Solid form of tert-butyl(S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate and methods for preparing them

Abstract

To provide a method for preparing solid crystalline form I of tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate.SOLUTION: Provided is a method comprising the steps of: dissolving tert-butyl (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate in ethyl acetate; heating the solution; cooling the solution; and adding diisopropyl ether to the solution.SELECTED DRAWING: Figure 8

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority and / or benefit of U.S. Provisional Patent Application No. 62 / 865,826, filed on 24 June 2019, which is incorporated herein by reference in its entirety and serves as the basis for the priority and / or benefit claimed in this application. The subject matter described herein relates to the solid state forms of tert-butyl(S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate, such as crystalline and amorphous forms, its pharmaceutical compositions, methods for preparation, and its use. [Background technology]

[0002] N-methyl-D-aspartate receptors (NMDA receptors) are thought to play a major role in synaptic plasticity, which underlies many higher-order cognitive functions such as memory acquisition, retention, and learning, as well as in certain cognitive pathways and pain perception. NMDA receptors also appear to be involved in broad-spectrum CNS dysfunction. Therefore, NMDA receptor modulators may offer pharmaceutical benefits. tert-butyl(S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate is disclosed in U.S. Patent No. 9,512,134 (the said patent is incorporated herein by reference in its entirety) as an NMDA receptor modulator that may be useful, for example, for the treatment of depression. There remains a need for a stable solid form of compound A that can be used in pharmaceutical compositions and in the manufacture thereof. [Overview of the project]

[0003] The following embodiments and examples described below are illustrative and illustrative, and are not intended to limit the scope. In one embodiment, a solid form of tert-butyl(S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate (hereinafter referred to as "Compound A") is provided. Compound A has the following structure:

[0004] [ka] It holds.

[0005] In some embodiments, a crystalline anhydrous form of compound A, represented as crystalline form I of compound A, is disclosed herein. In some embodiments, a crystalline dihydrate form of compound A, represented as crystalline form II of compound A, is disclosed herein. In some embodiments, amorphous forms of compound A are disclosed herein. In another embodiment, a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and compound A in solid form is disclosed herein. In some embodiments, pharmaceutical compositions comprising at least one pharmaceutically acceptable excipient and a crystalline form I of compound A are disclosed herein. In some embodiments, pharmaceutical compositions comprising at least one pharmaceutically acceptable excipient and crystalline form II of compound A are disclosed herein. In some embodiments, pharmaceutical compositions comprising pharmaceutically acceptable excipients and an amorphous form of compound A are disclosed herein.

[0006] In another embodiment, a method is disclosed for treating a subject in need of treatment for a disease or disorder responsive to NMDA modulation, such as major depressive disorder, comprising administering a therapeutically effective amount of a pharmaceutical composition to the subject in need, wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient and a solid form of compound A. In some embodiments, a method is disclosed for treating a subject in need of treatment for a disease or disorder responsive to NMDA modulation, such as major depressive disorder, comprising administering a therapeutically effective amount of a pharmaceutical composition to the subject in need, wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient and a crystalline form I of compound A. In some embodiments, a method is disclosed for treating a subject in need of treatment for a disease or disorder responsive to NMDA modulation, such as major depressive disorder, comprising administering a therapeutically effective amount of a pharmaceutical composition to the subject in need, wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient and a crystalline form II of compound A. In some embodiments, a method is disclosed for treating a subject in need of treatment for a disease or disorder responsive to NMDA modulation, such as major depressive disorder, comprising administering a therapeutically effective amount of a pharmaceutical composition to the subject in need, wherein the pharmaceutical composition comprises a pharmaceutically acceptable excipient and an amorphous form of compound A.

[0007] In another embodiment, a method for preparing the solid form of compound A is disclosed. In some embodiments, a method for preparing crystalline form I of compound A is disclosed. In some embodiments, a method for preparing crystalline form II of compound A is disclosed. In some embodiments, methods for preparing the amorphous form of compound A are disclosed. Some non-exclusive exemplary embodiments are listed below. Example Embodiment 1: Compound A:

[0008]

Chem.

[0009]

Chemical formula

[0010] [ka] It is a solid crystalline form, This is the crystalline form II of compound A, which is the solid crystalline form. Exemplary Embodiment 29: The solid crystalline form according to Exemplary Embodiment 28, wherein the powder X-ray diffraction pattern has peaks (2θ) selected from those having approximately the following values: 9.4, 10.8, 11.9, and 13.0. Exemplary Embodiment 30: The solid crystalline form according to Exemplary Embodiment 29, further having one or more peaks (2θ) in the powder X-ray diffraction pattern selected from approximately the following values: 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3. Exemplary Embodiment 31: The solid crystalline form according to Exemplary Embodiment 28, having a peak (2θ) in the powder X-ray diffraction pattern selected from approximately the following values: 9.4, 10.8, 11.9, 13.0, and 13.7. Exemplary Embodiment 32: The solid crystalline form according to Exemplary Embodiment 28, having a peak (2θ) in the powder X-ray diffraction pattern selected from approximately the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, and 16.0. Exemplary Embodiment 33: The solid crystalline form according to Exemplary Embodiment 28, having a peak (2θ) in the powder X-ray diffraction pattern selected from those having approximately the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, and 20.4. Exemplary Embodiment 34: The solid crystalline form according to Exemplary Embodiment 28, having a peak (2θ) in the powder X-ray diffraction pattern selected from approximately the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, and 21.3. Exemplary Embodiment 35: The solid crystalline form according to Exemplary Embodiment 28, having a peak (2θ) in the powder X-ray diffraction pattern selected from approximately the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3. Exemplary Embodiment 36: The solid crystalline form according to Exemplary Embodiment 28, having three, four, or five peaks (2θ) selected from approximately the following values ​​in the powder X-ray diffraction pattern: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3. Exemplary Embodiment 37: A solid crystalline form according to Exemplary Embodiment 28, having an XRPD pattern substantially similar to one of the two XRPD patterns shown in Figure 3. Exemplary Embodiment 38: A solid crystalline form according to any one of Exemplary Embodiments 28 to 37, having a DSC with endothermic peaks at approximately 82°C and approximately 159°C. Exemplary Embodiment 39: A solid crystalline form according to any one of Exemplary Embodiments 28 to 38, having a TGA that exhibits dehydration above approximately 60°C with a water loss of approximately 9.6% by mass. Exemplary Embodiment 40: A solid crystalline form according to any one of Exemplary Embodiments 28 to 39, having a DVS that exhibits a mass change of about 11% at 0% RH and 25°C, and whose mass does not lose water at 20% RH or higher. Exemplary Embodiment 41: A solid composition comprising a solid crystalline form described in any one of Exemplary Embodiments 28 to 40, wherein the solid composition does not contain any other solid form of compound A in an amount of at least 99% by mass, at least 95% by mass, at least 90% by mass, at least 80% by mass, at least 70% by mass, at least 60% by mass, or at least 50% by mass. Exemplary Embodiment 42: A pharmaceutical composition comprising a solid crystalline form and a pharmaceutically acceptable excipient as described in any one of Exemplary Embodiments 28 to 40. Exemplary Embodiment 43: The pharmaceutical composition according to Exemplary Embodiment 42, wherein the solid crystalline form is at least 99% by mass, at least 95% by mass, at least 90% by mass, at least 80% by mass, at least 70% by mass, at least 60% by mass, or at least 50% by mass of the total amount of tert-butyl(S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate in the pharmaceutical composition. Example Embodiment 44: Compound A:

[0011] [ka] The solid amorphous form. Exemplary Embodiment 45: A solid amorphous form according to Exemplary Embodiment 44, having an amorphous halo in the powder X-ray diffraction pattern. Exemplary Embodiment 46: A solid amorphous form according to Exemplary Embodiment 44, having an XRPD pattern substantially similar to that of Figure 7. Exemplary Embodiment 47: A pharmaceutical composition comprising the amorphous form and a pharmaceutically acceptable excipient described in any one of Exemplary Embodiments 44 to 46. Exemplary Embodiment 48: The pharmaceutical composition according to Exemplary Embodiment 47, wherein the amorphous form is at least 99% by mass, at least 95% by mass, at least 90% by mass, at least 80% by mass, at least 70% by mass, at least 60% by mass, or at least 50% by mass of the total amount of tert-butyl(S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate in the pharmaceutical composition. Exemplary Embodiment 49: A method for treating a subject in need of treatment for a disease or disorder in response to NMDA modulation, comprising administering to the subject in need of such treatment a therapeutically effective amount of the pharmaceutical composition described in any one of Exemplary Embodiments 26, 27, 42, 43, 47, and 46. Exemplary Embodiment 50: The disease or disorder is autism, anxiety, depression, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, mental disorder, psychotic symptoms, social withdrawal, obsessive-compulsive disorder (OCD), phobias, post-traumatic stress disorder, behavioral disorder, impulse control disorder, substance abuse disorder. The method according to exemplary embodiment 49, selected from (disorder), sleep disorders, memory impairment, learning disabilities, urinary incontinence, multiple system atrophy, progressive supranuclear palsy, Friedreich's ataxia, Down syndrome, fragile X syndrome, tuberous sclerosis, olivopontocerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, dementia, AIDS dementia, Alzheimer's disease, Huntington's disease, spasticity, myoclonus, muscle spasms, Tourette syndrome, epilepsy, cerebral ischemia, stroke, brain tumor, traumatic brain injury, cardiac arrest, myelopathy, spinal cord injury, peripheral neuropathy, acute neuropathic pain, and chronic neuropathic pain. Exemplary Embodiment 51: The method according to Exemplary Embodiment 50, wherein the substance abuse disorder is selected from withdrawal symptoms, opiate addiction, nicotine addiction, and ethanol addiction. Exemplary Embodiment 52: The method according to Exemplary Embodiment 50, wherein the memory impairment is selected from missing, lost, and impaired ability to create new memories. Exemplary Embodiment 53: The method according to Exemplary Embodiment 49, wherein the disease or disorder is major depressive disorder. Exemplary Embodiment 54: Orthorhombic crystal system, P212121 space group, and the following unit cell dimensions: a=5.85088(9)Å, b=11.57133(12)Å and c=25.8340(3)Å, α=β=γ=90°, V=1749.02(4)Å 3 The crystalline form of tert-butyl(S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate, having Z=4. Exemplary Embodiment 55: Orthorhombic crystal system, P212121 space group, and the following unit cell dimensions: a=8.9035(2)Å, b=10.5404(2)Å and c=21.3018(5)Å, α=β=γ=90°, V=1999.10(8)Å 3 The crystalline form of tert-butyl(S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate dihydrate, having Z=4. Exemplary Embodiment 56: Compound A, substantially as described herein:

[0012] [ka] The solid crystalline form. Exemplary Embodiment 57: Compound A, substantially as described herein:

[0013] [ka] Solid crystalline form I. Exemplary Embodiment 58: Compound A, substantially as described herein:

[0014] [ka] Solid crystalline form II. Exemplary Embodiment 59: Compound A, substantially as described herein:

[0015] [ka] The solid amorphous form.

[0016] Additional embodiments of each aspect will be apparent from the following description, drawings, examples, and claims. As can be understood from the foregoing and the following description, each and all features described herein, and each and all combinations of two or more such features, are included within the scope of this disclosure insofar as the features and combinations are included in a manner that is non-contradictory to each other. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention. Additional aspects and advantages of the present invention are expressed in the following description and claims, particularly when considered in conjunction with the appended examples and drawings. [Brief explanation of the drawing]

[0017] [Figure 1] Figure 1 shows the powder X-ray diffraction (XRPD) pattern obtained from experiments with crystalline form I of compound A, and the powder X-ray diffraction pattern calculated from the single-crystal structure of crystalline form I of compound A. [Figure 2] Figure 2 shows the differential scanning calorimetry (DSC) thermogram of crystalline form I of compound A. [Figure 3] Figure 3 shows the powder X-ray diffraction (XRPD) pattern obtained from experiments with crystalline form II of compound A, and the powder X-ray diffraction pattern calculated from the single-crystal structure of crystalline form II of compound A. [Figure 4] Figure 4 shows the thermogravimetric analysis (TGA) curve for crystalline form II of compound A. [Figure 5] Figure 5 shows the differential scanning calorimetry (DSC) thermogram of crystalline form II of compound A. [Figure 6]Figure 6 shows the desorption profile of the water vapor isotherm (DVS) at 25°C for crystalline form II of compound A. [Figure 7] Figure 7 shows the powder X-ray diffraction (XRPD) pattern obtained from experiments on the amorphous form of compound A. [Figure 8] Figure 8 shows the atomic displacement ellipsoid diagram of crystalline form I of compound A based on single-crystal X-ray analysis. [Figure 9] Figure 9 shows the packing diagram of crystalline form I of compound A, viewed along the axis. [Figure 10] Figure 10 shows the molecular conformation diagram of crystalline form II of compound A based on single-crystal X-ray analysis. Hydrogen atoms are omitted in the figure, and only heavy atoms (C, N, O) are shown. [Figure 11] Figure 11 shows the packing diagram of crystalline form II of compound A, viewed along the axis. [Modes for carrying out the invention]

[0018] I. Definition Various embodiments are described more fully below in this specification. However, such embodiments may be embodied in many different forms and should not be construed as limiting the embodiments described herein, but rather these embodiments are provided so that this disclosure is thorough and complete and fully conveys its scope to those skilled in the art. As used herein, the term “therapeutic dose” means an amount of the compound sufficient to demonstrate a benefit to an individual or subject. This amount prevents, alleviates, reduces, or otherwise reduces the severity of symptoms of a disease or disorder that responds to NMDA modulation, such as major depressive disorder. Where a range of values ​​is provided, the values ​​that lie between the upper and lower limits of that range, as well as any other stated or intervening values ​​within that stated range, are intended to be included within this disclosure. For example, if the range 1 μm to 8 μm is stated, then the ranges of 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μm are intended to be expressly disclosed, as are the ranges of values ​​greater than or equal to 1 μm and the ranges of values ​​less than or equal to 8 μm. The singular forms "a," "an," and "the" refer to multiple objects unless the context explicitly indicates otherwise. Therefore, for example, a reference to "excipients" can include not only a single excipient, but also two or more identical or different excipients. The term "about" means, in particular, in reference to a given quantity, to include deviations of plus or minus 5%, 15%, or 20%.

[0019] II. Solid State Form of Compound A The solid-state forms of compound A and methods for preparing them are disclosed herein. The solid state can be crystalline (the molecules in the solid state are arranged in a long-term, regularly repeating crystal lattice that can be described by a unit cell) or amorphous (the molecules in the solid state are not arranged in any significantly regularly repeating manner). Furthermore, with respect to the crystalline state in particular, compound A may exist in the crystal lattice as the sole component of the crystal lattice (e.g., compound A may exist in the crystalline solid state as an anhydrous or other non-solvated form). Alternatively, compound A may exist in the crystal lattice together with other molecules (e.g., water or other solvent molecules), and the other molecules also form part of the crystal lattice so that it exists as a whole in a fixed ratio with respect to compound A (e.g., with respect to water, as the dihydrate of compound A). Furthermore, those skilled in the art will also know that the crystalline state can often be imperfect, where there may be some vacancies in the crystal lattice and / or some impurities (e.g., molecules other than compound A, or stoichiometric solvent molecules) in part of the crystal lattice. However, even in such an imperfect form, the form may still be described as a specific crystalline form (for example, crystalline form I or crystalline form II as described herein).

[0020] The solid-state morphologies described herein can be identified by any one or more solid-state analysis methods. For example, crystalline morphologies I and / or II of compound A described herein can be characterized by any one or more of the following: X-ray diffraction (including powder X-ray diffraction), unit cell constants obtained from single crystals, differential scanning calorimetry, and thermogravimetric analysis.

[0021] In some embodiments, the solid-state morphologies described herein can be characterized according to powder X-ray diffraction (XRPD). However, it is known in the art that the intensity and / or measured peaks in powder X-ray diffractograms of different batches of solid-state morphologies may vary, for example, due to different experimental conditions and / or preferred adaptations. And, due to the precision of the instrument, the measurement error of the 2θ value is ±0.2 2θ. However, despite the principles such as experimental and machine errors, as well as such preferred adaptations, those skilled in the art can find sufficient information in the XRPD data provided herein and identify crystalline morphologies I and II without having to rely on all of the provided XRPDs.

[0022] Therefore, "substantially similar" exists between one XRPD pattern and another if, even if the relative intensities of the corresponding peaks are different, most of the peaks (e.g., more than 80 peaks) in the 2θ-degree range of 0–40° in one XRPD can be found to correspond to the peaks in another XRPD. Unless otherwise specified, the XRPDs described herein are obtained using Cu K-alpha lines at 1.54 A(λ), 40 kV, and 15 mA.

[0023] A. Crystalline form of compound A I A crystalline form I of compound A and a method for preparing it are provided herein. The crystalline form I of compound A is thought to be the anhydrous form of compound A. In some embodiments, the XRPD of crystalline morphology I described herein has peaks (2θ) selected from those having the following values: 6.9, 8.4, 10.3, and 12.8, each with a diffraction angle of ±0.2 degrees (2θ). In some embodiments, the XRPD of crystalline morphology I described herein further has one or more peaks (2θ) selected from those having the following values: 13.7, 15.3, 15.7, 16.8, 17.3, 18.5, and 19.9, each with a diffraction angle of ±0.2 degrees (2θ).

[0024] In some embodiments, the XRPD of crystalline morphology I described herein may have peaks (2θ) selected from those having the following values: 6.9, 8.4, 10.3, 12.8, and 13.7, each with a diffraction angle of ±0.2 degrees (2θ). In some embodiments, the XRPD of crystalline morphology I described herein may have peaks (2θ) selected from those having the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, and 15.7, each with a diffraction angle of ±0.2 degrees (2θ). In some embodiments, the XRPD of crystalline morphology I described herein may have peaks (2θ) selected from those having the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, and 16.8, each with a diffraction angle of ±0.2 degrees (2θ). In some embodiments, the XRPD of crystalline morphology I described herein may have peaks (2θ) selected from those having diffraction angles of ±0.2 degrees (2θ) for the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, and 17.3. In some embodiments, the XRPD of crystalline morphology I described herein may have peaks (2θ) selected from those having diffraction angles of ±0.2 degrees (2θ) for the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, 17.3, and 18.5. In some embodiments, the XRPD of crystalline form I described herein may have three, four, or five peaks (2θ) selected from those having diffraction angles of ±0.2 degrees (2θ) for the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, 17.3, 18.5, and 19.9.

[0025] In some embodiments, the crystalline morphology I described herein may have an XRPD substantially similar to one of the XRPDs shown in Figure 1. In some embodiments, crystalline morphology I of compound A can be characterized according to a DSC thermogram. For example, embodiments of crystalline morphology I described herein are provided, having a DSC thermogram substantially similar to that shown in Figure 2. Embodiments of crystalline morphology I described herein are also provided, having a DSC with an endothermic peak at approximately 159°C, e.g., approximately 159.21°C. In some embodiments, crystalline form I may be present in the solid composition. In some embodiments, the solid composition may consist almost entirely of compound A, but may contain some additional components (e.g., a solid composition obtained from the synthesis and / or purification of compound A, in which the composition may contain some residual solvents). In such a solid composition, solid compound A may exist almost entirely as crystalline form I, or it may exist as a mixture of crystalline form I and crystalline form II and / or amorphous solid forms of compound A. The presence and existence of crystalline form I in the solid composition can be determined by XRPD showing characteristic 2θ peaks for crystalline form I as described herein, as well as by other characterization methods described herein and / or that can be identified to those skilled in the art when reading this specification.

[0026] In some embodiments, the solid composition may contain crystalline form I and be substantially free of crystalline form II and / or amorphous form of compound A. For example, a solid composition containing crystalline form I may be free of at least 99% by mass, at least 95% by mass, at least 90% by mass, or at least 80% by mass of crystalline form II and / or amorphous form of compound A. Furthermore, for example, a solid composition containing crystalline form I may be free of at least 70% by mass or at least 60% by mass of crystalline form II and / or amorphous form of compound A. Even further, for example, a solid composition containing crystalline form I may be free of at least 50% by mass or more of crystalline form II and / or amorphous form of compound A. The amount of crystalline form I relative to crystalline form II and / or amorphous form of compound A can be determined by methods identifiable to those skilled in the art, such as powder X-ray diffraction, Raman spectroscopy, solid-state nuclear magnetic resonance, differential scanning calorimetry, and dynamic vapor adsorption.

[0027] In some embodiments, a solid composition containing crystalline form I may be substantially free of any other solid form (crystalline or amorphous) of compound A. For example, a solid composition containing crystalline form I may be free of at least 99% by mass, at least 95% by mass, at least 90% by mass, or at least 80% by mass of any other solid form of compound A. Furthermore, for example, a solid composition containing crystalline form I may be free of at least 70% by mass or at least 60% by mass of any other solid form of compound A. Even further, for example, a solid composition containing crystalline form I may be free of at least 50% by mass or more of any other solid form of compound A. The amount of crystalline form I relative to other forms of compound A can be determined by methods that are identifiable to those skilled in the art, such as powder X-ray diffraction, Raman spectroscopy, solid-state nuclear magnetic resonance, differential scanning calorimetry, and dynamic vapor adsorption. In some embodiments, the crystalline form I of compound A is orthorhombic, P212121 space group, and the following unit cell dimensions: a=5.85088(9)Å, b=11.57133(12)Å and c=25.8340(3)Å, α=β=γ=90°, V=1749.02(4)Å 3 It has a crystalline form with Z=4.

[0028] A method for preparing crystalline form I of compound A, comprising dissolving compound A in a first solvent (e.g., ethyl acetate) and heating the solution (e.g., to about 65-70°C); Methods are also provided that include cooling the solution (e.g., to about 25°C) and adding a second solvent (e.g., diisopropyl ether) to the solution. In some embodiments, the method further includes filtering and drying the collected solid. A method for preparing crystalline form I of compound A is also provided, comprising heating crystalline form II of compound A for dehydration. In some embodiments, the heating is carried out at about 80°C.

[0029] B. Crystalline form of compound A II The crystalline form II of compound A and a method for preparing it are provided herein. The crystalline form II of compound A is thought to be the hydrate form of compound A.

[0030] In some embodiments, the XRPD of crystalline form II described herein has peaks (2θ) selected from those having diffraction angles of ±0.2 degrees (2θ) for the following values: 9.4, 10.8, 11.9, and 13.0. In some embodiments, the XRPD of crystalline form II described herein further has one or more peaks (2θ) selected from those having diffraction angles of ±0.2 degrees (2θ) for the following values: 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3.

[0031] In some embodiments, the XRPD of crystalline form II described herein may have peaks (2θ) selected from those having the following values: 9.4, 10.8, 11.9, 13.0, and 13.7, each with a diffraction angle of ±0.2 degrees (2θ). In some embodiments, the XRPD of crystalline form II described herein may have peaks (2θ) selected from those having the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, and 16.0, each with a diffraction angle of ±0.2 degrees (2θ). In some embodiments, the XRPD of crystalline form II described herein may have peaks (2θ) selected from those having the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, and 20.4, each with a diffraction angle of ±0.2 degrees (2θ). In some embodiments, the XRPD of crystalline form II described herein may have peaks (2θ) selected from those having the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, and 21.3, each with a diffraction angle of ±0.2 degrees (2θ). In some embodiments, the XRPD of crystalline form II described herein may have three, four, or five peaks (2θ) selected from those having diffraction angles of ±0.2 degrees (2θ) for the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3. In some embodiments, the crystalline form II described herein may have an XRPD substantially similar to one of the two XRPDs shown in Figure 3.

[0032] In some embodiments, crystalline form II of compound A can be characterized by thermogravimetric analysis (TGA). For example, embodiments of crystalline form II described herein are provided, having a TGA showing that crystalline form II dehydrates above approximately 60°C with a loss of approximately 9.5% by mass of water. See, for example, Figure 4. In some embodiments, crystalline form II of compound A can be characterized according to a DSC thermogram. A crystalline form II described herein having a DSC thermogram indicates that form II dehydrates at about 82°C and then melts at about 159°C. For example, an embodiment of crystalline form II described herein is provided having a DSC thermogram substantially similar to that shown in Figure 5. Upon dehydration, this form transforms into crystalline form I, which melts at about 159°C, for example, about 159.56°C.

[0033] In some embodiments, crystalline form II of compound A can be characterized by DVS (dynamic vapor adsorption), which shows that crystalline form II loses about 11% of water at 0% relative humidity (RH) and does not lose water at 20% RH or higher. In some embodiments, crystalline form II may be present in the solid composition. In some embodiments, the solid composition may consist almost entirely of compound A, but may contain some additional components (e.g., a solid composition resulting from the conversion of a composition containing crystalline form I to a composition containing form II, where the original composition containing crystalline form I has some impurities such as residual solvent). In such a solid composition, solid compound A may exist almost entirely as crystalline form II, or it may exist as a mixture of crystalline form II and crystalline form I and / or amorphous solid form of compound A. The presence and existence of crystalline form II in the solid composition can be determined by XRPD showing characteristic 2θ peaks for crystalline form I as described herein, as well as by other characterization methods described herein and / or that can be identified to those skilled in the art when reading this specification.

[0034] In some embodiments, the solid composition may contain crystalline form II and be substantially free of crystalline form I and / or amorphous form of compound A. For example, a solid composition containing crystalline form II may be free of at least 99% by mass, at least 95% by mass, at least 90% by mass, or at least 80% by mass of crystalline form I and / or amorphous form of compound A. Furthermore, for example, a solid composition containing crystalline form II may be free of at least 70% by mass or at least 60% by mass of crystalline form I and / or amorphous form of compound A. Even further, for example, a solid composition containing crystalline form II may be free of at least 50% by mass or more of crystalline form I and / or amorphous form of compound A. The amount of crystalline form II relative to crystalline form I and / or amorphous form of compound A can be determined by methods that are identifiable to those skilled in the art, such as powder X-ray diffraction, Raman spectroscopy, solid-state nuclear magnetic resonance, differential scanning calorimetry, and dynamic vapor adsorption.

[0035] In some embodiments, a solid composition containing crystalline form II may be substantially free of any other solid form (crystalline or amorphous) of compound A. For example, a solid composition containing crystalline form II may be free of at least 99% by mass, at least 95% by mass, at least 90% by mass, or at least 80% by mass of any other solid form of compound A. Furthermore, for example, a solid composition containing crystalline form II may be free of at least 70% by mass or at least 60% by mass of any other solid form of compound A. Even further, for example, a solid composition containing crystalline form II may be free of at least 50% by mass or more of any other solid form of compound A. The amount of crystalline form II relative to other forms of compound A can be determined by methods that are identifiable to those skilled in the art, such as powder X-ray diffraction, Raman spectroscopy, solid-state nuclear magnetic resonance, differential scanning calorimetry, and dynamic vapor adsorption.

[0036] In some embodiments, the crystalline form II of compound A is orthorhombic, P212121 space group, and the following unit cell dimensions: a=8.9035(2)Å, b=10.5404(2)Å and c=21.3018(5)Å, V=1999.10(8)Å 3 It has a crystalline form accompanied by [something].

[0037] A method for preparing a crystalline form II of compound A is also provided, comprising mixing a crystalline form I of compound A with water for a period of time (e.g., about 4 hours), for example, by slurring. In some embodiments, the method further comprises filtering and drying the solid. In some embodiments, the amount of compound A slurried in water varies from 0.1 to 1.0 g per milliliter of water. In other embodiments, the amount of compound A slurried in water varies from 0.1 to 5.0 g per milliliter of water.

[0038] C. Amorphous form of compound A The amorphous form of compound A and a method for preparing it are also provided. In some embodiments, the amorphous forms described herein may have an XRPD substantially similar to that shown in Figure 7. In some embodiments, an amorphous form of compound A may be present in the solid composition. In some embodiments, the solid composition may consist almost entirely of compound A, but may contain some additional components (e.g., a solid composition obtained from spray drying of a solution of compound A in a solvent, which may contain some residual solvent). In such a solid composition, the solid compound A may exist almost entirely as an amorphous form of compound A, or it may exist as a mixture of the amorphous form of compound A and crystalline form I and / or crystalline form II of compound A. The existence and presence of the amorphous form of compound A in the solid composition can be determined by the XRPD showing its appearance in Figure 7 (i.e., no indication of crystallinity), as well as by other characterization methods described herein and / or identifiable to those skilled in the art when reading this specification.

[0039] In some embodiments, the solid composition may contain the amorphous form of compound A and be substantially free of crystalline form I and / or crystalline form II of compound A. For example, a solid composition containing the amorphous form of compound A may be free of at least 99% by mass, at least 95% by mass, at least 90% by mass, or at least 80% by mass of crystalline form I and / or crystalline form II of compound A. Furthermore, for example, a solid composition containing the amorphous form of compound A may be free of at least 70% by mass or at least 60% by mass of crystalline form I and / or crystalline form II of compound A. Even further, for example, a solid composition containing the amorphous form of compound A may be free of at least 50% by mass or more of crystalline form I and / or crystalline form II of compound A. The amount of amorphous form relative to crystalline form I and / or crystalline form II of compound A can be determined by methods that are identifiable to those skilled in the art, such as powder X-ray diffraction, Raman spectroscopy, solid-state nuclear magnetic resonance, differential scanning calorimetry, and dynamic vapor adsorption.

[0040] In some embodiments, a solid composition containing crystalline form I may be substantially free of any other non-amorphous solid form of compound A (e.g., crystalline solid form). For example, a solid composition containing crystalline form I may be free of at least 99% by mass, at least 95% by mass, at least 90% by mass, or at least 80% by mass of any other non-amorphous solid form of compound A. Furthermore, for example, a solid composition containing the amorphous form of compound A may be free of at least 70% by mass or at least 60% by mass of any other non-amorphous solid form of compound A. Even further, for example, a solid composition containing the amorphous form of compound A may be free of at least 50% by mass or more of any other non-amorphous solid form of compound A. The amount of amorphous form relative to other forms of compound A can be determined by methods identifiable to those skilled in the art, such as powder X-ray diffraction, Raman spectroscopy, solid-state nuclear magnetic resonance, differential scanning calorimetry, and dynamic vapor adsorption.

[0041] A method for preparing an amorphous form of compound A is also provided, comprising drying a solution of compound A in a solvent. In some embodiments, the solvent is acetone. In some embodiments, the ratio (g / mL) of compound A to acetone is in the range of 0.05 to 0.2. In some embodiments, drying is carried out in the form of spray drying.

[0042] III. Pharmaceutical Compositions and Their Use A pharmaceutical composition is provided comprising a crystalline form I of compound A and a pharmaceutically acceptable excipient. In some embodiments, the crystalline form I of compound A is at least 99% by mass, at least 95% by mass, at least 90% by mass, at least 80% by mass, at least 70% by mass, at least 60% by mass, or at least 50% by mass of the total amount of compound A in the pharmaceutical composition. A pharmaceutical composition is provided comprising a crystalline form II of compound A and a pharmaceutically acceptable excipient. In some embodiments, the crystalline form II of compound A is at least 99% by mass, at least 95% by mass, at least 90% by mass, at least 80% by mass, at least 70% by mass, at least 60% by mass, or at least 50% by mass of the total amount of compound A in the pharmaceutical composition. A pharmaceutical composition is provided comprising the amorphous form of compound A and pharmaceutically acceptable excipients. In some embodiments, the amorphous form of compound A constitutes at least 99% by mass, at least 95% by mass, at least 90% by mass, at least 80% by mass, at least 70% by mass, at least 60% by mass, or at least 50% by mass of the total amount of compound A in the pharmaceutical composition.

[0043] Typical excipients must be compatible with the other components of the composition and must not be harmful to the patient's health. Excipients may be solid, liquid, or both, and may be formulated as a single dose, for example, as tablets or capsules, with compound A, e.g., crystalline form I, crystalline form II, and / or amorphous form as described herein, which may be prepared in an amount of 0.05% to 95% by mass of compound A as described herein. Pharmaceutical compositions as described herein may be produced by known pharmaceutical methods, e.g., methods comprising mixing components with pharmaceutically acceptable excipients. In some embodiments, typical excipients may include, but are not limited to, microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate, glycine, disintegrants such as starch, cross-linked sodium carboxymethylcellulose, synthetic silicates, and high molecular weight polyethylene glycol, granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin, and gum arabic), and lubricants (such as magnesium stearate, glycerin, and talc).

[0044] A method is also provided for treating a subject in need of treatment for a disease or disorder in response to NMDA modulation, comprising administering a therapeutically effective amount of a pharmaceutical composition to the subject in need thereof, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and a solid form of compound A selected from crystalline form I, crystalline form II, and amorphous form of compound A disclosed herein. The disease or disorder may be a mental disorder or disorder, a neurological disorder or disorder, or a neurodegenerative disorder or disorder. In some embodiments, the disease or disorder is autism, anxiety, depression, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, mental disorder, psychotic symptoms, social withdrawal, obsessive-compulsive disorder (OCD), phobias, post-traumatic stress disorder, behavioral disorders, impulse control disorders, substance abuse disorders (e.g., withdrawal symptoms, opiate addiction, nicotine addiction, and ethanol addiction), sleep disorders, memory impairment (e.g., missing, lost, or impaired ability to form new memories), learning disabilities, urinary incontinence, polysomnia The following conditions are selected: cerebral atrophy, progressive supranuclear palsy, Friedreich's ataxia, Down syndrome, fragile X syndrome, tuberous sclerosis, olivopontocerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, dementia, AIDS dementia, Alzheimer's disease, Huntington's disease, spasticity, myoclonus, muscle spasms, Tourette syndrome, epilepsy, cerebral ischemia, stroke, brain tumor, traumatic brain injury, cardiac arrest, myelopathy, spinal cord injury, peripheral neuropathy, acute neuropathic pain, and chronic neuropathic pain. In some embodiments, the disease or disorder is major depressive disorder. [Examples]

[0045] IV. Examples The following examples are merely illustrative and not intended to be limiting. Unless otherwise specified, powder X-ray diffractograms were obtained using a Rigaku MiniFlex 600 with a D / tex detector, with radiation generated from a 15 mA and 40 kV Cu Kα source, by placing the sample in a sample holder with zero background. The instrument was operated over 2θ in the range of 3–45° with a scan step of 0.02° and a scan rate of 2° / min. DSC: Thermograms were obtained using a TA Instruments DSC Q2000. Approximately 1-2 mg of sample was weighed into a Tzero aluminum pan and sealed with a Tzero airtight lid. For crystalline morphology II samples, the lid was perforated with a pinhole. - DSC: The sample was scanned at 10°C / min from 20 to 180°C. TGA: Approximately 5-10 mg of the sample was heated at 10°C / min from room temperature to 250°C. DVS: The following methods were used for water vapor adsorption analysis using the DVS Advantage (surface measurement system). - Temperature: 25℃ - RH Program: 95, 90, 80, 70, 60, 50, 40, 35, 30, 20, 10, 0% - Dm / dt(% / min):0.0005 - Minimum equilibration time: 120 minutes - Maximum equilibration time: 2000 minutes

[0046] Single-crystal analysis of crystalline morphology I of compound A was performed using a Rigaku SuperNova diffractometer with a single Cu Kα (λ=1.54184Å) microfocus source at 300K using a Pilatus 200K hybrid pixel array detector. Refinement was performed using ShelXL. Single-crystal analysis of crystalline form II of compound A was performed using a Bruker AXS D8 Quest CMOS diffractometer with a quad-axis kappa stage, employing Cu Kα line (λ=1.54178 Å), an I-μ-S microsource X-ray tube with a transversely stepped multilayer optical system, a Photon2 CMOS region detector, and an Oxford Cryosystems cryogenic device at 150 K.

[0047] (Example 1) Preparation of Form I of Compound A The crystalline form I of compound A was prepared according to the following scheme.

[0048] [ka]

[0049] Step 1: Synthesis of compound H In a nitrogen-purged reactor, acetonitrile, D-proline (69.0 kg), molecular sieves, and chloral hydrate (106 kg) were added. The mixture was heated at 50°C for 5.3 hours. Proton NMR showed complete conversion. The reaction mixture was filtered through a pad of acetonitrile-soaked Celite and rinsed through acetonitrile. The filtrate was concentrated under vacuum at less than 45°C to a total volume of 100 L. n-butanol (140 L) was added, and the mixture was concentrated under vacuum at less than 45°C for 3.5 hours until no further distillates were observed. The mixture was kept overnight at 20°C, then cooled to 0-5°C and stirred. The precipitate was collected by pressure filtration and then washed with n-butanol. The resulting solid was dried under vacuum at 45°C to obtain compound H (108.7 kg, yield 74.2%). 1 H-NMR (DMSO-d6) δ 1.1-1.4 (m, 1H), 1.4-1.7 (m, 1H), 1.7-2.0 (m, 1H), 2.1-2.5 (m, 1H), 3.2-3.4 (m, 1H), 3.5-3.8 (m, 1H), 4.1-4.4 (m, 1H), 5.8 (s, 1H). MS (ESI) m / z (M-H+2H2O) -277.94.

[0050] Step 2: Synthesis of Compound F To a nitrogen-purged reactor, toluene, MTBE, and compound H (1 equivalent) were added. The resulting solution was cooled to -55 to -45°C. A solution of lithium diisopropylamide (LDA) in THF / n-heptane / ethylbenzene (26.8%, 1.1 equivalents) was added over 1.3 hours at -50 to -44°C. The resulting solution was stirred at -45±5°C for 37 minutes, and then cooled to -75 to -65°C. A solution of methyl formate (2 equivalents) in MTBE was added over 45 minutes at below -60°C, and then rinsed with MTBE. The mixture was stirred at -70 to -60°C for 44 minutes. Nitrogen was flowed into the second reactor, and deionized water and citric acid monohydrate were added. The resulting solution was cooled to 0 to 5°C, and the contents of the first reactor were added over 53 minutes at below 10°C, and then rinsed with MTBE. The mixture was heated to 11°C and the phases were separated. The aqueous layer was extracted with MTBE and then discarded. The main organic layer, followed by the MTBE washing solution, was washed with a 57% sodium chloride solution in water (1.8 vol). The combined organic matter was concentrated under vacuum at less than 50°C. Toluene (2×) was added, and the mixture was concentrated after each addition until the total volume reached 47 L. The mixture was cooled to 35°C and diluted with methylene chloride to obtain compound F as a crude solution in 65.1% yield. Crystallization of the crude compound F sample from MTBE / hexane yielded the analytical sample. 1 H-NMR (DMSO-d6) δ 1.7-1.8 (m, 1H), 1.8-1.9 (m, 1H), 2.2-2.3 (m, 2H), 3.3-3.4 (m, 1H), 3.5-3.6 (m, 1H), 5.9 (s, 1H), 9.5 (s,1H). MS (ESI) m / z (M+H) + 272.0.

[0051] Step 3: Synthesis of Compound D A solution of crude compound F, methylene chloride, and compound G (1.2 equivalents) were charged into a nitrogen-purged reactor. The resulting suspension was heated at 30 - 35 °C for 6 hours and then stirred overnight at 20 - 25 °C with compound E. An analytical sample of compound E was isolated via silica gel column chromatography (using methylene chloride / ethyl acetate as eluent), followed by crystallization from ethyl acetate / hexane. 1 H-NMR (DMSO-d6) δ 1.2 (d, 3H, J = 8 Hz ), 1.8 - 1.9 (m, 2H), 2.0 - 2.1 (m, 1H), 2.2 - 2.3 (m, 1H), 3.1 - 3.2 (m, 1H), 3.2 - 3.3 (m, 1H), 3.6 - 3.8 (m, 2H), 4.7 (d, 2H, J = 15 Hz), 5.5 (s,1H), 7.2 (s, 1H), 7.5 (s, 1H). MS (ESI) m / z (M+H) + 372.0.

[0052] The mixture of crude compound E was cooled to 20 °C, and sodium triacetoxyborohydride (3.0 equivalents) was added over 1.5 hours at 20 - 29 °C. Then the mixture was stirred at 30 - 35 °C for 5 hours. Water was added over 49 minutes at 15 - 20 °C with gas evolution. The medium was stirred and then the phases were separated. The aqueous layer was extracted twice with methylene chloride (2×). The combined organics were washed with saturated aqueous sodium bicarbonate. The methylene chloride extract was assayed by HPLC and found to contain pure compound D with a yield of 78.9%. An analytical sample of compound D was crystallized from toluene / hexane and water. 1 H-NMR (DMSO-d6) δ 1.1 (d, 3H, J = 8 Hz ), 1.8 - 1.9 (m, 2H), 2.0 - 2.1 (m, 2H), 2.7 - 2.8 (m, 2H), 3.1 - 3.2 (m, 1H), 3.3 - 3.4 (m, 1H), 3.6 - 3.7 (m, 1H), 4.7 (d, 2H, J = 6 Hz), 5.6 (s,1H), 7.0 (s, 1H), 7.1 (s, 1H). MS (ESI) m / z (M+H) + 374.1.

[0053] Step 4: Synthesis of Compound C A crude solution of compound D was concentrated under vacuum at a temperature below 45°C to a total volume of 110 L. Acetonitrile was added, and the mixture was concentrated to a total volume of 110 L. Acetonitrile, water, and triethylamine (6 equivalents) were added, and the mixture was heated to 45°C and then stirred. The mixture was concentrated under vacuum at a temperature below 50°C to a total volume of less than 110 L. Acetonitrile and then isopropanol were added. The mixture was cooled to 15-20°C, MTBE was added over 1 hour at 15-20°C, the resulting slurry was stirred at 15-20°C, and the product was collected by filtration. The crude solid was slurried in methanol and stirred at 60-65°C, and the suspension was then slowly cooled to 20-25°C. The product was collected by filtration, washed with methanol, and the solid was dried under vacuum at 50°C to obtain compound C in 72.4% yield. 1 H-NMR (MeOH-d4) δ 1.23 (3H, d, J = 6.4Hz); 1.9-2.1 (m, 3H), 2.2-2.3 (m, 1H), 2.9 (d, 1H, J = 13Hz), 3.0 (d, 1H, J = 6 Hz), 3.1 (d, 1H, J = 13Hz), 3.2-3.3 (m, 1H), 3.4-3.5 (m, 1H), 3.8 (quintet, 1H, J=6Hz). MS (ESI) m / z (M+H) + 246.2.

[0054] Step 5: Synthesis of Compound B Acetone, water, and compound C (1 equivalent) were successively added to a nitrogen-purged reactor. Triethylamine (6 equivalents) was added to the medium at below 30°C for 20 minutes, and rinsed with acetone. A solution of di-tert-butyl dicarbonate (1.3 equivalents) was added to the mixture at below 30°C, and rinsed with acetone (13 L). The mixture was stirred at 20-30°C. A solution of di-tert-butyl dicarbonate (0.5 equivalents) in acetone was added to the mixture. A solution of di-tert-butyl dicarbonate (0.5 equivalents) in acetone was added. The mixture was concentrated at atmospheric pressure to a total volume of 65 L. Acetone, then THF, was added, and the mixture was concentrated to a total volume of 65 L. The resulting suspension was cooled to 0-5°C, and the precipitate was collected by filtration, washed with THF, and dried under vacuum at 45°C to obtain compound B in 90.5% yield. 1 H-NMR (DMSO-d6) δ 1.1 (d, 3H, J = 6 Hz ), 1.3 (s, 5H), 1.4 (s, 4H), 1.7-1.8 (m, 2H), 1.9-2.0 (m, 1H), 2.2-2.4 (m, 1H), 2.5-3.1 (m, MS (ESI) m / z (M+H) + 346.3.

[0055] Step 6: Synthesis of Compound A THF and compound B (1 equivalent) were added to a nitrogen-purged reactor. Triethylamine (1.8 equivalents) was added at 20-25°C and rinsed with THF. A solution of diethyl chlorophosphate (1.8 equivalents) in THF was added at 20-33°C. After stirring at 25-33°C, a solution of sodium chloride in water was added at 25-30°C to separate the phases. The aqueous layer was extracted twice with ethyl acetate. The combined organic matter was concentrated under vacuum at less than 60°C to a total volume of 65-70 L. Ethyl acetate was added and the mixture was concentrated to a total volume of 65-70 L. Ethyl acetate, followed by a solution of sodium chloride in water (60 L), was added to the mixture. Then, phosphoric acid was added to adjust the pH to 2.0. The mixture was stirred at 20-25°C, the phases were separated, and the aqueous solution was discarded. The organic layer was washed with a mixture of sodium chloride and aqueous ammonia, and the washings were back-extracted with ethyl acetate. The combined organic matter was mixed with activated carbon, stirred overnight, then filtered through ethyl acetate-soaked Celite, and rinsed with ethyl acetate. The filtrate was concentrated to a total volume of 100 L under vacuum at less than 60°C. Ethyl acetate was added, and the mixture was concentrated to 100 L after each addition. Ethyl acetate was added, and the mixture was cooled to 20-25°C. The mixture was heated to 45-55°C, and the residual solid was removed by filtration, washed with ethyl acetate, and discarded.

[0056] Step 7: Crystallization of compound A into crystalline form I The filtrate was concentrated under vacuum at a temperature below 60°C to a total volume of 105 L. The mixture was heated to 65-70°C and then cooled to 25°C. Diisopropyl ether was added, and the mixture was stirred at 20-25°C. The precipitate was collected by filtration, washed with diisopropyl ether, and then dried at 50°C to obtain compound A as a white crystalline powder in a yield of 62.7%. 1 H-NMR (DMSO-d6) δ 1.1 (m, 3H), 1.3 (s, 4H), 1.4 (s, 5H), 1.7-1.9 (m, 2H), 2.0-2.3 (m, 2H), 3.1-3.5 (m, 3H), 3.5-4.0 (m, 3H), 4.9 (m, 1H), 7.1-7.6 (m, 2H). MS (ESI) m / z (M+Na)+ 350.2. The XRPD obtained from the sample of compound A described above was substantially the same as that shown in Figure 1 (upper panel), indicating crystalline morphology I of compound A.

[0057] Figure 1 shows the powder X-ray diffraction pattern calculated from the single-crystal structure of crystalline form I of compound A. Figures 8-9 show the atomic displacement ellipsoid and packing diagrams of crystalline morphology I of compound A, based on single-crystal X-ray analysis. Crystalline morphology I of compound A is orthorhombic, P212121 space group, and the following unit cell dimensions: a=5.85088(9)Å, b=11.57133(12)Å and c=25.8340(3)Å, α=β=γ=90°, V=1749.02(4)Å 3 Z=4. For a formula weight of Z=4 and 327.38 g / mol, the calculated density is 1.243 g / cm³. 3 That is the case. The computer programs used for single-crystal analysis and the calculation of XRPDs include ShelXL, CrysAlisPro, Olex2, ShelXT, and Mercury.

[0058] (Example 2) Preparation of compound A in form II In one experiment, approximately 200 mg of crystalline form I of compound A from Example 1 was weighed into a 4 mL scintillation vial, and 1 mL of Milli-Q water was added to the vial. The vial was thoroughly rotated at room temperature for 12 days. The residue was filtered under vacuum and air-dried at room temperature for 2 days (approximately 22°C and 60% RH). The dried solid was ground using a mortar and pestle, and the XRPD shown in the upper panel of Figure 3 was obtained. The solid was also subjected to DVS testing and lost approximately 11% water at 0% RH. The DVS plot is shown in Figure 6, which indicates that crystalline form II of compound A did not lose water at 20% RH or higher. In another experiment, approximately 2 g of crystalline form I of compound A from Example 1 was weighed into a 20 mL scintillation vial, and 4 mL of Milli-Q water was added to the vial. The resulting suspension was stirred with a spatula and left at room temperature for 1 day. The residue was then filtered under vacuum and dried in a vacuum oven at room temperature for approximately 20 hours. An XRPD was obtained after drying, and form II was confirmed as it was substantially the same as the upper panel in Figure 3. A DSC shown in Figure 5 was obtained after drying, showing a possible dehydration event at approximately 82°C, followed by melting at approximately 159°C. The TGA obtained after drying, shown in Figure 4, showed a mass loss of 9.6%, consistent with that of the dihydrate. The dried sample was then dehydrated in a TGA pan at 80°C (gradient from room temperature to 80°C at 10°C / min, followed by isothermal for 2 minutes). XRPD and DSC were performed on the dehydrated samples, confirming that the samples contained residual amorphous material and a very small amount of crystalline form II, while being mostly crystalline form I.

[0059] The X-ray diffraction pattern calculated from the single-crystal structure of crystalline form II of compound A is shown in the lower panel of Figure 3. Figures 10-11 show the atomic conformation and packing diagrams for crystalline form II of compound A, based on single-crystal X-ray analysis. Crystalline form II of compound A is orthorhombic, P212121 space group, and the following unit cell dimensions: a=8.9035(2)Å, b=10.5404(2)Å and c=21.3018(5)Å, α=β=γ=90°, V=1999.10(8)Å 3 Z=4. For the formula weights of Z=4 and 363.41, the calculated density is 1.207 g / cm³. 3 That is the case. The computer programs used for single-crystal analysis and the calculation of XRPDs include Apex3 v2017.3-0 (Bruker, 2017), SAINT V8.38A (Bruker, 2016), SHELXS97 (Sheldrick, 2008), SHELXL2018 / 3 (Sheldrick, 2015, 2018), and SHELXLE Rev937 (Hubschle et al., 2011).

[0060] (Example 3) Preparation of the amorphous form of compound A One gram of compound A in crystalline form I was dissolved in 10 mL of acetone. The material was spray-dried using a Buchi mini spray dryer B-290. The inlet temperature was 65°C and the outlet temperature was 44°C. The spray-dried material was weighed to 0.44 g (yield 44%) and analyzed using XRPD. The XRPD results are shown in Figure 7.

[0061] (Example 4) The transformation between crystalline form I and crystalline form II Competitive slurries in a mixture of water and isopropanol indicate that the phase boundary between crystalline form I and crystalline form II is between water activity values ​​of 0.66 and 0.78 at 25°C. At water activity values ​​above 0.78, crystalline form II is the stable form, while at water activity values ​​below 0.66, crystalline form I is the stable form.

[0062] Throughout this specification, publications such as U.S. and foreign patent applications, academic papers, and book chapters are referenced. All such publications, unless otherwise indicated, are expressly incorporated by reference, including any supplemental / supporting information sections published with their corresponding bibliographies, for all purposes.

[0063] While many exemplary embodiments and designs have been discussed above, those skilled in the art will recognize certain modifications, alterations, additions, and subordinate combinations thereof. Therefore, the appended claims below and the claims introduced hereafter herein are intended to be interpreted as encompassing all such modifications, alterations, additions, and subordinate combinations as falling within their true intent and scope. Preferred embodiments of the present invention are as follows: [1] Compound A: JPEG0007858096000011.jpg3946 A method for preparing the solid crystalline form I of, The process involves dissolving compound A in ethyl acetate and heating the solution. The step of cooling the solution, and Step of adding diisopropyl ether to the solution Methods that include... [2] The method according to [1], wherein the solution is heated to approximately 65°C to approximately 70°C. [3] The method according to [1], wherein the solution is cooled to approximately 25°C. [4] The method according to any one of the above [1] to [3], wherein the solid crystalline form I of compound A has a peak (2θ) in the powder X-ray diffraction pattern selected from approximately the following values: 6.9, 8.4, 10.3, and 12.8. [5] The method according to [4], wherein the solid crystalline form I of compound A further has one or more peaks (2θ) in the powder X-ray diffraction pattern selected from those having approximately the following values: 13.7, 15.3, 15.7, 16.8, 17.3, 18.5, and 19.9. [6] The method according to any one of [1] to [3], wherein the solid crystalline form I of compound A has a peak (2θ) in the powder X-ray diffraction pattern selected from approximately the following values: 6.9, 8.4, 10.3, 12.8, and 13.7. [7] The method according to any one of the above [1] to [3], wherein the solid crystalline form I of compound A has a peak (2θ) in the powder X-ray diffraction pattern selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, and 15.7. [8] The method according to any one of items [1] to [3], wherein the powder X-ray diffraction pattern has a peak (2θ) selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, and 16.8. [9] The method according to any one of the above [1] to [3], wherein the solid crystalline form I of compound A has a peak (2θ) in the powder X-ray diffraction pattern selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, and 17.3.

[10] The method according to any one of the above [1] to [3], wherein the solid crystalline form I of compound A has a peak (2θ) in the powder X-ray diffraction pattern selected from those having approximately the following values: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, 17.3, and 18.5.

[11] The method according to any one of the above [1] to [3], wherein the solid crystalline form I of compound A has three, four, or five peaks (2θ) selected from those having approximately the following values ​​in the powder X-ray diffraction pattern: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, 17.3, 18.5, and 19.9.

[12] The method according to any one of the claims [1] to [3], wherein the solid crystalline form I of compound A has an XRPD pattern substantially similar to one of the XRPD patterns shown in Figure 1.

[13] The method according to any one of [1] to

[12] , wherein the solid crystalline form I of compound A has a DSC having an endothermic peak at approximately 159°C.

[14] Compound A: JPEG0007858096000012.jpg4047 It is a solid crystalline form, This is the crystalline form II of compound A, which is the solid crystalline form.

[15] The solid crystalline form described in

[14] , having a peak (2θ) in the powder X-ray diffraction pattern selected from approximately the following values: 9.4, 10.8, 11.9, and 13.0.

[16] The solid crystalline form according to

[15] , further having one or more peaks (2θ) in the powder X-ray diffraction pattern selected from approximately the following values: 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3.

[17] The solid crystalline form described in

[14] , having a peak (2θ) in the powder X-ray diffraction pattern selected from approximately the following values: 9.4, 10.8, 11.9, 13.0, and 13.7.

[18] The solid crystalline form described in

[14] , having a peak (2θ) in the powder X-ray diffraction pattern selected from approximately the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, and 16.0.

[19] The solid crystalline form described in

[14] , having a peak (2θ) in the powder X-ray diffraction pattern selected from those having approximately the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, and 20.4.

[20] The solid crystalline form described in

[14] , having a peak (2θ) in the powder X-ray diffraction pattern selected from approximately the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, and 21.3.

[21] The solid crystalline form described in

[14] , having a peak (2θ) in the powder X-ray diffraction pattern selected from approximately the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3.

[22] The solid crystalline form according to

[14] , having three, four, or five peaks (2θ) selected from those having approximately the following values ​​in the powder X-ray diffraction pattern: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3.

[23] The solid crystalline form described in

[14] , having an XRPD pattern substantially similar to one of the two XRPD patterns shown in Figure 3.

[24] A solid crystalline form according to any one of the above

[14] to

[23] , having a DSC with endothermic peaks at approximately 82°C and approximately 159°C.

[25] A solid crystalline form according to any one of the above

[14] to

[24] , having a TGA that exhibits dehydration at over approximately 60°C with a loss of approximately 9.6 mass% of water.

[26] A solid crystalline form according to any one of the above

[14] to

[25] , having a DVS that shows a mass change of about 11% at 0% RH and 25°C, and whose mass does not lose water at 20% RH or above.

[27] A solid composition comprising the solid crystalline form described in any one of

[14] to

[26] above, wherein the solid composition does not contain any other solid form of compound A in an amount of at least 99% by mass, at least 95% by mass, at least 90% by mass, at least 80% by mass, at least 70% by mass, at least 60% by mass, or at least 50% by mass.

[28] A pharmaceutical composition comprising a solid crystalline form described in any one of the above items

[14] to

[26] and a pharmaceutically acceptable excipient.

[29] The pharmaceutical composition according to

[28] , wherein the solid crystalline form is at least 99% by mass, at least 95% by mass, at least 90% by mass, at least 80% by mass, at least 70% by mass, at least 60% by mass, or at least 50% by mass of the total amount of tert-butyl(S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate in the pharmaceutical composition.

[30] Compound A: JPEG0007858096000013.jpg4046 The solid amorphous form.

[31] The solid amorphous form according to

[30] , having an amorphous halo in the powder X-ray diffraction pattern.

[32] The solid amorphous form described in

[30] having an XRPD pattern substantially similar to that of Figure 7.

[33] A pharmaceutical composition comprising the amorphous form described in any one of the above items

[30] to

[32] and a pharmaceutically acceptable excipient.

[34] The pharmaceutical composition according to

[33] , wherein the amorphous form is at least 99% by mass, at least 95% by mass, at least 90% by mass, at least 80% by mass, at least 70% by mass, at least 60% by mass, or at least 50% by mass of the total amount of tert-butyl(S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate in the pharmaceutical composition.

[35] A method for treating a subject in need of treatment for a disease or disorder in response to NMDA modulation, comprising the step of administering to the subject in need of such treatment a therapeutically effective amount of the pharmaceutical composition described in any one of the above items

[28] ,

[29] ,

[33] , and

[34] .

[36] The aforementioned diseases or disorders include autism, anxiety, depression, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, mental disorders, psychotic symptoms, social withdrawal, obsessive-compulsive disorder (OCD), phobias, post-traumatic stress syndrome, behavioral disorders, impulse control disorders, substance abuse disorders, sleep disorders, memory impairment, learning disabilities, urinary incontinence, multiple system atrophy, progressive supranuclear palsy, Friedreich's ataxia, Down syndrome, fragile X syndrome, and tuberous sclerosis. The method according to

[35] above, selected from cerebral palsy, olivopontocerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, dementia, AIDS dementia, Alzheimer's disease, Huntington's disease, spasticity, myoclonus, muscle spasms, Tourette syndrome, epilepsy, cerebral ischemia, stroke, brain tumor, traumatic brain injury, cardiac arrest, myelopathy, spinal cord injury, peripheral neuropathy, acute neuropathic pain, and chronic neuropathic pain.

[37] The method according to

[36] , wherein the substance abuse disorder is selected from withdrawal symptoms, opiate addiction, nicotine addiction and ethanol addiction.

[38] The method according to

[36] , wherein the memory impairment is selected from missing, lost, and impaired ability to create new memories.

[39] The method according to

[35] , wherein the disease or disorder is major depressive disorder.

[40] Orthorhombic system, P2 1 2 1 2 1 The space group and the following unit cell dimensions: a=8.9035(2)Å, b=10.5404(2)Å, and c=21.3018(5)Å, α=β=γ=90°, V=1999.10(8)Å 3 The crystalline form of tert-butyl(S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate dihydrate, having Z=4.

[41] Compound A, substantially as described herein: JPEG0007858096000014.jpg4047 Solid crystalline form II.

[42] Compound A, substantially as described herein: JPEG0007858096000015.jpg4047 The solid amorphous form.

Claims

1. Compound A: A method for preparing the solid crystal form II of, The process includes the step of forming a slurry with water from the crystalline form I of compound A. The crystalline form I of compound A has three, four, or five peaks (2θ) selected from the following values ​​in its powder X-ray diffraction pattern: 6.9, 8.4, 10.3, 12.8, 13.7, 15.3, 15.7, 16.8, 17.3, 18.5, and 19.9, with each diffraction angle being ±0.2 degrees (2θ). The solid crystal form II of compound A has peaks (2θ) in the powder X-ray diffraction pattern with the following values: 9.4, 10.8, 11.9, and 13.0, with each diffraction angle being ±0.2 degrees (2θ). method.

2. The method according to claim 1, wherein the slurrying step takes about 4 hours.

3. The method according to claim 1, wherein the amount of compound A, which has been slurryed in water, varies from 0.1 to 5.0 g per milliliter of water.

4. The method according to claim 1, wherein the solid crystal form II of compound A further has one or more peaks (2θ) in a powder X-ray diffraction pattern selected from the following values: 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3, each having a diffraction angle of ±0.2 degrees (2θ).

5. The method according to claim 1, wherein the solid crystal form II of compound A has peaks (2θ) in the powder X-ray diffraction pattern having the following values: 9.4, 10.8, 11.9, 13.0, and 13.7, and each diffraction angle is ±0.2 degrees (2θ).

6. The method according to claim 1, wherein the solid crystal form II of compound A has peaks (2θ) in the powder X-ray diffraction pattern having the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, and 16.0, and each diffraction angle is ±0.2 degrees (2θ).

7. The method according to claim 1, wherein the solid crystal form II of compound A has peaks (2θ) in the powder X-ray diffraction pattern having the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, and 20.4, and each diffraction angle is ±0.2 degrees (2θ).

8. The method according to claim 1, wherein the solid crystal form II of compound A has peaks (2θ) in the powder X-ray diffraction pattern having the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, and 21.3, and each diffraction angle is ±0.2 degrees (2θ).

9. The method according to claim 1, wherein the solid crystal form II of compound A has peaks (2θ) in the powder X-ray diffraction pattern having the following values: 9.4, 10.8, 11.9, 13.0, 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3, and each diffraction angle is ±0.2 degrees (2θ).

10. The method according to claim 1, wherein the solid crystal form II of compound A has a DSC having endothermic peaks at 82°C and 159°C.

11. The solid crystal form II of compound A is orthorhombic, P2 1 2 1 2 1 The space group, and the following unit cell dimensions: a = 8.9035(2) Å, b = 10.5404(2) Å, and c = 21.3018(5) Å, V = 1999.10(8) Å 3 The method according to claim 1, having a crystalline form accompanied by

12. The method according to claim 1, wherein the solid crystal form II of compound A is a dihydrate.

13. Orthorhombic system, P2 1 2 1 2 1 The space group and the following unit cell dimensions: a = 8.9035(2) Å, b = 10.5404(2) Å, and c = 21.3018(5) Å, α = β = γ = 90°, V = 1999.10(8) Å 3 A crystalline form of tert-butyl(S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate dihydrate having Z=4.

14. The crystalline form of tert-butyl(S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate dihydrate has peaks (2θ) with the following values: 9.4, 10.8, 11.9, and 13.0, with diffraction angles of ±0.2 degrees (2θ) for each.

15. A crystalline form of tert-butyl(S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate dihydrate according to claim 14, further having one or more peaks (2θ) selected from having the following values: 13.7, 15.5, 16.0, 20.0, 20.4, 21.3 and 23.3, each having a diffraction angle of ±0.2 degrees (2θ).

16. Compound A: A pharmaceutical composition comprising crystalline form II of [compound name] and a pharmaceutically acceptable excipient, wherein the crystalline form II of compound A has an orthorhombic system, P2 1 2 1 2 1 space group, and the following unit cell dimensions: a = 8.9035(2) Å, b = 10.5404(2) Å and c = 21.3018(5) Å, α = β = γ = 90°, V = 1999.10(8) Å 3 , Z = 4, pharmaceutical composition.

17. Compound A: A pharmaceutical composition comprising a crystalline form II of compound A and a pharmaceutically acceptable excipient, wherein the crystalline form II of compound A has peaks (2θ) in a powder X-ray diffraction pattern having the following values: 9.4, 10.8, 11.9, and 13.0, and each diffraction angle is ±0.2 degrees (2θ).

18. The pharmaceutical composition according to claim 17, wherein the crystalline form II of compound A further has one or more peaks (2θ) in a powder X-ray diffraction pattern selected from the following values: 13.7, 15.5, 16.0, 20.0, 20.4, 21.3, and 23.3, each having a diffraction angle of ±0.2 degrees (2θ).

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