESCRIPTION OF THE INVENTION
A solid-state form, such as a crystal form (including co-crystals), may be referred to herein as being characterized by graphical data “as set forth in” a Figure (FIG.). Such data include, for example, X-ray powder diffraction (XRPD) patterns, differential sacnning calorimetry (DTA) thermograms, thermogravimetric analysis (TGA) graphs, differential scanning calorimetry (DSC) patterns, Infra-Red (IR) diffraction patterns. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid-state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Pirtobrutinib, which is designated Form N, Form S or a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan referred to herein as being characterized by graphical data “as set forth in” a Figure will thus be understood to include a crystal form of Pirtobrutinib, which is designated Form N, Form S or a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Pirtobrutinib of the present invention may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.

As used herein, the term “isolated” in reference to crystal forms (including co-crystals) of Pirtobrutinib of the present invention corresponds to crystal forms (including co-crystals) of Pirtobrutinib that is physically separated from the reaction mixture in which it is formed.

The term “co-crystal” as used herein is defined as a crystalline material including two or more molecules in the same crystalline lattice and associated by non-ionic and non-covalent bonds. In some embodiments, the cocrystal includes two molecules which are in natural state.

Reference throughout this specification to “embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases for example, “in one embodiment” or “in another embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

A “pharmaceutical composition” refers to a formulation of a compound (a crystalline form of Pirtobrutinib, or a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan) of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.

“Effective amount” or “therapeutically effective amount” refers to an amount of a compound (a crystalline form of Pirtobrutinib, or a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan) according to the invention, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician. The amount of a compound (a crystalline form of Pirtobrutinib, or a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan) according to the invention which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art.

The terms “subject” or “patient” refer to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. In some embodiments, the subject is a mammal (or the patient). In some embodiments the subject (or the patient) is human, domestic animals (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats and pigs), and/or laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys). In one embodiment, the subject (or the patient) is a human. “subject in need thereof” refers to a human who may have or is suspect to have diseases or conditions that would benefit from certain treatment; for example, being treated with the compounds (a crystalline form of Pirtobrutinib, or a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan) disclosed herein according to the present application.

Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

The term “substantially pure” herein means Pirtobrutinib having purity of greater than or equal to 99 by weight and compound of Formula (V) present in an amount relative to Pirtobrutinib less than about 0.2% w/w or compound of Formula present (VI) less than about 0.2% w/w by area percentage of HPLC relative to Pirtobrutinib.

“Pharmaceutically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

A reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” often abbreviated as “RT” This means that the temperature of the mixture is close to, or the same as, that of the space, e.g., the room or fume hood, in which the mixture is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

“HPLC” refers to high performance liquid chromatography.

In one aspect, the present invention provides a crystalline form of Pirtobrutinib, which is designated Form N.
In one embodiment, the crystalline form of Pirtobrutinib, which is designated Form N, is characterized by an x-ray powder diffraction (XRPD) pattern comprising peaks at about 10.2°, 11.3°, 16.6°, 20.2°, and 25.1° 2? ± 0.2° 2?.
In another embodiment, the crystalline form of Pirtobrutinib, which is designated Form N, is characterized by an x-ray powder diffraction (XRPD) pattern comprising peaks at about 10.2°, 11.3°,14.4°,15.3°, 16.7°, 20.2° and 25.1°
In another embodiment, the crystalline form of Pirtobrutinib, which is designated Form N, is characterized by an x-ray powder diffraction (XRPD) pattern comprising peaks at about 10.2°, 11.3°, 14.4°,15.3°, 16.7°, 20.2°, 22.0° and 25.1°;

In another embodiment, the crystalline form of Pirtobrutinib, which is designated Form N, is characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 1.
In another embodiment, the crystalline form of Pirtobrutinib, which is designated Form N, is characterized by a differential scanning calorimetry (DSC) thermogram substantially as set forth in FIG. 2.
In another embodiment, the crystalline form of Pirtobrutinib, which is designated Form N, is characterized differential scanning calorimetry (DSC) thermogram having peaks at about 151.2 °C, 171.7, and 193.0 °C 0 ± 0.2 °C.
.
In another embodiment, the crystalline form of Pirtobrutinib, which is designated Form N, is characterized by a thermogravimetric analysis (TGA) graph substantially as set forth in FIG. 3.
In another embodiment, the crystalline form of Pirtobrutinib, which is designated Form N, may be characterized by the data set forth in the following table A.
TABLE A
X-ray powder diffraction peaks of a crystalline Form N of Pirtobrutinib
Peak position
(° 2? ± 0.2° 2?)
5.1
7.2
9.1
10.2
11.4
12.6
14.4
15.3
15.9
16.3
16.8
16.9
17.8
18.5
19.6
20.3
21.1
21.3
24.1
25.1
26.1
27.2
28.6
29.1
30.2
30.9
32.5
33.9
35.9
37.18
38.5

In another aspect, the present invention provides a crystalline form of Pirtobrutinib, which is designated Form N, characterized by data selected from one or more of the following:
(i) an X-ray powder diffraction pattern substantially as set forth in FIG. 1;
(ii) an X-ray powder diffraction pattern having one or more peaks at 10.2° 11.3°, 16.6°, 20.2°, and 25.1° 2? ± 0.2° 2?;
(iii) a differential sacnning calorimetry (DTA) thermogram substantially as set forth in FIG. 2;
(iv) a differential sacnning calorimetry (DTA) thermogram having at least a peak at about 193.0 °C;
(v) a thermogravimetric analysis (TGA) graph substantially as set forth in FIG. 3;
or
(vi) any combination of (i)-(v).

In yet another aspect, the present invention provides a crystalline form N of Pirtobrutinib which is isolated, and which contains no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Pirtobrutinib.

In yet another aspect, the present invention provides a process for the preparation of a crystalline form of Pirtobrutinib designated Form N, which comprises:
a) heating a mixture of Pirtobrutinib in a solvent to a temperature less than or equal to about 65 °C to form a solution;
b) cooling the solution to a temperature of about 20 °C to 30 °C;
c) adding the solution to water at a temperature of about 0 °C to 5 °C to form a mixture;
d) stirring the mixture at a temperature of about 0 °C to 5 °C for about 3 to 7 hours;
e) isolating the crystalline Form N of Pirtobrutinib.

In one embodiment of this aspect, the solvent can be an organic solvent, preferably an aliphatic alcohol.
In another embodiment, heating the mixture of Pirtobrutinib in a solvent to a temperature of 60 °C to 65 °C.
In another embodiment, the process comprises heating the mixture of Pirtobrutinib in methanol to a temperature of 60 °C to 65 °C.
In another embodiment, adding the solution to water can be carried out under stirring.
In another embodiment, the water can be pre-cooled to a temperature of 0 °C to 5 °C.
In another embodiment, stirring the mixture can be for about 4 to 6 hours, e.g., about 4.5 hours.

In still another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of Pirtobrutinib, which is designated Form N, and at least one pharmaceutically acceptable excipient.

In still another aspect, the present invention provides a pharmaceutical composition prepared by combining a therapeutically effective amount of a crystalline form of Pirtobrutinib, which is designated Form N, and at least one pharmaceutically acceptable excipient.

In still another aspect, the present invention provides a use of a crystalline form of Pirtobrutinib, which is designated Form N, for the preparation of a pharmaceutical composition and/or formulation, wherein the pharmaceutical formulation is a tablet or a capsule.

In still another aspect, the present invention provides a use of a crystalline form of Pirtobrutinib, which is designated Form N, in the preparation of another crystalline form of Pirtobrutinib, or a co-crystal or a salt thereof.

In another aspect, the present invention provides another crystalline form of Pirtobrutinib, which is designated Form S, characterized by data selected from one or more of the following:
(i) Also provided herein is Form S of compound of Formula I characterized by having an X-ray powder diffraction pattern comprising peaks at 14.9°, 17.0°, 20.7°, 21.3° and 24.7± 0.2° 2?;
ii)Also provided herein is Form S of compound of Formula I characterized by having an X-ray powder diffraction pattern comprising peaks at 4.8, 14.9°, 17.0°, 20.7°, 21.3° and 24.7± 0.2° 2?;
(iii)Also provided herein is Form S of compound of Formula I characterized by having an X-ray powder diffraction pattern comprising peaks at 4.8, 14.9°, 10.5° 17.0°, 20.7°, 21.3° and 24.7± 0.2° 2?;
(iv)Also provided herein is Form S of compound of Formula I having a differential scanning calorimetry (DSC) thermogram substantially as set forth in FIG. 5
(v) Also provided herein is Form S of compound of Formula I having differential scanning calorimetry (DSC) thermogram having at least a peak at about 170.7 and 189. ± 0.2 °C.
In yet another aspect, the present invention provides a crystalline form of Pirtobrutinib designated Form S, which is isolated, and which contains no more than about 10% of any other crystalline forms of Pirtobrutinib.
In yet another aspect, the present invention provides a process for the preparation of a crystalline form N of Pirtobrutinib, which comprises heating the Form N at about 160 °C for 4 hours.
In another embodiment, the crystalline form of Pirtobrutinib, which is designated Form N, may be characterized by the data set forth in the following table B.
TABLE B
X-ray powder diffraction peaks of a crystalline Form S of Pirtobrutinib
Peak position
(° 2? ± 0.2° 2?)
4.8
6.3
9.9
10.2
10.5
11.2
12.9
13.6
14.3
14.9
15.6
16.0
16.5
17.0
17.2
17.7
18.3
19.2
19.6
19.8
20.4
20.7
21.1
21.3
23.0
23.2
24.1
24.8
25.1
25.4
26.0
26.7
27.2
27.7
28.0
28.9
29.7
30.2
31.5
32.3
32.6
32.9
33.9
34.1

In another aspect, the present invention provides a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan.

In one embodiment, the invention provides a co-crystal that includes Pirtobrutinib and glutaric acid as the co-crystal former. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and glutaric acid as the co-crystal former, wherein the molar ratio of Pirtobrutinib and glutaric acid is about 1:0.5. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and glutaric acid as the co-crystal former characterized by an x-ray powder diffraction (XRPD) pattern having peaks at about 18.9°, 21.5°, and 23.6° 2? ± 0.2° 2?. The x-ray powder diffraction (XRPD) pattern having one or more further peaks further peaks at about 12.1°, 22.2°, and 24.9° 2? ± 0.2° 2?. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and glutaric acid as the co-crystal former characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 6. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and glutaric acid as the co-crystal former having peaks in its differential scanning calorimetry (DSC) thermogram at about 138 °C and at about 170 °C. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and glutaric acid as the co-crystal former characterized by differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 7.
In another embodiment, a co-crystal that includes Pirtobrutinib and glutaric acid as the co-crystal former may be characterized by the data set forth in the following table C. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and glutaric acid as the co-crystal former characterized by an Infra-Red (IR) diffraction pattern substantially as set forth in FIG. 8.

TABLE C
X-ray powder diffraction peaks of a co-crystal that includes Pirtobrutinib and glutaric acid as the co-crystal former
Peak position
(° 2? ± 0.2° 2?)
9.8
10.4
10.8
11.8
12.1
13.4
14.6
15.2
16.5
17.3
17.8
18.5
18.9
19.1
19.6
20.9
21.5
21.7
22.2
23.1
23.6
24.9
26.3
27.0
27.3
28.2
28.4
29.9
30.9

In one embodiment, the invention provides a co-crystal that includes Pirtobrutinib and oxalic acid as the co-crystal former. In another embodiment, the oxalic acid is oxalic acid dihydrate. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and oxalic acid as the co-crystal former, wherein the molar ratio of Pirtobrutinib and glutaric acid is about 1:0.5. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and oxalic acid as the co-crystal former characterized by an x-ray powder diffraction (XRPD) pattern having peaks at about 15.6°, 20.3°, and 21.1° 2? ± 0.2° 2?. The x-ray powder diffraction (XRPD) pattern having one or more further peaks further peaks at about 11.3°, 17.0°, 22.6°, and 29.7° 2? ± 0.2° 2?. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and oxalic acid as the co-crystal former characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 9. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and oxalic acid as the co-crystal former having peaks in its differential scanning calorimetry (DSC) thermogram at about 171 °C and at about 189 °C. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and oxalic acid as the co-crystal former characterized by differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 10. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and oxalic acid as the co-crystal former characterized by an Infra-Red (IR) diffraction pattern substantially as set forth in FIG. 11.
In another embodiment, a co-crystal that includes Pirtobrutinib and oxalic acid as the co-crystal former may be characterized by the data set forth in the following table D.

TABLE D
X-ray powder diffraction peaks of a co-crystal that includes Pirtobrutinib and oxalic acid as the co-crystal former
Peak position
(° 2? ± 0.2° 2?)
7.4
11.3
15.6
17.0
19.0
20.3
21.1
22.6
23.1
23.8
24.5
25.2
26.8
28.0
29.7
31.8
32.4

In one embodiment, the invention provides a co-crystal that includes Pirtobrutinib and L-tryptophan as the co-crystal former. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and L-tryptophan as the co-crystal former, wherein the molar ratio of Pirtobrutinib and glutaric acid is about 1:1. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and L-tryptophan as the co-crystal former characterized by an x-ray powder diffraction (XRPD) pattern having peaks at about 13.2°, 16.9°, and 20.4° 2? ± 0.2° 2?. The x-ray powder diffraction (XRPD) pattern having one or more further peaks at about 7.5°, 14.7°, 19.3°, 22.1°, 24.4°, 26.5°, and 27.8° 2? ± 0.2° 2?. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and L-tryptophan as the co-crystal former characterized by an x-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 12. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and L-tryptophan as the co-crystal former having a peak in its differential scanning calorimetry (DSC) thermogram at about 213 °C. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and L-tryptophan as the co-crystal former characterized by differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 13. In another embodiment, the invention provides a co-crystal that includes Pirtobrutinib and L-tryptophan as the co-crystal former characterized by an Infra-Red (IR) diffraction pattern substantially as set forth in FIG. 14.
In another embodiment, a co-crystal that includes Pirtobrutinib and L-tryptophan as the co-crystal former may be characterized by the data set forth in the following table 3.
TABLE 3
X-ray powder diffraction peaks of a co-crystal that includes Pirtobrutinib and L-tryptophan as the co-crystal former
Peak position
(° 2? ± 0.2° 2?)
7.4
9.8
11.3
13.2
14.7
15.1
15.7
17.0
17.1
18.5
19.3
20.4
21.4
22.1
24.4
25.1
25.6
26.5
27.8
28.3
29.2
30.8
33.0
33.8

In yet another aspect, the present invention provides a co-crystal of the formula (Pirtobrutinib)m : (CCF)n, wherein CCF is a co-crystal former selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan; and m and n, independently, are an integer of 0.5 to 1.5.
In one embodiment, m can be 1 and n can be 0.5. In another embodiment, both m and n can be 1.
In still another aspect, the present invention provides a method of making a co-crystal comprising: grinding, heating, co-subliming, co-melting, or contacting Pirtobrutinib with the co-crystal former under crystallization conditions so as to form the co-crystal in solid phase, wherein the co-crystal former is selected from glutaric acid, oxalic acid, or L-tryptophan.

In one embodiment of this aspect, the method comprises:
a) contacting Pirtobrutinib and a co-crystal former selected from glutaric acid, oxalic acid, or L-tryptophan to form a mixture;
b) grinding the mixture in the presence of a first organic solvent;
c) adding a second organic solvent and grinding the mixture;
d) isolating the co-crystal comprising Pirtobrutinib and the co-crystal former.

In another embodiment, the method comprises grinding the mixture in a mortar and pestle.
In another embodiment, the first organic solvent can be ethyl acetate and the second organic solvent can be n-heptane.

In still another aspect, the present invention provides a method of making a co-crystal comprising providing a pre-existing co-crystal as a seed to form the co-crystal, wherein the pre-existing co-crystal comprises: (i) Pirtobrutinib and (ii) glutaric acid, oxalic acid, or L-tryptophan; and the co-crystal to be formed comprises: (a) an active ingredient selected from Pirtobrutinib and (b) a co-crystal former selected from glutaric acid, oxalic acid, or L-tryptophan.

In still another aspect, the present invention provides a method of making a co-crystal comprising: treating Pirtobrutinib with glutaric acid, oxalic acid, or L-tryptophan at an elevated temperature to form the co-crystal.

In one embodiment of this aspect, Pirtobrutinib is mixed with glutaric acid, oxalic acid, or L-tryptophan at an elevated temperature in a range of about 60 °C and about 120°C, In another embodiment, the elevated temperature can be in a range of about 65 °C and about 100°C. In another embodiment, the elevated temperature can be in a range of about 70 °C and about 95°C.

In another embodiment of this aspect, the method further comprises optionally adding a seed of a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan.

In another embodiment of this aspect, the method comprises:
a) dissolving Pirtobrutinib and a co-crystal former selected from glutaric acid, oxalic acid, or L-tryptophan in a first organic solvent;
b) optionally filtering the solution;
c) cooling the solution to a temperature of about 20 °C to 30 °C;
d) optionally adding a seed of a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan;
e) stirring the mixture at room temperature;
f) optionally adding a second organic solvent;
g) optionally stirring the mixture for about 0.5 to 2 hours; and
h) isolating the co-crystal comprising Pirtobrutinib and the co-crystal former.

In one embodiment, dissolving Pirtobrutinib and a co-crystal former selected from glutaric acid, oxalic acid, or L-tryptophan in a first organic solvent at an elevated temperature in a range of about 60 °C and about 120°C, In another embodiment, the elevated temperature can be in a range of about 65 °C and about 100°C. In another embodiment, the elevated temperature can be in a range of about 70 °C and about 95°C.
In another embodiment, the first organic solvent can be isopropyl acetate, methanol, water or combinations thereof.
In another embodiment, optionally filtering the solution when the solution is hot.
In another embodiment, stirring the mixture at room temperature of step e) can be for about 3 to 20 hours, e.g., about 4 hours or about 18 hours.
In another embodiment, stirring the mixture at room temperature of step e) can be carried out along with the addition of seed crystals of the co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan.
In another embodiment, the second organic solvent can be n-heptane.
In another embodiment, the isolation of the co-crystal comprising Pirtobrutinib and the co-crystal former may be carried out by filtration, distillation, decantation, vacuum drying, evaporation, or a combination thereof. Preferably, the obtained co-crystal comprising Pirtobrutinib and the co-crystal former can be further dried at an elevated temperature. Preferably, the drying is carried out at a temperature between about 35 °C and about 60 °C, more preferably, between about 45 °C and about 55° C. Preferably the drying takes place over a period of about 8 hours to about 36 hours, more preferably, about 10 hours to about 24 hours, and, most preferably, about 15 hours.

In still another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan, and at least one pharmaceutically acceptable excipient.

In still another aspect, the present invention provides a pharmaceutical composition prepared by combining a therapeutically effective amount of a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan, and at least one pharmaceutically acceptable excipient.

In still another aspect, the present invention provides a use of a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan for the preparation of a pharmaceutical composition and/or formulation, wherein the pharmaceutical formulation is a tablet or a capsule.

In still another aspect, the present invention provides a use of a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan, in the preparation of another crystalline form of Pirtobrutinib, or a co-crystal or a salt thereof.

In still another aspect, the present invention provides a method of treating diseases including mantle cell lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma cancer, Waldenstrom’s macroglobulinemia, follicular lymphoma, marginal zone lymphoma, multiple sclerosis, arthritis, rheumatoid arthritis which comprises administering to a subject in need thereof a therapeutically effective amount of a crystalline form of Pirtobrutinib, which is designated Form N or a co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan of this invention or a composition of this invention.

In another aspect, the present invention provides a process for the preparation of a compound of Formula (II), an intermediate of Pirtobrutinib,

Formula (II)
which involves
treating a compound of formula (III) and compound of Formula (IV)

Formula (III) Formula (IV)
in the presence of a base and a palladium catalyst,
wherein the base is a phosphate base or a carbonate base selected from potassium carbonate (K2CO3), lithium carbonate, Calcium carbonate, tripotassium phosphate (K3PO4), sodium carbonate (Na2CO3), or trisodium phosphate (Na3PO4).

The starting materials, the compound of formula (III) can be prepared as per scheme 1 and the compound of Formula (IV) can be prepared according to methods known from the literature, for example WO2017/103611 A1 (US10695323 and US10342780).
The Scheme 1 for the preparation of compound of Formula (III) is depicted below:

In some embodiments, the base is phosphate base or a carbonate base selected from potassium carbonate (K2CO3) or tripotassium phosphate (K3PO4). In some embodiments, the base is potassium carbonate (K2CO3).

In some embodiments, the palladium catalyst comprises a palladium-XPhos complex, wherein XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.
In some embodiments, the palladium catalyst is a palladium-XPhos complex, wherein XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. The palladium-XPhos complex can be employed as a pre-prepared reagent or alternatively can be prepared in situ. In some embodiments, the palladium catalyst can be prepared in situ.
In some embodiments, the palladium-XPhos complex is prepared in situ by mixing a Pd(0) or a Pd(II) source with XPhos. In some embodiments, the Pd(0) or the Pd(II) source comprises Tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), Palladium(II) acetate Pd(OAc)2, Palladium(II) chloride (PdCl2) or any combination thereof. For example, the palladium-XPhos complex is prepared in situ by mixing Pd(OAc)2 and XPhos. In some embodiments, the palladium-XPhos complex contains Pd(OAc)2 and XPhos in a ratio of about 1:1.1, 1:1.5 or 1:2. In an specific embodiment, the palladium-XPhos complex contains Pd(OAc)2 and XPhos in a ratio of about 1:2.

In some embodiments, treating the compound of formula (III) or a pharmaceutically acceptable salt thereof and compound of Formula (IV) or a pharmaceutically acceptable salt thereof can be performed in any suitable solvent system. In one specific embodiment, it is performed in a solvent system that includes water and an organic solvent selected from tetrahydrofuran (THF) or 2-methyltetrahydrofuran (2-MeTHF) or a combination thereof. In another specific embodiment, it is performed in a solvent system that includes water and THF. In another specific embodiment, it is performed in a solvent system that includes water and 2-MeTHF.

In some embodiments, treating the compound of formula (III) or a pharmaceutically acceptable salt thereof and compound of Formula (IV) or a pharmaceutically acceptable salt thereof can be performed under an inert atmosphere, and can be performed at a temperature of about 75°C to about 100°C for a time of about 1.5 hours to about 5 hours.

In some embodiments, treating the compound of formula (III) or a pharmaceutically acceptable salt thereof and compound of Formula (IV) or a pharmaceutically acceptable salt thereof can be performed in the presence of a base and a palladium catalyst, wherein the base is potassium carbonate (K2CO3) and wherein the palladium catalyst is palladium-XPhos complex, wherein XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, at a temperature of about 80°C to about 85°C for a time of about 2 hours to about 3 hours.

In some embodiments, the compound of Formula (II) may be isolated from the mixture by a technique which includes, for example, filtration, filtration under vacuum, decantation, and centrifugation.

In some embodiments, the compound of Formula (II) is isolated with a better yield of greater than about 80%, 82% or greater than about 83%. In some embodiments, the compound of Formula (11) or a salt thereof, is isolated with a better yield greater than about 84%.

In still another aspect, the present invention provides a process for the preparation of Pirtobrutinib of Formula (I) or a salt thereof,

Formula (I)
which involves:
a) treating a compound of formula (III) and compound of Formula (IV)

Formula (III) Formula (IV)
in the presence of in the presence of a base and a palladium catalyst, to obtain a compound of Formula (II), wherein the base is a phosphate base or a carbonate base selected from potassium carbonate (K2CO3), Lithium carbonate, Calcium carbonate tripotassium phosphate (K3PO4), sodium carbonate (Na2CO3), or trisodium phosphate (Na3PO4); and

Formula (II)
b) converting the compound of Formula (II) to Pirtobrutinib of Formula (I) or a salt thereof.

In still another aspect, the present invention provides a compound of Formula (IX):

Wherein R= C1-C8 alkyl
In some embodiments, the base is selected from potassium carbonate (K2CO3) or tripotassium phosphate (K3PO4). In some embodiments, the base is potassium carbonate (K2CO3).

In some embodiments, the palladium catalyst comprises a palladium-XPhos complex, wherein XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

In some embodiments, the palladium catalyst is a palladium-XPhos complex, wherein XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. The palladium-XPhos complex can be employed as a pre-prepared reagent or alternatively can be prepared in situ. In some embodiments, the palladium catalyst can be prepared in situ.
In some embodiments, the palladium-XPhos complex is prepared in situ by mixing a Pd(0) or a Pd(II) source with XPhos. In some embodiments, the Pd(0) or the Pd(II) source comprises Tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), Palladium(II) acetate Pd(OAc)2, Palladium(II) chloride (PdCl2) or any combination thereof. For example, the palladium-XPhos complex is prepared in situ by mixing Pd(OAc)2 and XPhos. In some embodiments, the palladium-XPhos complex contains Pd(OAc)2 and XPhos in a ratio of about 1:1.1, 1:1.5 or 1:2. In an specific embodiment, the palladium-XPhos complex contains Pd(OAc)2 and XPhos in a ratio of about 1:2.

In some embodiments, treating the compound of formula (III) or a pharmaceutically acceptable salt thereof and compound of Formula (IV) or a pharmaceutically acceptable salt thereof can be performed in any suitable solvent system. In one specific embodiment, it is performed in a solvent system that includes water and an organic solvent selected from tetrahydrofuran (THF) or 2-methyltetrahydrofuran (2-MeTHF) or a combination thereof. In another specific embodiment, it is performed in a solvent system that includes water and THF. In another specific embodiment, it is performed in a solvent system that includes water and 2-MeTHF.

In some embodiments, treating the compound of formula (III) or a pharmaceutically acceptable salt thereof and compound of Formula (IV) or a pharmaceutically acceptable salt thereof can be performed under an inert atmosphere, and can be performed at a temperature of about 75°C to about 100°C for a time of about 1.5 hours to about 5 hours.
In some embodiments, treating the compound of formula (III) or a pharmaceutically acceptable salt thereof and compound of Formula (IV) or a pharmaceutically acceptable salt thereof can be performed in the presence of a base and a palladium catalyst, wherein the base is potassium carbonate (K2CO3) and wherein the palladium catalyst is palladium-XPhos complex, wherein XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, at a temperature of about 80°C to about 85°C for a time of about 2 hours to about 3 hours.

In some embodiments, the compound of Formula (II) may be isolated from the mixture by a technique which includes, for example, filtration, filtration under vacuum, decantation, and centrifugation.

In some embodiments, the compound of Formula (II) is isolated with a better yield of greater than about 80%, 82% or greater than about 83%. In some embodiments, the compound of Formula (11) or a salt thereof, is isolated with a better yield greater than about 88%.
In some embodiments, converting the compound of Formula (II) to Pirtobrutinib of Formula (I) can be done according to methods known from the literature, for example WO 2017/103611 A1, General Procedure M.
In some embodiments, the converting the compound of Formula (II) to Pirtobrutinib of Formula (I) can be done by partial hydrolysis with sodium hydroxide (NaOH) or potassium hydroxide (KOH), lithium hydroxide (LiOH), etc.) under mild heating and monitoring the reaction carefully.
In some embodiments, the converting the compound of Formula (II) to Pirtobrutinib of Formula (I) can be done in presence of 30% hydrogen peroxide (H2O2) and 6% sodium hydroxide (NaOH) solution.

In still another aspect the invention further provides composition comprising Pirtobrutinib where in Pirtobrutinib has purity greater than 99% by weight and desmethyl impurity of compound of Formula (V) present in an amount less than about 0.2% by weight by area percentage of HPLC.
In one embodiment, the desmethyl impurity compound (X) comprises the structure :

Formula (X)
In still another aspect the invention further provides composition comprising Pirtobrutinib where in Pirtobrutinib has purity greater than 99% by weight and (R) isomer of Pirtobrutinib compound of Formula (VI) present in an amount less than about 0.2% by weight by area percentage of HPLC.
In one embodiment, compound (XI) comprises the structure:

Formula (XI)
In another general aspect there is provided a process for the preparation of substantially pure Pirtobrutinib.

In some embodiments, the Pirtobrutinib comprises less than about 0.2% by weight, less than about 0.15% by weight, less than about 0.15% by weight or less than about 0.1% by weight of compound of Formula (V) relative to Pirtobrutinib by area percentage of HPLC.

In some embodiments, the Pirtobrutinib comprises less than about 0.2% by weight, less than about 0.15% by weight, less than about 0.15% by weight or less than about 0.1% by weight of compound of Formula (VI) relative to Pirtobrutinib by area percentage of HPLC.

X-ray powder diffraction (XRPD):
XRPD patterns were acquired at room temperature using a PANalytical diffractometer. Instrument parameters: Make: PANalytical diffractometer; Model: X’pert Pro; Detector: X’celerator; Active Length: 2.122; Used Wavelength: K-Alpha1; Scan parameters: Voltage (kV) and Current (mA) 45kV, 40mA; Scan range (°2?) 3-40; Step size (°2?) 0.0167113; Scan step time (s) 40; Anti-scattering slit (mm) 1°.
Thermogravimetric analysis (TGA):
Data were collected on a TA instrument, TGA55 model. 5-10 mg sample was weighted in a platinum pan. Sample was purged with 60 mL/min of N2 flow and heated in the range RT to 300 °C with heating rate of 10 °C/min.

Differential scanning calorimetry (DSC):
Data were collected on a Mettler Toledo instrument. 3-5 mg sample was weighted in a pan hermetically closed with the pin hole. Sample was purged with 40 mL/min of N2 flow and heated in the range of 30-300 °C with heating rate of 10K/min

Infra-Red (IR):
Data were collected on a Perkin-Elmer instrument with Attenuated Total Reflectance (ATR) sampling accessory. The data were collected and analyzed using Spectrum ES software.

EXAMPLES
Preparation of Form N, Co-crystal
Preparation of starting material:
Pirtobrutinib can be prepared according to methods known from the literature, from examples in WO2017/103611A1 and WO2022/056100A1, and an improved process as disclosed hereinafter.

Example 1: Preparation of Crystalline Form N of Pirtobrutinib
Pirtobrutinib (2.5 g) was dissolved in methanol (6.25 mL) by heating at 60 °C to 65 °C, and then cooled to room temperature. The solution was then added over precooled water (125 mL) at 0 °C to 5 °C, under stirring. The mixture was stirred at 0 °C to 5 °C for 4 hours 30 minutes. The mixture was then filtered and suck dried under vacuum. The wet material was dried further in vacuum tray dryer at 50 °C to 55 °C for 15 hours.
Yield: 2.19 g.

Example 2: Preparation of co-crystals of Pirtobrutinib and glutaric acid
Pirtobrutinib (100 mg, 0.000208 mole) and glutaric acid (27.6 mg, 0.000208 mole) was taken in a mortar and pestle and co-grinded for 5 minutes by adding 3 or 4 drops of ethyl acetate. Thereafter, 3 or 4 drops of n-Heptane was added and further grinded for 5 minutes, to obtain co-crystals of Pirtobrutinib and glutaric acid as a solid.
Yield: 90 mg

Example 3: Preparation of co-crystals of Pirtobrutinib and glutaric acid
A mixture of Pirtobrutinib (2.5 g, 0.0052 mole) and glutaric Acid (0.69 g, 0.0052 mole) was dissolved in isopropyl acetate (15 mL) by heating at 90 °C to 95 °C. The solution was filtered hot with micron filter and kept for stirring at room temperature with addition of seed (0.05 g prepared as per Example 1, above). After stirring for 4 hours, n-Heptane (5 mL) was added and stirred for another 1 hour. The mixture was filtered and suck dried for 10 minutes to obtain a wet material (2.49 g). The wet material was further dried in vacuum tray dryer at 50 °C for 15 hours.
Yield: 2.485 g

Example 4: Preparation of co-crystals of Pirtobrutinib and oxalic acid
Amorphous Pirtobrutinib (50 mg, 0.000104 mole) and oxalic acid dihydrate (13.1 mg, 0.000104 mole) was taken in a mortar and pestle and co-grinded for 5 minutes by adding 3 or 4 drops of ethyl acetate. Thereafter, 3 or 4 drops of n-Heptane was added and further grinded for 5 minutes, to obtain co-crystals of Pirtobrutinib and glutaric acid as a solid.
Yield: 42 mg

Example 5: Preparation of co-crystals of Pirtobrutinib and oxalic acid
A mixture of Pirtobrutinib (2.5 g, 0.0052 mole) and oxalic acid dihydrate (0.655 g, 0.0052 mole) was dissolved in isopropyl acetate (12.5 mL) by heating at 90 °C to 95 °C. The solution was filtered hot with micron filter and kept for stirring at room temperature with addition of seed (0.05 g prepared as per Example 4, above). After stirring for 4 hours, n-Heptane (4 mL) was added and stirred for another 1 hour. The mixture was filtered and suck dried for 10 minutes to obtain a wet material (2.4 g). The wet material was further dried in vacuum tray dryer at 50 °C for 15 hours.
Yield: 2.385 g

Example 6: Preparation of co-crystals of Pirtobrutinib and L-Tryptophan.
A mixture of Pirtobrutinib (2 g, 0.00417 mole) and L-tryptophan (0.852 g, 0.00417 mole) was dissolved in a mixture of methanol and water (80 mL (4:1 v/v)) by heating at 70 °C to 75 °C. The solution was filtered hot with micron filter and kept for stirring at room temperature. After stirring for 18 hours, the mixture was filtered and suck dried for 30 minutes to obtain a wet material (2.19 g). The wet material was further dried in vacuum tray dryer at 50 °C for 15 hours.
Yield: 2.18 g

Example 7: Preparation of 5-amino-3-{4-[(5-fluoro-2-methoxybenzamido)-methyl]phenyl}-1-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-4-carbonitrile (Compound of Formula (II))

Formula (II)
5-amino-3-(4-bromophenyl)-1-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-4-carbonitrile (2 g, 5.56 mmole) compound of Formula (IV) and 5-fluoro-2-methoxy-N-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]benzamide compound of Formula (III) ( 2.06 g, 6.66 mmole) were taken in tetrahydrofuran (20 ml) and stirred for 5 minutes. Potassium carbonate (1.15 g, 8.31 mmole), water (6 ml) were added and stirred for 10 minutes at room temperature. 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos) (0.265, 0.05 mmole) was added to the mixture and the reaction mixture was degassed twice and replaced with nitrogen. Palladium acetate (62.5 mg, 0.025 mmole) was added to the mixture and the reaction mixture was degassed twice and replaced with nitrogen. The temperature was raised to 80°C to 85°C and stirred for 2 to 3 hours. After completion of reaction, 1,2-diaminopropane (1 g) was added and stirred for 30 minutes at 60°C. Ethyl acetate (20 ml) was added and the mixture was stirred. The ethyl acetate layer was separated and washed with water (10 ml). The ethyl acetate layer was concentrated under reduce pressure and the residue obtained was dissolved in methanol (10 ml). Water (10 ml) was added and the solid obtained was filtered, washed with water (4 ml) and dried under reduce pressure at 45°C to 50°C to obtain the titled compound.
Yield: 2.18 g (84.8%) and HPLC purity: 98.8%

Example 8: Preparation of 5-amino-3-{4-[(5-fluoro-2-methoxybenzamido)methyl]phenyl}-1-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-4-carboxamide (Pirtobrutinib of Formula (I))
5-amino-3-{4-[(5-fluoro-2-methoxybenzamido)methyl]phenyl}-1-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-4-carbonitrile (Compound of Formula (II) (50 gm, 0.108 mole) stirred with methane sulfonic acid ( 200 ml), water 3.9g, 0.216 mole) at 80-85°C for 6 hrs, after 6 hrs cooled to 15-20 C. Slowly added into separate flask having water (200ml), ~25% aq NH3 ( 250 ml) at temp NMT 15C in 90 min. Added ethyl acetate 250 ml, stirred for 10 min and discorded aq layer. Ethyl acetate removed and residue dissolved in ethanol (300 ml), material crystallized by addition of n-heptane at (300 ml) resulted 44 gm of compound of formula (I) with yield 85% having HPLC purity 99.8%.
Example 9: Preparation of Crystalline Form S of Pirtobrutinib
Form N of Pirtobrutinib (2 mg ) is heated in an analytical pan at 160 °C for 3-4 hours to obtain form S of Pirtobrutinib.
The foregoing description of the specific embodiments so fully reveals the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the aspects/embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.
Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the disclosure to achieve one or more of the desired objects or results.
Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application.
The numerical values mentioned for the various physical parameters, dimensions or quantities are only approximations and it is envisaged that the values higher/lower than the numerical values assigned to the parameters, dimensions or quantities fall within the scope of the disclosure, unless there is a statement in the specification specific to the contrary.
While considerable emphasis has been placed herein on the components and component parts of the preferred embodiments, it will be appreciated that many embodiments can be made and that many changes can be made in the preferred embodiments without departing from the principles of the disclosure. These and other changes in the preferred embodiment as well as other embodiments of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.
,CLAIMS:1. A crystalline form N of a compound of Formula (I) characterized by having an X-ray powder diffraction pattern comprising peaks at ° 2? values of 10.2°,11.3°,16.7°, 20.2°, and 25.1° ±0.2.

2. The crystalline form of claim 1, characterized by a differential scanning calorimetry (DSC) thermogram substantially as set forth in FIG. 2; or a differential scanning calorimetry (DSC) thermogram having at least a peak at about 193.0 °C.

3. A crystalline form of Pirtobrutinib, which is designated Form S of a compound of Formula (I) characterized by having an X-ray powder diffraction pattern comprising peaks at ° 2? value of 14.9°, 17.0°, 20.7°, 21.3° and 24.7± 0.2° 2?.

4. A co-crystal comprising Pirtobrutinib and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glutaric acid, oxalic acid, and L-tryptophan.

5. The co-crystal as claimed in claim 4, characterized by an x-ray powder diffraction (XRPD) pattern having peaks at about 18.9°, 21.5°, and 23.6° 2? ± 0.2° 2?, wherein the co-crystal former is glutaric acid and the molar ratio of Pirtobrutinib and glutaric acid is about 1:0.5

6. The co-crystal as claimed in claim 4, characterized by an x-ray powder diffraction (XRPD) pattern having peaks at about 15.6°, 20.3°, and 21.1° 2? ± 0.2° 2?, wherein the co-crystal former is oxalic acid and the molar ratio of Pirtobrutinib and oxalic acid is about 1:0.5

7. The co-crystal as claimed in claim 4, characterized by an x-ray powder diffraction (XRPD) pattern having peaks at about 13.2°, 16.9°, and 20.4° 2? ± 0.2° 2?, wherein the co-crystal former is L-tryptophan and the molar ratio of Pirtobrutinib and L-tryptophan is about 1:1.

8. A process for the preparation of a compound of Formula (II), an intermediate of Pirtobrutinib,
9.
Formula (II)
which comprises
i) treating a compound of formula (III) and compound of Formula (IV)

(a) Formula (III) Formula (IV)
in the presence of a base and a palladium catalyst,
wherein the base is a phosphate base or a carbonate base selected from potassium carbonate (K2CO3), tripotassium phosphate (K3PO4), sodium carbonate (Na2CO3), or trisodium phosphate (Na3PO4) and palladium catalyst comprises a palladium XPhos complex, wherein XPhos is 2 dicyclohexylphosphino 2',4', triisopropylbiphenyl

9. A process for the preparation of Pirtobrutinib of Formula (I) or a salt thereof,

which involves:
i) treating a compound of formula (III) and compound of Formula (IV)

Formula (III) Formula (IV)
in the presence of in the presence of a base and a palladium catalyst, to obtain a compound of Formula (II), wherein the base is a phosphate base or a carbonate base selected from potassium carbonate (K2CO3), tripotassium phosphate (K3PO4), sodium carbonate (Na2CO3), or trisodium phosphate (Na3PO4); and and palladium catalyst comprises a palladium XPhos complex, wherein XPhos is 2 dicyclohexylphosphino 2',4', triisopropylbiphenyl; and

Formula (II)
ii) converting the compound of Formula (II) to Pirtobrutinib of Formula (I) or a salt thereof.

10. A desmethyl compound of Formula (V):

11. A composition comprising: Pirtobrutinib wherein the Pirtobrutinib has a purity of greater than or equal to 99% by weight; and wherein the compound of Formula (V) is present in the composition in an amount relative to Pirtobrutinib of less than about 0.2% by weight by area percentage of HPLC.