Salts and Solid Forms of Sonrotoclax Intermediate

Disclosed herein are salts and solid forms of sonrotoclax intermediate and processes for its preparation.

FIELD

Disclosed herein are salts and solid forms of sonrotoclax intermediate and processes for making sonrotoclax.

BACKGROUND

The process of making sonrotoclax disclosed therein is not ideal for scale-up as the intermediate methyl 4-(2-{(2S)-2-[2-(propan-2-yl)phenyl]pyrrolidin-1-yl}-7-azaspiro[3.5]nonan-7-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzoate (Compound 2) was obtained as an oil or liquid with low chemical purity. Thus, a new process for making sonrotoclax is desirable.

SUMMARY

Provided herein are salts of Compound 2, and crystalline forms, and amorphous forms thereof. Further provided herein are methods of making the salts of Compound 2, and crystalline forms and amorphous forms thereof. Further provided herein are methods of making sonrotoclax using the salts of Compound 2, and crystalline forms and amorphous forms thereof.

DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art. All patents, patent applications, and publications referred to herein are incorporated by reference.

As used herein, the term “solvate” refers to a crystalline form of Compound 2 which contains solvent.

As used herein, the term “crystal form” or “crystalline form” refers to a solid form that is crystalline. In certain embodiments, a crystal form of a substance may be substantially free of amorphous forms and/or other crystal forms. In certain embodiments, a crystal form of a substance may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, or less than about 50% by weight of one or more amorphous forms and/or other crystal forms. In certain embodiments, a crystal form of a substance may be physically and/or chemically pure. In certain embodiments, a crystal form of a substance may be about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% physically and/or chemically pure.

As used herein, and unless otherwise specified, the term “amorphous” or “amorphous form” means that the substance, component, or product in question is not substantially crystalline as determined by X-ray diffraction. In particular, the term “amorphous form” describes a disordered solid form, i.e., a solid form lacking long range crystalline order. In certain embodiments, an amorphous form of a substance may be substantially free of other amorphous forms and/or crystal forms. In certain embodiments, an amorphous form of a substance may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, or less than about 50% by weight of one or more other amorphous forms and/or crystal forms on a weight basis. In certain embodiments, an amorphous form of a substance may be physically and/or chemically pure. In certain embodiments, an amorphous form of a substance be about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% physically and/or chemically pure.

As used herein, the term “about” when used in reference to XRPD peak positions refers to the inherent variability of peaks depending on the calibration of the instrument, processes used to prepare the crystalline forms of the present disclosure, age of the crystalline forms and the type of instrument used in the analysis. The variability of the instrumentation used for XRPD analysis was about ±0.2° 20.

As used herein, the term “about” when used in reference to DSC endothermic peak onset refers to the inherent variability of peaks depending on the calibration of the instrument, method used to prepare the samples of the present disclosure, and the type of instrument used in the analysis. The variability of the instrumentation used for DSC analysis was about ±1° C.

The term “about” as used herein other than the former definition, unless indicated otherwise, denotes that a number (e.g., temperature, pH, volume, etc.) can vary within ±10%, preferably within ±5%.

Experimental measurements, results, or observations, such as XRPD patterns, DSC thermograms, NMR spectra, DVS isotherms or TGA thermal curves, are said to be “substantially in accordance” with another XRPD pattern, DSC thermogram, NMR spectra, DVS isotherm or TGA thermal curve when one skilled in the art would consider them to represent the same single crystalline form of the same compound. Thus, an XRPD pattern, DSC thermogram, NMR spectra, DVS isotherm or TGA thermal curve that is substantially in accordance with one or more figures provided herein may be identical or, more likely, may be somewhat different. For example, an XRPD pattern that is somewhat different from one or more of the figures may not necessarily show each of the lines of the diffraction pattern presented herein and/or may show a slight change in appearance or intensity of the lines or a shift in the position of the lines. These differences typically result from differences in the conditions involved in obtaining the data or differences in the purity of the sample used to obtain the data. A person skilled in the art is capable of determining if a sample of a crystalline compound is of the same form as or a different form from a form disclosed herein by comparison of the XRPD pattern, DSC thermogram, NMR spectra, DVS isotherm, or TGA thermal curve of the sample and the corresponding XRPD pattern, DSC thermogram, NMR spectra, DVS isotherm or TGA thermal curve disclosed herein.

Surprisingly, salts of Compound 2, preferably oxalate salt of Compound 2, even more preferably the crystalline of oxalate salt of Compound 2 is a solid with very low viscosity and very good stability. The crystalline form of the oxalate salt of Compound 2, especially Form B of the oxalate can be obtained with a very good purity without further purification, which is suitable for large-scale industrial process. The particle size of Form B is 1-50 μm, preferably is 1-30 μm, more preferably is 5-20 μm, even more preferably is 5-10 μm. Such particle size can be obtained by filtration easily and quickly.

Aspect 1. A salt of formula (I):

Aspect 4. The salt of Aspect 1, which the salt is an oxalate salt of Formula (II):

Aspect 5. A crystalline form of a compound of Formula IV

Aspect 7. The crystalline form of any one of Aspects 5-6, wherein n is about 0.5 to about 3;

Aspect 9. The crystalline form of any one of Aspects 5-8, wherein m is a number about 0.0 to about 3.0, preferably about 0.0 to about 2.0, more preferably m is a number selected from the group consisting of 0.1±0.1, 0.5±0.1, 1.0±0.2, 1.5±0.2 and 2.0±0.2, even more preferably, m is 0˜0.2, 0.95˜1.05, 1.05˜1.15, 1.45˜1.55, 1.90˜2.10; more preferably, m is 0.98˜1.02, 1.08˜1.12 or 1.48˜1.52, 1.95˜2.15; even more preferably, m is 0, 0.1, 0.2, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5 or 7.0.

Aspect 10. A crystalline form of the oxalate salt of Compound 2, which is

Aspect 11. A crystalline form of the oxalate salt of Compound 2, which is

Aspect 12. A crystalline form of the oxalate salt of Compound 2, characterized by a powder X-ray diffraction pattern substantially in accordance with that depicted in a figure selected from the group consisting of FIG. 1A, FIG. 2A, FIG. 3A, and FIG. 4A.

Aspect 13. A process for preparing a crystalline form of the oxalate salt of Compound 2, comprising:

Aspect 14. The process for preparing a crystalline form of Aspect 13, wherein the time of Procedure (1) is 0-10 days, preferably is 0-7 days, more preferably is 2-4 days, even more preferably is 1, 2, 3, 4 or 5 days;

Aspect 15. The process for preparing a crystalline form of Aspect 13-14, wherein the oxalate salt/EtOH (mg/ml) in Procedure (1) is 1:1 to 100:1, preferably is 1:1 to 50:1, more preferably is 20:1 to 40:1, even more preferably is 30:1;

Aspect 16. The process for preparing a crystalline form of the oxalate salt of Compound 2, wherein the temperature of Procedure (1) is 0 to 50° C., preferably is 10 to 40° C., more preferably is 20 to 30° C., even more preferably is 20 to 25° C. or room temperature;

Aspect 17. The process for the preparation of the crystalline form of Aspect 13-16, wherein the starting material is selected from amorphous, type A, B, C, D; preferably is amorphous.

Aspect 18. The process for preparing a crystalline form of Aspect 13-17, wherein the process further comprises:

Aspect 19. The crystalline form of any one of Aspects 5-12 or the salt of any one of Aspects 1-4 is used as an intermediate of preparing sonrotoclax.

Aspect 20. Provided here is a process of preparing sonrotoclax,

or a salt thereof, comprising reacting a salt of formula (I), with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

In one embodiment of Aspect 20, the reaction happens at the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 4-dimethylaminopyridine (DMAP).

Aspect 21. Provided here is a method of preparing sonrotoclax,

or a salt thereof, comprising reacting a salt of formula (I), with an acid or a base, to provide (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid,

or a salt thereof.

In one embodiment of Aspect 21, the acid is HCl, or the base is NaOH.

Aspect 22. Provided here is a method of making sonrotoclax comprising reacting (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid,

or a salt thereof, with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

In one embodiment of Aspect 22, the reaction happens at the presence of EDCI and DMAP.

In one embodiment of Aspect 23, provided here is a method for preparing a pharmaceutical composition comprising Sonrotoclax, comprising mixing Sonrotoclax with a pharmaceutically acceptable excipient, wherein Sonrotoclax is prepared according to the method provided here.

Numbered Embodiments

Embodiment 1. A salt of formula (I):

Embodiment 4. The salt of Embodiment 1, which the salt is an oxalate salt of Formula (II):

Embodiment 5. A crystalline form of a salt of Formula IV

Embodiment 7. The crystalline form of any one of Embodiments 5-6, wherein n is about 0.5 to about 3;

Embodiment 9. The crystalline form of any one of Embodiments 5-8, wherein m is a number about 0.0 to about 3.0, preferably about 0.0 to about 2.0, more preferably m is a number selected from the group consisting of 0.1±0.1, 0.5±0.1, 1.0±0.2, 1.5±0.2 and 2.0±0.2, even more preferably, m is 0˜0.2, 0.95˜1.05, 1.05˜1.15, 1.45˜1.55, 1.90˜2.10; more preferably, m is 0.98˜1.02, 1.08˜1.12 or 1.48˜1.52, 1.95˜2.15; even more preferably, m is 0, 0.1, 0.2, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5 or 7.0.

Embodiment 10. The crystalline form of any one of Embodiments 5-9, which is

Embodiment 11. The crystalline form of any one of Embodiments 5-10, which is

Embodiment 12. The crystalline form of any one of Embodiments 5-11, substantially characterized by a powder X-ray diffraction pattern selected from the group consisting of FIG. 1A, FIG. 2A, FIG. 3A, and FIG. 4A.

Embodiment 13. A process for the preparation of the crystalline form of any one of Embodiments 5-12, comprising:

Embodiment 14. The process for the preparation of the crystalline form of embodiment 13, wherein the time of Procedure (1) is 0-10 days, preferably is 0-7 days, more preferably is 2-4 days, even more preferably is 1, 2, 3, 4 or 5 days;

Embodiment 15. The process for the preparation of the crystalline form of embodiment 13-14, wherein the oxalate salt/EtOH (mg/ml) in Procedure (1) is 1:1 to 100:1, preferably is 1:1 to 50:1, more preferably is 20:1 to 40:1, even more preferably is 30:1;

Embodiment 16. The process for the preparation of the crystalline form of embodiment 13-15, wherein the temperature of Procedure (1) is 0 to 50° C., preferably is 10 to 40° C., more preferably is 20 to 30° C., even more preferably is 20 to 25° C. or room temperature;

Embodiment 17. The process for the preparation of the crystalline form of embodiment 13-16, wherein the starting material is selected from amorphous, type A, B, C, D; preferably is amorphous.

Embodiment 18. The process for the preparation of the crystalline form of embodiment 13-17, wherein the process further comprises:

Embodiment 19. The process of the crystalline form of any one of Embodiments 5-12 or the salt of any one of Embodiments 1-4, wherein the crystalline form or the salt is used as an intermediate of preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide.

EXAMPLES

Abbreviations

Category
Acronyms
Full Name/Description

Analytical
DSC
Differential scanning calorimetry

Techniques
DVS
Dynamic vapor sorption

HPLC
High Performance Liquid

Chromatography

NMR
Nuclear magnetic resonance

TGA
Thermogravimetric analysis

Solvent
MeOH
Methanol

EtOH
Ethanol

IPA
Isopropyl alcohol

IPAc
Isopropyl acetate

MEK
Methyl ethyl ketone

NaOH
Sodium hydroxide

BE
Birefringence with Extinction

IPC
In process control

Vol or vol.
Volume

Instruments and Parameters

For XRPD analysis, a PANalytical Empyrean and X'Pert3 X-ray powder diffractometer were used to characterize the physical forms obtained in the present disclosure, without special instructions. The XRPD parameters used are listed as follows.

Scan mode
Continuous
Continuous

For XRPD analysis, a Bruker D8 advanced X-Ray Powder diffractometer or equivalent was also used to characterize Form A and Form U. The XRPD parameters used are listed as follows.

Fixed incident beam optics
Primary Soller slit: 2.5 deg

Scan mode
Continuous PSD fast

Scan type
Coupled Two Theta/Theta

TGA and DSC were used to characterize the physical forms obtained in the present disclosure, without special instructions, wherein TGA data were collected using a TA Q500/Q5000 TGA from TA Instruments; and DSC was performed using a TA Q200/Q2000 DSC from TA Instruments. Detailed parameters used are listed as follows.

Method
Ramp
Ramp
Modulated

temperature
temperature
temperature

For TGA and DGA analysis of Form A or U, some instruments were also used to conduct the testing, wherein TGA data were collected using a NETZSCH TG 209 F1 Instruments; and DSC was performed using a TA Q 20 or TA DSC 250 Instruments. Detailed parameters used are listed as follows.

Parameters
TGA
DSC

Method
Ramp
Ramp

Sample pan
Aluminum, open
Aluminum, Sealed

Temperature
RT - desired temperature
RT - desired temperature

DVS of the obtained forms in the present disclosure was measured via an SMS (Surface Measurement Systems) DVS Intrinsic, without special instructions (Method A). The relative humidity at 25° C. was calibrated against deliquescence point of LiCl, Mg(NO3)2 and KCl. Parameters for the DVS test are listed as follows.

Parameters
DVS

Sample size
10~20 mg

Gas and flow rate
N2, 200 mL/min

duration

Max. equilibrium time
180 min

DVS of Form A and U was also measured via an SMS (Surface Measurement Systems) DVS Intrinsic (Method B). The relative humidity at 25° C. was calibrated against deliquescence point of LiCl, Mg(NO3)2, and KCl. Parameters for DVS test are listed as follows.

Parameters
DVS

Gas and flow rate
N2, 200 mL/min

Max. equilibrium time
180 min

The single crystal X-ray diffraction data were collected at 120 K using Rigaku XtaLAB Synergy R (CuK radiation, 1.54184 Å) diffractometer. The instrument parameters are listed as follows.

Instrument
Rigaku XtaLAB Synergy R

Low Temperature Devices
Cryostream-700

The following Examples are intended to further illustrate certain embodiments of the disclosure and are not intended to limit the scope of the disclosure.

Seven acids and seven organic solvents were used for the salt formation of Compound 2, see Table 1.

In one example, Compound 2 (1.0 g, 1.73 mmol) in MTBE (10 mL) solution and oxalic acid (0.16 g, 1.73 mmol) was added dropwise. The reaction mixture was stirred for about 6 hours and filtered to obtain a wet cake of methyl 4-(2-{(2S)-2-[2-(propan-2-yl)phenyl]pyrrolidin-1-yl}-7-azaspiro[3.5]nonan-7-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzoate oxalate salt (Compound 3). The solid has low hydroscopic property, also the solid has poor static electricity capacity so it's not easy to adsorb to objects.

Other salts of Compound 2 was produced by a procedure similar to that disclosed for Compound 3 by using other acids. The other acids were used as the following amounts, D-(−)-tartaric (0.26 g, 1.73 mmol), p-toluenesulfonic acid (0.3 g, 1.73 mmol), D-DTTA (0.67 g, 1.73 mmol), Citric acid (0.33 g, 1.73 mmol), Malic acid (0.23 g, 1.73 mmol), Maleic acid (0.20 g, 1.73 mmol); and the other organic solvents were used with 10 mL volume.

The corresponding physical forms of Compound 2 salt was recited in Table 1. The result showed that, when the acid used in salt formation was Oxalic acid or D-DTTA, the obtained salt was solid form in certain organic solvents. Considering simplify the process D-DTTA/MTBE and Oxalic acid/MTBE were preferred as the salt formation systems, while D-DTTA (M.W. 386.35 g/mol) may cause more waste to the reaction compared with Oxalic acid (M.W. 90.03 g/mol).

Solvent
D-(—)-tartaric
Oxalic acid
acid
D-DTTA
Citric acid
Malic acid
Maleic acid

2-MeTHF
oil
oil
Clean solution
Clean solution
oil
Clean solution
Clean solution

MTBE
moisture
Fine solid
moisture absorption
Fine solid
moisture
moisture
moisture

absorption

absorption
absorption
absorption

IPAc
moisture
moisture
Clean solution
oil
moisture
oil
oil

absorption
absorption

absorption

Acetone
Clean solution
Clean solution
Clean solution
Clean solution
Clean
Clean solution
Clean solution

solution

MeOH
Clean solution
Clean solution
Clean solution
Clean solution
Clean
Clean solution
Clean solution

solution

EA
oil
oil
Clean solution
Clean solution
oil
oil
Clean solution

DCM
Clean solution
Clean solution
Clean solution
Clean solution
Clean
Clean solution
Clean solution

solution

Synthesis of Compound-3

Free base of 3 (21 g) was dissolved in methyl tert-butyl ether (110 g). The temperature was adjusted to 20° C.-30° C., then the solution of oxalic acid (3.33 g) in methyl tert-butyl ether (110 g) was added within 2 h. The solution was stirred at 20° C.-30° C. for 16 h. The resulting solid was filtered, washed with methyl tert-butyl ether (20 g). The filtered solid was dried at a temperature below 45° C. for 20-28 h as amorphous.

Example 1A: Preparation of Compound 3 Form A (Form A)

Crystalline Form A of Compound 3 sample was obtained via slow evaporation of a solution of Compound 3 in amorphous form in EtOH at RT.

Procedure: 30 mg of an amorphous solid of Compound 3 was weighed into a 3-mL glass vial, and 1 mL of EtOH was added into the vial to get a clear solution. The solution was evaporated at RT for 3 days to induce precipitation to obtain Crystalline Form A.

The X-ray powder diffraction (XRPD) pattern (conducted on Bruker D8 advanced X-Ray Powder diffractometer) was used to characterize the obtained Form A, which showed that Form A was in a crystalline form, see FIG. 1A. The characteristic peaks and percent peak intensities obtained from the XRPD analysis are listed in Table 1A.

XRPD pattern of Compound 3 Form A

TGA result indicated 2.7% of weight loss from 100 to 150° C. and 14% of weight loss from 160 to 250° C. DSC result showed three endothermic peaks at 51° C., 114° C. and 192° C. (onset temperature), respectively (FIG. 1B). In the 1H NMR spectrum, about 0.27% of EtOH was observed (FIG. 1C).

Example 2A: Preparation of Compound 3 Form B (Form B)

Crystalline Form B of Compound 3 sample was obtained via slow evaporation of a solution of Compound 3 in an amorphous form in DCM at RT.

Procedure: 30 mg of amorphous solid of Compound 3 was weighed into a 3-mL glass vial, and 1 mL of DCM was added into the vial to get a clear solution. The solution was evaporated at RT to induce precipitation to obtain Crystalline Form B.

The XRPD pattern was used to characterize the obtained Form B which showed that Form B was in a crystalline, see FIG. 2A. The characteristic peaks and percent peak intensities obtained from the XRPD analysis are listed in Table 2A.

XRPD pattern of Compound 3 Form B

TGA result indicated 0.9% of weight loss from 100 to 150° C. and 8.6% of weight loss from 170 to 250° C. DSC result showed three endothermnic peaks at 53° C., 124° C. and 192° C. (onset temperature), respectively (FIG. 2B). In the 1H NMR spectrum, about 3% of DCM was observed (FIG. 2C).

Example 3A: Preparation of Compound 3 Form C (Form C)

Crystalline Form C of Compound 3 sample was obtained via slurrying Compound 3 in an amorphous form in CPME at RT.

Procedure: 30 mg of amorphous solid of Compound 3 was weighed into a 3-mL glass vial, and 0.5 mL of CPME was added into the vial to get a suspension. The mixture was stirred at RT magnetically with a speed of 800 RPM for 4 days to obtain Crystalline Form C.

The XRPD pattern was used to characterize the obtained Form C which showed that Form C was in a crystalline, see FIG. 3A. The characteristic peaks and percent peak intensities obtained from the XRPD analysis are listed in Table 3A.

XRPD pattern of Compound 3 Form C

TGA result indicated 4.1% of weight loss from 95 to 150° C. and 14.8% of weight loss from 150 to 250° C. DSC result showed two endothermic peaks at 131° C. and 194° C. (onset temperature), respectively (FIG. 3B). In the 1H NMR spectrum, about 5.9% of CPME was observed (FIG. 3C).

Example 4A: Preparation of Compound 3 Form D (Form D)

Crystalline Form D of Compound 3 sample was obtained via slurrying Compound 3 in an amorphous form in toluene at 80° C.

Procedure: 30 mg of amorphous solid of Compound 3 was weighed into a 3-mL glass vial, and 0.5 mL of toluene was added into the vial to get a suspension. The mixture was stirred at 80° C. magnetically with a speed of 800 RPM for 4 days to obtain Crystalline Form D.

The XRPD pattern was used to characterize the obtained Form D which showed that Form D was in a crystalline, see FIG. 4A. The characteristic peaks and percent peak intensities obtained from the XRPD analysis are listed in Table 4A.

XRPD pattern of Compound 3 Form D

TGA result indicated 3.1% of weight loss from 120 to 170° C. and 13.5% of weight loss from 170 to 250° C. DSC result showed two endothermic peaks at 132° C. and 194° C. (onset temperature), respectively (FIG. 4B). In the 1H NMR spectrum, about 5.2% of toluene was observed (FIG. 4C).