Salts of ovicetrapib and methods for producing the same and intermediates

Abstract

To provide a method for producing ovicetrapib compounds and salts thereof, such as calcium salts. [Solution] Similarly, amorphous ovicetrapib hemicalcium is provided herein. Novel intermediates for use in the synthesis of ovicetrapib and its salts are also provided, including ovicetrapib HCl and mesylates for use in the synthesis of ovicetrapib and amorphous ovicetrapib hemicalcium. The disclosure provides amorphous calcium salts of ovicetrapib, such as amorphous ovicetrapib hemicalcium.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the interests and priority of U.S. Provisional Application No. 63 / 358,363, filed on 5 July 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] introduction Prospective epidemiological studies have shown a strong association between low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular disease (CVD) risk. The application of statin therapy to lower these atherosclerotic LDL-C levels results in a significant reduction in CVD-related morbidity and mortality: for every 1 mmol / L reduction in LDL-C, an estimated 22% reduction in CVD events and a 10% reduction in all-cause mortality are associated. Despite these remarkable benefits, a significant residual disease burden persists, impacting both individual patients and global healthcare costs. Novel therapies are needed to further reduce this residual CVD risk in patients.

[0003] One pathway to lower LDL-C and increase high-density lipoprotein cholesterol (HDL-C) levels is to inhibit cholesterol ester transfer protein (CETP). CETP is a plasma protein primarily secreted by the liver and adipose tissue. During triglyceride exchange, CETP mediates the transfer of cholesteryl esters from HDL to apolipoprotein B (apoB)-containing particles (mainly LDL and very low-density lipoprotein VLDL), thereby lowering the cholesterol content in HDL and favoring the cholesterol content in VLDL. Therefore, it has been hypothesized that CETP inhibition would retain cholesteryl esters in HDL-C and reduce the cholesterol content in the atherosclerotic apoB fraction.

[0004] Clinical trials have shown that obicetrapib, also known as ((2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester) or a pharmaceutically acceptable salt thereof, is a potent CETP inhibitor. The structure of obicetrapib is: The following equation (I): [ka] It will be listed.

[0005] The preparation of ovicetrapib is disclosed, for example, in U.S. Patent No. 7,872,126. Example 177 teaches the formation of ovicetrapib as a free acid, as can be seen in formula (I). Example 178 teaches the formation of the sodium salt of ovicetrapib from ovicetrapib by exchanging the acidic proton of the free acid portion of ovicetrapib with a sodium atom. In Example 179, the calcium salt of ovicetrapib is taught. Since calcium is an alkaline earth metal, it has a charge of +2 when ionized. Therefore, the neutral salt will have two ovicetrapib anions for each calcium cation (each in a proton-free state from the carboxylic acid group of ovicetrapib). The salt produced in Example 179 is a hemicalcium salt in that the neutral amorphous ovicetrapib calcium salt molecule contains half the number of calcium atoms as there are ovicetrapib anions.

[0006] The molecular formula of amorphous ovicetrapibhemicalcium is (C 32 H 30The formula is N4O5F9)2Ca. When discussing salts of ovicetrapib, particularly calcium salts such as hemicalcium salts, it is understood that ovicetrapib loses one proton to form such salts. Thus, the term amorphous ovicetrapib hemicalcium means that the salt portion of each ovicetrapib moiety is not formula (I) (i.e., ovicetrapib) but formula (I) with a proton subtracted. Example 179 explicitly teaches that the resulting hemicalcium salt of ovicetrapib is crystalline. However, this crystalline form has undesirable properties, such as poor physical stability.

[0007] Compared to other known CETP inhibitors, ovicetrapib requires relatively low doses to achieve near-complete CETP inhibition. Typically, repeated doses of as little as 2.5 mg of the ovicetrapib compound per day (once daily) have been shown to be sufficient to achieve near-complete CETP inhibition. These are considerably lower doses than those that would have to be used with other CETP inhibitors. Furthermore, clinical trials have also shown that ovicetrapib is well-tolerated and does not cause serious side effects.

[0008] Although methods for the production of ovicetrapib have been described (see, for example, WO2005 / 095409A2 and U.S. Patents 7,872,126 and 8,158,640, Examples 1 and 177-180; WO2007 / 116922A1 and U.S. Patent 8,084,611; and WO2016 / 024858 and U.S. Patent 10,112,904), the prior art produces unfavorable solid forms. All of these references are incorporated herein by reference. Furthermore, the methods already described have relatively low yields and are not particularly suitable for industrial-scale implementation. Therefore, there is a need for improved solid-state ovicetrapib, as well as alternative methods for producing ovicetrapib and its pharmaceutically acceptable salts with improved yield, purity, and stability. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] U.S. Patent No. 7,872,126 [Patent Document 2] International Publication No. 2005 / 095409 [Patent Document 3] U.S. Patent No. 8,158,640 [Patent Document 4] International Publication No. 2007 / 116922 [Patent Document 5] U.S. Patent No. 8,084,611 [Patent Document 6] International Publication No. 2016 / 024858 [Patent Document 7] U.S. Patent No. 10,112,904 [Overview of the project] [Means for solving the problem]

[0010] Summary of the Invention This disclosure provides amorphous calcium salts of ovicetrapib, such as amorphous ovicetrapib hemicalcium.

[0011] This disclosure further provides HCl ovicetrapib, including crystalline ovicetrapib HCl compounds, and other compounds useful as intermediates in the production of ovicetrapib, such as compound 1D, including the compound of formula (VI) and crystalline compound 1D.

[0012] This disclosure provides (i) a method for producing ovicetrapib including intermediates such as crystalline ovicetrapib HCl compounds, (ii) a method for producing other compounds useful as intermediates in the production of ovicetrapib, such as compound 1D including the compound of formula (VI) and crystalline compound 1D, and (iii) a method for producing amorphous calcium salts of ovicetrapib, such as amorphous ovicetrapib hemicalcium.

[0013] The disclosure also provides pharmaceutical compositions comprising, for example, amorphous ovicetrapib calcium salts such as amorphous ovicetrapib hemicalcium and one or more pharmaceutically acceptable carriers.

[0014] This disclosure further provides a method for treating a patient who has a cardiovascular disease or who is at increased risk of developing such a disease, the method comprising the step of administering an amorphous ovicetrapib calcium salt, such as amorphous ovicetrapib hemicalcium, to such a patient.

[0015] These and other features, aspects and advantages of the present invention will be better understood with reference to the following description and accompanying drawings. [Brief explanation of the drawing]

[0016] [Figure 1] Figure 1 shows the X-ray powder diffraction pattern of amorphous obicetrapibhemicalcium.

[0017] [Figure 2] Figure 2 shows the X-ray powder diffraction pattern of amorphous obicetrapibhemicalcium.

[0018] [Figure 3] Figure 3 shows the X-ray powder diffraction pattern of amorphous obicetrapibhemicalcium.

[0019] [Figure 4] Figure 4 shows the infrared spectrum of amorphous obicetrapibhemicalcium.

[0020] [Figure 5] Figure 5 shows the 1H-NMR spectrum of amorphous ovicetrapibhemicalcium.

[0021] [Figure 6]Figure 6 shows the X-ray powder diffraction pattern of crystalline obisetrapibhemicalcium.

[0022] [Figure 7] Figure 7 shows a stacked plot of X-ray powder diffraction patterns from a stability study of crystalline obisetrapibhemicalcium.

[0023] [Figure 8] Figure 8 is a stacked plot of X-ray powder diffraction patterns from a stability study of amorphous obicetrapibhemicalcium.

[0024] [Figure 9] Figure 9 is a polarized light microscope image of amorphous obicetrapibhemicalcium.

[0025] [Figure 10] Figure 10 is a polarized light microscope image of crystalline ovicetrapibhemicalcium.

[0026] [Figure 11] Figure 11 is a plot of the thermogravimetric analysis of amorphous obicetrapibhemicalcium.

[0027] [Figure 12] Figure 12 is a modulated differential scanning calorimetry thermogram (with pinholes) of amorphous obicetrapibhemicalcium.

[0028] [Figure 13] Figure 13 is a modulated differential scanning calorimetry thermogram (with pinholes) of amorphous obicetrapib hemicalcium.

[0029] [Figure 14] Figure 14 is a modulated differential scanning calorimetry thermogram (with pinholes) of crystalline obisetrapibhemicalcium.

[0030] [Figure 15] Figure 15 shows the solid-state 13C-NMR spectra of amorphous and crystalline ovicetrapibhemicalcium.

[0031] [Figure 16] Figure 16 shows the solid-state 13C-NMR spectrum of crystalline obisetrapibhemicalcium.

[0032] [Figure 17] Figure 17 shows the solid-state 13C-NMR spectrum of amorphous obicetrapibhemicalcium.

[0033] [Figure 18] Figure 18 shows the X-ray powder diffraction patterns of crystalline ovicetrapib HCl and crystalline ovicetrapib HCl that has been at least partially desolvated.

[0034] [Figure 19] Figure 19 shows the X-ray powder diffraction pattern of crystalline ovicetrapib HCl.

[0035] [Figure 20] Figure 20 shows the X-ray powder diffraction pattern of the crystalline compound 1D.

[0036] [Figure 21] Figure 21 shows the 1H-NMR spectrum of compound 1D.

[0037] [Figure 22] Figure 22 shows the X-ray powder diffraction pattern of crystalline ovicetrapib hydrochloride in form A.

[0038] [Figure 23] Figure 23 shows the X-ray powder diffraction pattern of crystalline ovicetrapib hydrochloride in form B.

[0039] [Figure 24] Figure 24 shows the X-ray powder diffraction pattern of crystalline ovicetrapib hydrochloride in form C.

[0040] [Figure 25] Figure 25 shows the X-ray powder diffraction pattern of crystalline ovicetrapib hydrochloride in form D.

[0041] [Figure 26] Figure 26 shows the asymmetric units derived from the single-crystal structure of crystalline ovicetrapib hydrochloride.

[0042] [Figure 27] Figure 27 shows the calculated X-ray powder diffraction pattern of a single crystal of crystalline ovicetrapib hydrochloride.

[0043] [Figure 28] Figure 28 shows the superposition of the calculated pattern in Figure 27 with the X-ray powder diffraction patterns of crystalline ovicetrapib hydrochloride of form A and crystalline ovicetrapib hydrochloride of form B. [Modes for carrying out the invention]

[0044] Detailed description of the invention Many embodiments of this disclosure provide amorphous ovicetrapib calcium salts. In particular, amorphous ovicetrapib hemicalcium is provided. This disclosure further covers various methods for producing amorphous ovicetrapib calcium, and more particularly amorphous ovicetrapib hemicalcium.

[0045] The amorphous obisetrapibhemicalcium disclosed herein can be distinguished from the crystalline obisetrapibhemicalcium disclosed in U.S. Patent No. 7,872,126. A common technique used to distinguish between crystalline and amorphous materials is X-ray powder diffraction. However, this technique has limitations, particularly when crystalline materials are disordered. In the case of amorphous obisetrapibhemicalcium, the X-ray powder diffraction patterns of two different lots of amorphous obisetrapibhemicalcium are shown in Figures 1 and 2. These patterns exhibit the familiar "halo" type features associated with amorphous materials. The X-ray powder diffraction patterns from Figure 2 have peaks at approximately 3.4°(2θ), approximately 7.0°(2θ), and approximately 9.2°(2θ). Similarly, another sample in Figure 3 also has X-ray powder diffraction peaks at approximately 3.4°(2θ), 7.0°(2θ), and 9.2°(2θ). Amorphous obi-cetrapib hemi-calcium can be characterized using the X-ray powder diffraction patterns in either Figure 1, Figure 2, or Figure 3, however, sometimes sharper, larger angle peaks are present, such as those observed at approximately 31.7°(2θ) (as shown in Figure 2), and if present, these peaks are due to sodium chloride. In Figure 3, another sample of amorphous obi-cetrapib hemi-calcium identified peaks at approximately 3.4°(2θ), 7.0°(2θ), and 9.2°(2θ). The peak at approximately 5.6°(2θ) in Figure 3 was determined to be due to the Kapton foil used in the measurement setup described in Example 20. The X-ray powder pattern of the crystalline obisetrapibhemicalcium prepared in Example 16 is shown in Figure 6. It also exhibits halo-like behavior, which can serve as an indicator of disorder in the case of crystalline compounds.

[0046] Examples 18, 19, 20, 21, and 22 illustrate various X-ray powder diffraction procedures. The procedure of Example 18 was generally used to collect the data described in Figures 1, 6, 7, and 8. Example 19 was generally used for Figure 2. Example 20 was generally used for Figure 3. Example 21 was generally used for Figures 18, 19, and 20 (Figure 20 is for compound 1D rather than crystalline ovicetrapib HCl). Example 22 was generally used for Figures 22-25 and Figure 28.

[0047] The use of the term "amorphous" in "amorphous ovicetrapib hemicalcium" does not mean that the material is completely devoid of regularity. Some degree of regularity still exists in the sample, as indicated by the presence of peaks in the X-ray powder diffraction pattern. Therefore, as used herein, the term "amorphous" in "amorphous ovicetrapib hemicalcium" does not mean that the X-ray powder diffraction pattern must contain pure amorphous halos (although halo-like features may be present). Rather, the term means that irregularity is present, but the amorphous phase is distinct from the crystalline phase discussed below.

[0048] Another technique that can be used to distinguish between crystalline and amorphous materials is polarized optical microscopy ("PLM"). In PLM, materials are observed through polarized light, and by observing the material through cross-polarizers, it is possible to distinguish whether it is an anisotropic (e.g., crystalline) material or an isotropic (e.g., amorphous compound) material. Anisotropic materials exhibit birefringence, revealing themselves by showing a color change through the polarizers when exposed to polarized light that has passed through them. Isotropic materials, on the other hand, do not exhibit birefringence or color change when exposed to polarized light.

[0049] In Figure 9, amorphous obisetrapibhemicalcium was analyzed by polarized light microscopy as described in Example 17. As shown in Figure 9, the material does not exhibit birefringence under examination, indicating that it is amorphous. By comparison, Figure 10 is a polarized light micrograph of crystalline obisetrapibhemicalcium prepared according to Example 16. In particular, the particles shown in Figure 10 (which is black and white) show considerably brighter contrast. In the corresponding color version, the figure is multicolored. Thus, Figure 10 indicates that it is crystalline. Furthermore, the crystals in Figure 10 are larger than the particles presented in the polarized light micrograph of amorphous obisetrapibhemicalcium in Figure 9. Thus, the absence of PLM and / or birefringence can be used to characterize amorphous obisetrapibhemicalcium.

[0050] Further techniques may be used to distinguish amorphous obisetrapibhemicalcium from crystalline obisetrapibhemicalcium, and thus these other techniques can be used to characterize amorphous obisetrapibhemicalcium. One such technique is modulated differential scanning calorimetry, also known as "mDSC". The difference in the heat required to raise the temperature of a sample compared to a reference sample is measured as a function of temperature and can be measured using modulated differential scanning calorimetry (mDSC). The mDSC thermogram can also measure the glass transition temperature, which can be used to characterize amorphous materials. In Figure 12, the procedure is described in Example 25, and the mDSC thermogram of amorphous obisetrapibhemicalcium is measured using an open sample holder, which allows for the expulsion of volatile gases during measurement. In Figure 12, the opening was made by making a hole in the lid of a pan to create a pinhole. In this sample, a glass transition temperature of approximately 110°C was recorded.

[0051] In relation to thermal measurements, the term "approximately" generally refers to a variation of plus or minus 1°C. In comparison, crystalline obisetrapibhemicalcium has a higher glass transition temperature under identical conditions, with the three measurements in Figure 14 showing a range between approximately 118°C and approximately 125.5°C. In some embodiments, the glass transition temperature of amorphous obisetrapibhemicalcium is between approximately 109°C and 112°C when measured with a pinhole. In one of the samples, Example 26, the glass transition temperature of amorphous obisetrapibhemicalcium was found to be approximately 111°C (111.32°C at the midpoint), as shown in Figure 13. This was measured with a start of approximately 102°C (101.62°C) and an end point of approximately 118°C (117.58°C).

[0052] The glass transition temperature of amorphous ovicetrapibhemicalcium can also be measured using mDSC with a sealed pan. The type of sample preparation can affect the measured glass transition temperature. In such cases, the glass transition temperature may drop to below approximately 100°C, particularly between approximately 70°C and 92°C, depending on the humidity.

[0053] Other thermal techniques, such as thermogravimetric analysis (TGA), can also be used to analyze and characterize amorphous ovicetrapib hemicalcium. Figure 11 is a thermogravimetric thermogram of amorphous ovicetrapib hemicalcium, showing a weight loss of less than 1% when heated to about 200°C. Such weight losses can range from about 0.8% to about 0.95%, including, for example, between about 0.84% ​​and about 0.92%. In Figure 11, the weight loss was found to be about 0.85%. Such a particular substance was found to have a water content of about 1.5%. In some embodiments, the water content can be even higher, ranging from about 0% to about 5% water, including up to about 4% by weight, up to about 3% by weight, and between about 0.5% to 1.5% by weight.

[0054] solid state 1313C-NMR spectroscopy is another technique that can be used to characterize amorphous materials. Figure 15 shows both crystalline obicetrapibhemicalcium and amorphous obicetrapibhemicalcium in solid states. 13 The 1C-NMR spectra are shown, with Figures 16 and 17 showing crystalline obicetrapibhemicalcium and amorphous obicetrapibhemicalcium, respectively. There are at least two differences in the spectra. The crystalline phase has a peak at approximately 22.1 ppm, which is absent in the amorphous phase. Furthermore, the peak at approximately 29.5 ppm is prominent in the crystalline phase, while it is almost absent in the amorphous phase. Therefore, the solid state at approximately 22.1 ppm is... 13 Amorphous obicetrapibhemicalcium can be characterized by the absence of a 1C-NMR peak and / or a prominent peak of approximately 29.5 ppm. Furthermore, the solid state is shown in Figure 17. 13 The solid state is virtually identical to the C-NMR spectrum. 13 Amorphous obisetrapibhemicalcium can be characterized using 1C-NMR spectroscopy. The absence of a peak in this context does not necessarily mean the absence of intensities such as 22.1 ppm or 29.5 ppm; rather, the intensity may be that of crystalline obisetrapibhemicalcium. 13 As seen in the 1C-NMR spectrum, this means it is not prominent.

[0055] The properties of crystalline materials are generally different from those of amorphous materials. Thermodynamically, crystalline materials are physically more stable than amorphous materials. Therefore, there is a thermodynamic driving force that converts amorphous compounds into crystalline compounds. Thus, if a physical conversion of the solid form is thought to exist, it is generally expected that the solid form will change from amorphous to crystalline under accelerated stress conditions. However, in the case of ovicetrapibhemicalcium, the opposite is true.

[0056] Figure 6 is a plot of the measured X-ray powder diffraction patterns of crystalline obisetrapibhemicalcium, and Figure 7 is a plot of the X-ray powder diffraction patterns of crystalline obisetrapibhemicalcium measured under stress conditions. Figure 7 shows four diffraction patterns based on the stability study described in Example 27. Pattern 1 is the X-ray powder diffraction pattern of an amorphous obisetrapibhemicalcium sample. Pattern 2 is the X-ray powder diffraction pattern of a crystalline obisetrapibhemicalcium sample. In Pattern 3, a crystalline obisetrapibhemicalcium sample was exposed to 70°C at 75% relative humidity for one day. As can be seen from Pattern 3, the X-ray powder diffraction pattern shows that the crystallinity was almost completely lost on that day. After 7 days under the same conditions, the result is still the same as that observed in Pattern 4. A similar experiment was performed on amorphous obisetrapibhemicalcium shown in Figure 8. Pattern 1 was measured before the sample reached a stable state. Exposure of the substance to the same 70°C and 75% relative humidity conditions did not induce crystallization, and the substance remained amorphous after 7 days (Pattern 2) and 14 days (Pattern 3). Therefore, these experiments suggest that, contrary to expectations, the amorphous form of obisetrapibhemicalcium is more stable than crystalline obisetrapibhemicalcium.

[0057] In some embodiments of this disclosure, stable amorphous ovicetrapib hemicalcium is provided herein. In these embodiments, amorphous ovicetrapib hemicalcium is physically more stable than crystalline ovicetrapib hemicalcium under typical pharmaceutical use and processing conditions.

[0058] While we do not wish to be bound by theory, at least with regard to the thermodynamically more stable crystalline phase under pharmacologically relevant processing and usage conditions, it is conceivable that the amorphous phase would be kinetically stabilized in this case. The resulting stability profile indicates that amorphous ovicetrapib hemicalcium is preferable to the corresponding crystalline phase for drug development and use. Despite its greater physical adaptability, amorphous ovicetrapib hemicalcium is more soluble than the highly insoluble crystalline ovicetrapib hemicalcium.

[0059] Solubility is a particular challenge, especially in the case of ovicetrapib. At 20°C, for example, the solubility of ovicetrapib in water was measured to be substantially less than 0.1 mg / mL. It would be desirable to have ovicetrapib in solid form to deliver large amounts of ovicetrapib.

[0060] Solubility is a thermodynamic quantity of a substance, but it is possible to measure the dynamic solubility of a substance without necessarily reaching thermodynamic equilibrium. Such measurements provide solubility under metastable conditions and, for example, provide information about the amount of substance that dissolves as a function of time.

[0061] The amorphous form has higher dynamic solubility and dissolution rate than the crystalline form (and consequently, ovicetrapib itself). The dynamic solubility of both crystalline ovicetrapib hemicalcium and amorphous ovicetrapib hemicalcium was determined in Biolilevant medium at various pH levels, namely approximately 5.0 (FeSSIF conditions) and approximately 6.5 (FaSSIF conditions), as described in Example 28.

[0062] Table 1 shows the measured solubility of amorphous ovicetrapib hemicalcium in relation to crystalline ovicetrapib hemicalcium over a 2-hour period in FeSSIF medium at 37°C. In both cases, amorphous ovicetrapib hemicalcium had a higher concentration in solution than the corresponding crystalline substance for all measured time points. The concentrations in Table 1 are those of ovicetrapib (i.e., free acid). [Table 1]

[0063] Table 2 shows a similar experiment at 37°C, but in FaSSIF medium at pH 6.5. Similar to Table 1, in both batches, amorphous ovicetrapib hemicalcium had a higher concentration in solution than the corresponding crystalline substance for all measured time points. The concentrations in Table 2 are those of ovicetrapib (i.e., free acid). [Table 2] Amorphous ovicetrapib hemicalcium dissolves faster than its corresponding crystalline phase, allowing for the availability of a larger quantity of the drug for immediate use, and potentially higher bioavailability in the amorphous phase than in the crystalline phase.

[0064] Amorphous ovicetrapib hemicalcium is also advantageous because, unlike many amorphous organic compounds, it does not readily absorb moisture. For example, when exposed to relative humidity close to 90%, moisture absorption of less than approximately 5% is typically measured. This lack of hygroscopicity is advantageous because it does not require special handling or storage conditions. Other disadvantages generally associated with the manufacture and use of amorphous materials are also absent. For example, amorphous materials are often difficult to purify chemically. However, amorphous ovicetrapib hemicalcium can be conventionally produced here with a chemical purity of 99.9% or higher.

[0065] In some embodiments of this disclosure, substantially pure amorphous ovicetrapib hemicalcium is provided. In these embodiments and other embodiments, the chemical purity of the substantially pure amorphous ovicetrapib hemicalcium is 99.9% or higher.

[0066] In many embodiments of this disclosure, a method is provided for preparing an amorphous calcium salt of ovicetrapib, such as amorphous ovicetrapib hemicalcium, comprising the steps of: treating ovicetrapib with an acid to form a salt, solvate, or composition; isolating the resulting salt, solvate, or composition; and treating such salt, solvate, or composition with a calcium source to produce an amorphous ovicetrapib calcium salt, such as amorphous ovicetrapib hemicalcium. The resulting salt can then be isolated.

[0067] Examples of calcium sources include calcium salts such as calcium halides and soluble calcium salts. In many embodiments, the calcium source is calcium chloride.

[0068] The preparation of amorphous salts of ovicetrapib calcium, such as amorphous ovicetrapib hemicalcium, has been found to be carried out in the presence of intermediate salts, solvates, or compositions (such compositions include the corresponding acid used to make the salt). Direct treatment of ovicetrapib with a calcium base such as calcium hydroxide has been found not to be a feasible method for producing amorphous salts of ovicetrapib calcium due to either low solubility, weak available bases, or both. Rather, the preparation of amorphous ovicetrapib hemicalcium has been found to be feasible by using intermediate salts such as sodium salts. However, even when using sodium salts, it is preferable for the purposes of purity and yield to utilize additional salts or salt type substitutions associated with the sodium salt of ovicetrapib (such as the use of compositions or solvates rather than actual salts). In particular, the use of salts, solvates, or compositions makes it possible to produce very pure amorphous calcium salts of ovicetrapib, such as amorphous ovicetrapib hemicalcium.

[0069] Exemplary salts that may be prepared as intermediates include those derived from sulfonates (e.g., besilates, tosilates, napsilates, cansilates, esylates, edisylates, or mesilates), sulfates (e.g., methylsulfates), halogens (e.g., chloride ions, iodide ions, or bromide ions), acetates, aspartates, benzoates, bicarbonates, tartrates, carbonates, citrates, decanoates, fumarates, gluceptates, glucons, glutamates, glycolates, hexanoates, hydroxynaphthoates, isethionates, lactates, lactobionates, malates, maleates, mandelates, mucinates, nitrates, octanoates, oleates, pamoates, pantothenates, phosphates, polygalacturonates, propions, salicylates, stearates, succinates, tartrates, or theoclates. If the intermediate is a solvate or composition, the corresponding acid may be used or present. Furthermore, in the case of a solvate, the intermediate may further contain a solvent such as an organic solvent or water, in which case the solvate becomes a hydrate. One such organic solvent is CPME (cyclopentyl methyl ether).

[0070] In some embodiments, the intermediate is a solvate of an acid. In these embodiments and other embodiments, the intermediate is a solvate of an acid and an organic solvent. In some specific embodiments, the intermediate is a solvate containing an acid and a solvent. In some of these embodiments, the acid is hydrochloric acid and the solvent is CPME.

[0071] In many aspects of this disclosure, the disclosure includes methods for preparing amorphous ovicetrapib calcium salts, such as amorphous ovicetrapib hemicalcium. The disclosure further includes amorphous ovicetrapib calcium salts, including amorphous ovicetrapib hemicalcium, thus prepared. In one such preparation, an intermediate referred herein as crystalline ovicetrapib HCl is used in a method for preparing amorphous ovicetrapib calcium, such as amorphous ovicetrapib hemicalcium.

[0072] In many aspects of this disclosure, amorphous ovicetrapibhemicalcium is prepared by chemical synthesis using formula (IH): [ka] An intermediate represented by is used. y varies so that the mass% of HCl varies from 0.01% to 8% by weight, and is thought to further contain organic solvents associated with the solvate, etc. In some embodiments, y varies from 0.002 to 1.5. In some embodiments, y varies from 0.3 to 1. In some embodiments, y varies from 0.4 to 0.6, including between 0.5 and 0.6. In some embodiments, the solvate of formula (IH) is isolated in its crystalline form. In many embodiments, the solvent is CPME. Other solvents that can form solvates include toluene and heptane.

[0073] In this specification, the prepared ovicetrapib HCl is typically crystalline. Furthermore, the term crystalline ovicetrapib HCl may include CPME as a solvate when CPME is used in the preparation of crystalline ovicetrapib HCl. In formula (IH), the solvate is a solvate of an organic solvent, and in many embodiments, the solvent is CPME. In some embodiments, this disclosure provides compositions comprising crystalline ovicetrapib HCl.

[0074] Formula (IH) is called ovicetrapib HCl, and when crystalline, it is called crystalline ovicetrapib HCl. One crystal structure of the solid form of crystalline ovicetrapib HCl has been elucidated and is consistent with that of crystalline ovicetrapib HCl of form B.

[0075] The crystal structure was elucidated according to Example 34, and the single crystal was prepared according to Example 33. This structure is a complex multicomponent crystal, exhibiting six ovicetrapib moieties, two of which are neutral and four of which are charged as an asymmetric unit. There are four protonated ovicetrapib molecules, each protonated at the nitrogen on the pyrimidine ring of ovicetrapib, and four chloride ions. Two chloride ions appear to associate with two of the protonated nitrogens, respectively, supporting the formation of a salt, while the other two chloride ions coordinate to the carboxyl moiety. This structure contains heptane and cyclopentyl methyl ether (CPME) solvent molecules. There are void spaces of unknown content, with sufficient room for the solvent and / or HCl, but no room for ovicetrapib. Although not bound by theory, crystalline HCl ovicetrapib is considered to be a mixed salt solvate. In the reaction producing formula (IH), when CPME is used to supply HCl, the chloride ion content of formula (IH) was found to be in the range of approximately 2.5% to 3.0% by weight, which is lower than what is expected for a neutral salt (i.e., approximately 4.8% by weight).

[0076] In many embodiments, when CPME is used in this manner, it is found in the material upon crystallization. When CPME is used in the reaction to supply dry HCl and is thus found in the crystallized material, the resulting crystalline formula (IH) material is referred to as crystalline ovicetrapib HCl, and its X-ray powder diffraction pattern is shown in Figure 18. The advantage of using crystalline ovicetrapib HCl as an intermediate is that the resulting amorphous ovicetrapib hemicalcium typically has a chemical purity of 99.9% or higher. Chemical purity is a quantitative value that indicates whether or not other chemical entities are present other than the compound being measured. For example, amorphous ovicetrapib hemicalcium with a chemical purity of 99.9% means that less than 0.1% of the compound in the sample of amorphous ovicetrapib hemicalcium are other entities. Physical purity refers to the amount of other solid forms of the same compound present, which in the case of amorphous ovicetrapibhemicalcium is crystalline ovicetrapibhemicalcium. The disclosures herein provide physically pure amorphous ovicetrapibhemicalcium, meaning that it does not contain or substantially contains crystalline ovicetrapibhemicalcium. Unless otherwise specified herein, the purity measurements presented herein are measurements of chemical purity.

[0077] When used herein, HCl ovicetrapib is not limited to crystalline ovicetrapib HCl. In fact, crystalline ovicetrapib HCl may become amorphous upon desolvation.

[0078] Under stress conditions, crystalline obicetrapib HCl loses its crystallinity. In Figure 18, Pattern 2 reflects crystalline obicetrapib HCl subjected to mild drying treatment, whereby surface solvent is removed, confirming that this compound is crystalline. For comparison, the sample whose X-ray powder diffraction was measured as Pattern 1 was subjected to a more intensive drying treatment at 55°C for 48 hours under a pressure of 2 mbar. As is evident, such drying transformed the material from crystalline to amorphous, likely due to the loss of HCl and desolvation of CPME. For example, 1 Using 1H-NMR spectroscopy, it was shown that CPME is present in the upper pattern, but is substantially absent in the lower amorphous pattern. Therefore, the amorphous pattern represents HCl obicetrapib that is not crystalline obicetrapib HCl. It may be obicetrapib, but it is considered to have HCl associated with obicetrapib as a solvate, and thus is HCl obicetrapib, but has a chloride content lower than that normally observed within the range observed for crystalline obicetrapib HCl. In some embodiments, the chloride content is less than 0.1% by weight, such as between about 0.01% by weight and 0.1% by weight.

[0079] Crystalline obicetrapib HCl may be characterized by an X-ray powder diffraction pattern comprising a peak at about 9.8° (2θ). In some embodiments, crystalline obicetrapib HCl may be characterized by an X-ray powder diffraction pattern comprising one or more peaks at about 8.1° (2θ), about 9.8° (2θ), about 13.8° (2θ), about 16.7° (2θ), or about 19.5° (2θ). Table 3 presents exemplary peaks that may be present in crystalline obicetrapib HCl. In some embodiments, crystalline obicetrapib HCl may be characterized by an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern in Figure 19.

[0080] The substance analyzed in Figure 19 appears to have been measured in a way that did not detect a peak between approximately 4.3°(2θ) and approximately 4.7°(2θ). In fact, for each of the crystalline ovicetrapib hydrochloride forms A, B, C, and D, a peak is present and located between approximately 4.3°(2θ) and approximately 4.7°(2θ). Therefore, crystalline ovicetrapib hydrochloride can be characterized by an X-ray powder diffraction pattern that includes a peak between approximately 4.3°(2θ) and approximately 4.7°(2θ). [Table 3]

[0081] Several forms of crystalline ovicetrapib hydrochloride are disclosed herein. In some embodiments, crystalline ovicetrapib hydrochloride of form A is provided. The preparation of crystalline ovicetrapib hydrochloride of form A is described in Example 29. The X-ray powder diffraction pattern of crystalline ovicetrapib hydrochloride of form A is shown in Figure 22. Table 4 shows exemplary peaks that may be present in crystalline ovicetrapib hydrochloride of form A. [Table 4-1] [Table 4-2]

[0082] In some embodiments, crystalline ovicetrapib hydrochloride of form A may be characterized by an X-ray powder diffraction pattern including a peak at about 8.6°(2θ), two peaks between about 9.7°(2θ) and about 10.4°(2θ), and two peaks at about 8.6°(2θ) and about 9.0°(2θ). In some embodiments, crystalline ovicetrapib hydrochloride of form A has an X-ray powder diffraction pattern substantially identical to the X-ray powder diffraction pattern in Figure 22.

[0083] In some embodiments, crystalline ovicetrapib hydrochloride of form B is provided. The preparation of crystalline ovicetrapib hydrochloride of form B is described in Example 30. The X-ray powder diffraction pattern of crystalline ovicetrapib hydrochloride of form B is shown in Figure 23. Table 5 shows exemplary peaks that may be present in crystalline ovicetrapib hydrochloride of form B. [Table 5]

[0084] In some embodiments, crystalline ovicetrapib hydrochloride of form B may be characterized by an X-ray powder diffraction pattern containing peaks at approximately 6.5°(2θ), approximately 8.8°(2θ), and approximately 11.0°(2θ). In some embodiments, crystalline ovicetrapib hydrochloride of form B has an X-ray powder diffraction pattern substantially identical to the X-ray powder diffraction pattern in Figure 23.

[0085] In some embodiments, crystalline ovicetrapib hydrochloride of form C is provided. The preparation of crystalline ovicetrapib hydrochloride of form C is described in Example 31. The X-ray powder diffraction pattern of crystalline ovicetrapib hydrochloride of form C is shown in Figure 24. Table 6 shows exemplary peaks that may be present in crystalline ovicetrapib hydrochloride of form C. [Table 6]

[0086] In some embodiments, crystalline ovicetrapib hydrochloride of form C has an X-ray powder diffraction pattern substantially identical to the X-ray powder diffraction pattern in Figure 24.

[0087] In some embodiments, crystalline ovicetrapib hydrochloride of form D is provided. The preparation of crystalline ovicetrapib hydrochloride of form D is described in Example 32. The X-ray powder diffraction pattern of crystalline ovicetrapib hydrochloride of form D is shown in Figure 25. Table 7 shows exemplary peaks that may be present in crystalline ovicetrapib hydrochloride of form D. [Table 7]

[0088] In some embodiments, crystalline ovicetrapib hydrochloride of form D has an X-ray powder diffraction pattern substantially identical to that of the X-ray powder diffraction pattern in Figure 25.

[0089] Single-crystal X-ray diffraction is another technique that can be used to elucidate the structure of crystalline materials. A single-crystal structure solution showing the asymmetric units of the crystalline ovicetrapib hydrochloride prepared according to Example 33 is presented in Figure 26. The unit cell parameters are found in Table 8 below. [Table 8]

[0090] Although irregular, this solution yields a pattern similar to that of crystalline ovicetrapib hydrochloride of form B, despite the use of a solvent system capable of yielding crystalline ovicetrapib hydrochloride of form A in its preparation. This solution exhibits four protonated ovicetrapib moieties (each 1-protonated at the N3 nitrogen on the pyrimidine ring), and each of the four chloride anions is NH at N3 of the pyrimidine ring in the lattice unit. + It is hydrogen-bonded to the unit. This structure further contains two neutral ovicetrapib molecules and solvent molecules of heptane and CPME. One CPME molecule and one heptane molecule are thought to be present in the unit cell. There are further void spaces that may contain at least one additional heptane molecule, and possibly up to four additional heptane molecules.

[0091] This crystal structure suggests a complex, variable structure associated with crystalline ovicetrapib hydrochloride. It is a solvate, given the presence of CPME and heptane.

[0092] Using single-crystal data, the powder patterns observable in Figure 27 were calculated. Figure 28 shows a superposition of the calculated patterns, the X-ray powder diffractions of crystalline ovicetrapib hydrochloride in form A, and crystalline ovicetrapib hydrochloride in form B. Pattern 1 is associated with crystalline ovicetrapib hydrochloride in form A, pattern 2 is associated with the calculated pattern, and pattern 3 is associated with crystalline ovicetrapib hydrochloride in form B. Pattern 2 appears similar to pattern 3.

[0093] Another intermediate used in the preparation of ovicetrapib is formula (VI) [ka] It is an intermediate (where Y 1 A is a protecting group (for example, as described herein), and A n- (where n is an anion and n is an integer between 1 and 3).

[0094] In one embodiment, the compound of formula (VI) is such that n is 1 and Y 1 is t-butyl, compound 1D: [ka] It is a mesylate salt having the following structure.

[0095] Compound 1D 1The 1H-NMR spectrum (in solution) can be seen in Figure 21. Crystalline compound 1D may be characterized by an X-ray powder diffraction pattern containing one or more peaks at approximately 5.2°(2θ) or approximately 9.1°(2θ). In some embodiments, crystalline compound 1D may be characterized by an X-ray powder diffraction pattern containing one or more peaks at approximately 5.2°(2θ), approximately 9.1°(2θ), approximately 15.9°(2θ), approximately 16.5°(2θ), approximately 17.2°(2θ), approximately 18.6°(2θ), and approximately 19.2°(2θ). Table 9 presents exemplary peaks that may be present in crystalline compound 1D (the peak at approximately 5.2°(2θ) was not measured in reflection mode due to instrument limitations). In some embodiments, crystalline compound 1D may be characterized by an X-ray powder diffraction pattern substantially identical to that in Figure 20. [Table 9-1] [Table 9-2]

[0096] For example, crystalline compounds such as crystalline compound 1D and crystalline ovicetrapib HCl can be characterized by X-ray powder diffraction. The X-ray powder diffraction pattern is an xy graph with x²θ (diffraction angle) on the x-axis and intensity on the y-axis. Peaks are usually represented and referred to by their position on the x-axis rather than their intensity on the y-axis, because peak intensity can be particularly sensitive to the orientation of the sample (Pharmaceutical Analysis, Lee). See & Web, pp.255-257 (2003). Therefore, intensity is not typically used to characterize solid morphologies. Crystalline morphologies can be characterized using data from X-ray powder diffraction in several ways. For example, crystalline ovicetrapib HCl compounds or crystalline compound 1D can be characterized using the entire output values ​​of an X-ray powder diffraction pattern from a diffractometer. However, smaller subsets of such data are also suitable, and usually suitable, for characterizing such compounds. For example, these compounds can be characterized using a collection of one or more peaks derived from such patterns. When the phrase "one or more peaks" is presented from a list of peaks from an X-ray powder diffraction pattern, it generally means that any combination of the enumerated peaks may be used for characterization. Furthermore, the presence of other peaks in the X-ray powder diffraction pattern does not generally negate or otherwise restrict such characterization.

[0097] In addition to variations in peak intensity, there may also be variations in the position of peaks along the x-axis. However, this variation can usually be taken into consideration when reporting peak positions for characterization purposes. Such variations in peak positions along the x-axis can stem from several causes (e.g., sample preparation, particle size, water content, solvent content, instrument parameters, data analysis software, and sample orientation). For example, samples of the same crystalline material prepared under different conditions may yield slightly different diffractograms, and different X-ray instruments can be operated using different parameters, which can result in slightly different diffraction patterns for the same crystalline solid. Due to these causes of variation, it is common practice to describe X-ray diffraction peaks using the word "approximately" before the peak value (°2θ). For the purposes of the data reported herein, a value of generally ±0.2°(2θ) is intended to be reported with such variation whenever disclosed herein, whether or not the word "approximately" is present. Variation may be even higher in some cases, depending on instrument conditions, including how well the instrument is maintained.

[0098] In some embodiments, the crystalline compound 1D may further feature an X-ray powder diffraction pattern substantially identical to that of the X-ray powder pattern in Figure 20.

[0099] In many aspects of this disclosure, a method for preparing amorphous calcium salts of ovicetrapib, such as amorphous ovicetrapib hemicalcium, i. A step of treating ovicetrapib with HCl to obtain crystalline ovicetrapib HCl, ii. Step of isolating crystalline ovicetrapib HCl, iii. A step of preparing an amorphous calcium salt of ovicetrapib, such as amorphous ovicetrapib hemicalcium, from the crystalline ovicetrapib HCl isolated in step (ii), and iv. Steps to isolate amorphous calcium salts of ovicetrapib, such as amorphous ovicetrapib hemicalcium. A method is provided that includes this.

[0100] In other aspects of this disclosure, a method for preparing ovicetrapib is described. (a) A step of preparing the compound of formula (IV) by coupling the compound of formula (II) or a salt thereof with the compound of formula (III); [ka] (In the formula, X 1 is a leaving group, Y 1 (is a protecting group) (b) A step of preparing the carbamate of formula (V) from the compound of formula (IV) and isolating it as a solid salt of formula (VI): [ka] (In the formula, Y 1 is a protecting group, and A n- (where n is an anion and n is an integer between 1 and 3) (c) If necessary, desalt the compound of formula (VI) and alkylate it with the compound of formula (VII) to obtain the compound of formula (VIII): [ka] (In the formula, X 2 is a leaving group, Y 1 (is a protecting group), and (d) Step of converting the compound of formula (VIII) to ovicetrapib. Includes, A method is provided in which reaction steps (a) to (d) are carried out in an organic solvent, compounds (IV), (V), and (VIII) are not isolated from the organic solvent under certain circumstances, and the method does not require chromatography.

[0101] The reactions in steps (a) to (d) of the subject method are carried out in a solvent, and the intermediate compounds of formulas (IV), (V), and (VIII) do not need to be isolated from their individual solvents if they are further processed to the final product. This means that some solvent exchange takes place between reaction step (x) and reaction step (x+1) so that the compound remains in solution during the solvent exchange by evaporating at least a portion of the solvent used in step (x) and adding the solvent of step (x+1) stepwise. The intermediate compound of formula (VI) may be isolated from the solvent as a salt in solid form, and thus this salt can be washed to remove impurities. This isolation step ensures that the downstream product is of sufficient purity. The subject method does not need to include a purification step using chromatography, such as column chromatography, to achieve the levels of chemical purity described herein. Method for preparing amorphous calcium salts (such as amorphous ovicetrapib hemicalcium) - Steps (i) to (ii) from aspects (i) to (iv)

[0102] In some embodiments of the method for preparing amorphous calcium salts of ovicetrapib, such as amorphous ovicetrapib hemicalcium, the method includes step (i), i.e., treating ovicetrapib in an organic solvent with HCl to obtain crystalline ovicetrapib HCl.

[0103] In some embodiments, crystalline ovicetrapib HCl has a purity of 98% or higher, such as 98.5% or higher, 99% or higher, 99.5% or higher, or even higher.

[0104] In some embodiments, the HCl in step (i) is present in a suitable solvent. Such a solvent may be an aqueous solvent or an organic solvent. In some embodiments, the organic solvent used in step (i) includes a mixture of the solvent and the antisolvent. In some embodiments, the solvent is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether, N-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, 1,2-difluorobenzene, toluene, hexafluoroisopropanol, and water. In some embodiments, the antisolvent is selected from n-heptane, n-hexane, n-pentane, and cyclohexane.

[0105] In some embodiments, HCl has sufficient solubility in the antisolvent so that the antisolvent can be used as a suitable solvent. In some embodiments, the organic solvent used in step (i) comprises a mixture of cyclopentyl methyl ether and n-heptane. In some embodiments, the organic solvent used in step (i) further comprises toluene. In some embodiments, toluene is the main component of the organic solvent.

[0106] In some embodiments, step (i) includes preparing ovicetrapib in a mixture of cyclopentyl methyl ether and n-heptane, raising the temperature to between 35°C and 40°C while stirring, adding dry HCl to the cyclopentyl methyl ether and raising the temperature again to between 50°C and 55°C, and then adding further n-heptane as an antisolvent. At this point, a small amount of the reaction mixture can be extracted as needed and cooled to a temperature between 10°C and 15°C to obtain a slurry of crystalline ovicetrapib HCl crystals in a mixture of cyclopentyl methyl ether and n-heptane (hereinafter referred to as the "seed crystal slurry"). If necessary, all or part of the crystalline ovicetrapib HCl seed crystal slurry can then be added back to the reaction mixture. This seed assists in nucleation, but is not necessary. Next, the resulting reaction mixture is cooled to a temperature between 5°C and 15°C (e.g., 10°C to 15°C), and then crystalline ovicetrapib HCl is crystallized from the system while stirring. In some embodiments, the crystalline ovicetrapib HCl is crystallized for 12 hours or longer, followed by filtration (e.g., through a filter dryer), one or more washes as needed with a mixture of cyclopentyl methyl ether and n-heptane, and drying. In some cases, the wet filter cake of crystalline ovicetrapib HCl is dried in stages under vacuum using temperatures of 25°C to 30°C, 30°C to 40°C, 40°C to 50°C, and then 50°C to 55°C, such as 25°C, 35°C, 46°C, and 54°C.

[0107] In some embodiments, the method for preparing crystalline ovicetrapib HCl involves adding seed crystals (e.g., as a seed crystal slurry). Seed crystals of the HCl compound can be formed as a slurry by extracting a small amount of the reaction mixture after adding dry HCl and the antisolvent n-heptane in cyclopentyl methyl ether according to step (i) described above, and cooling to a temperature between 10°C and 15°C to obtain a slurry of crystalline ovicetrapib HCl crystals in cyclopentyl methyl ether and n-heptane.

[0108] Therefore, in one embodiment, step (i) includes the steps of preparing crystalline ovicetrapib HCl in a mixture of cyclopentyl methyl ether and n-heptane, raising the temperature to between 35°C and 45°C while stirring, adding dry HCl to the cyclopentyl methyl ether, raising the temperature again to between 50°C and 55°C, adding further n-heptane as an antisolvent, and adding seed crystals of the HCl compound (e.g., as a seed crystal slurry prepared as described herein) as needed, cooling to a temperature between 5°C and 15°C (e.g., 10°C and 15°C), and then crystallizing the crystalline ovicetrapib HCl from the system while stirring. In some embodiments, the crystalline ovicetrapib HCl is crystallized for 12 hours or longer, filtered, washed once or more as needed with a mixture of cyclopentyl methyl ether and n-heptane, and then dried. In some embodiments, crystalline ovicetrapib HCl is dried under vacuum. In some embodiments, crystalline ovicetrapib HCl is dried in a vacuum drying cabinet for 10 hours or longer at a pressure of 25 mbar and a temperature of 55°C. In some embodiments, after the drying procedure, crystalline ovicetrapib HCl contains less than 0.1% by weight of residual cyclopentyl methyl ether.

[0109] In some embodiments, step (i) is to prepare a cyclopentyl methyl ether solution of ovicetrapib at a concentration between 30 and 40% by weight, such as 33 to 37% by weight, relative to the weight of the solution (the first organic solvent used in step (d), such as toluene, is less than 1% by weight and n-heptane is less than 1% by weight), add n-heptane, raise the temperature to 35°C to 45°C while stirring, add dry HCl to the cyclopentyl methyl ether, and raise the temperature again to 50°C to 55°C. The steps include: preparing the mixture; adding an additional n-heptane as an antisolvent; optionally adding a seed crystal of crystalline ovicetrapib HCl (for example, as a seed crystal slurry prepared as described herein); cooling to a temperature between 10°C and 15°C; then crystallizing crystalline ovicetrapib HCl from the system while stirring for at least 12 hours, and subsequently filtering; washing once or multiple times with a mixture of cyclopentyl methyl ether and n-heptane; and drying under vacuum or the like. In some embodiments, the amount of toluene is considerably higher.

[0110] In some embodiments, crystalline ovicetrapib HCl from step (i) is isolated in step (ii). In some embodiments, the isolated crystalline ovicetrapib HCl has a purity of 98% or higher, such as 98.5% or higher, 99% or higher, 99.5% or higher, 99.7% or even higher.

[0111] Another embodiment of the present disclosure relates to crystalline obisetrapib HCl obtained or obtainable by the methods defined herein.

[0112] Further embodiments of this disclosure relate to HCl ovicetrapib, including crystalline ovicetrapib HCl.

[0113] In some embodiments, crystalline obisetrapib HCl is stored at controlled room temperature and under a nitrogen atmosphere to protect it from moisture and prevent the formation of amorphous solids, such as from desolvation. Method for preparing amorphous calcium salts of ovicetrapib, such as amorphous ovicetrapib hemicalcium - Steps (iii) to (iv) from aspects (i) to (iv)

[0114] In some embodiments of the method for preparing amorphous calcium salts of ovicetrapib, such as amorphous ovicetrapib hemicalcium, the method comprises steps (iii) to (iv), a step of preparing amorphous calcium salts of ovicetrapib from crystalline ovicetrapib HCl isolated in step (ii), and a step of isolating amorphous calcium salts of ovicetrapib, such as amorphous ovicetrapib hemicalcium.

[0115] In some embodiments of the method for isolating the amorphous calcium salt of ovicetrapib by step (iv), the amorphous calcium salt of ovicetrapib is in the form of amorphous ovicetrapib hemicalcium: [ka] It is located there.

[0116] In some embodiments of the method for preparing ovicetrapib, step (iii) is as follows: (iii-1) In an organic solvent, convert the crystalline ovicetrapib HCl from step (ii) to obtain ovicetrapib. (iii-2) The step of treating ovicetrapib in an organic solvent with aqueous sodium hydroxide to form the sodium salt of ovicetrapib, (iii-3) A step in which the sodium salt of ovicetrapib is treated with aqueous calcium chloride to form amorphous ovicetrapib hemicalcium. Includes, The compounds in steps (iii-1) and (iii-2) are not isolated.

[0117] Therefore, in some embodiments, step (iii-1) is as follows: (aa) A step in which crystalline obisetrapib HCl is prepared as the material isolated in step (ii), (bb) A step in which crystalline ovicetrapib HCl is dissolved in a mixture of water and isopropyl acetate while stirring. In some embodiments, step (bb) is performed at a temperature between 15°C and 25°C. (cc) A step of separating the phases and subjecting the obtained organic phase to a step of washing with water once or more times after each washing step, wherein after each washing step the aqueous phase is separated to obtain the washed organic phase, and (dd) The washed organic phase obtained from step (cc) is subjected to two or more distillations at a temperature of 50°C or below (e.g., 30°C or below) (with intermediate addition of ethanol) to obtain an ethanol solution of ovicetrapib. Includes.

[0118] In some embodiments, step (iii-2) is as follows: (ee) Add an aqueous NaOH solution to the solution obtained in step (dd), and stir the resulting mixture for at least 4 hours at a temperature between 20°C and 25°C to obtain a solution of the sodium salt of ovicetrapib, and (ff) A step in which the solution obtained in step (ee) is filtered as needed. Includes.

[0119] In some embodiments, step (iii-3) is as follows: (gg) Prepare a CaCl2 solution by adding deionized water to CaCl2 while stirring, then add ethyl acetate as a cosolvent, and stir the resulting mixture for 10 to 30 minutes. (hh) The CaCl2 solution obtained in step (gg) is cooled to a temperature of 8°C to 12°C, and at that temperature, while stirring, it is added through a filter to the solution obtained in step (ff) or (ee). (ii) A step of stirring the slurry obtained from step (hh) for about 1 to about 10 hours. In some embodiments of step (ii), the stirring is carried out at a temperature between 8°C and 12°C. (jj) A step of isolating the solid from the slurry obtained in step (ii) by filtration. In some embodiments of step (jj), the isolation is carried out at a temperature between 8°C and 12°C. (kk) A step of washing the filtration residue obtained in step (jj) with water one or more times. In some embodiments of step (kk), the washing is carried out at a temperature between 8°C and 12°C, and (ll) The washed residue obtained in step (kk) is dried under vacuum or the like at a temperature of 40°C to 50°C for more than 16 hours (such as 50 hours, 100 hours, 150 hours, or 200 hours or longer) to obtain amorphous ovicetrapibhemicalcium (sometimes also referred to as compound 3 herein). Includes.

[0120] In some embodiments, amorphous ovicetrapib hemicalcium is subjected to a subsequent reprocessing procedure. In some embodiments, amorphous ovicetrapib hemicalcium is dissolved in ethanol (such as twice the weight of ethanol relative to amorphous ovicetrapib hemicalcium) at a temperature of 25°C to 50°C, then cooled to 10°C to 15°C, then filtered and placed in a mixture of aqueous calcium chloride solution and ethyl acetate, which is also cooled to 10°C to 15°C, then filtered and washed with water, and further reprocessed by drying under vacuum at 45°C or below for 20 hours or longer.

[0121] In some embodiments of step (iv), amorphous ovicetrapib hemicalcium is isolated to a purity of 95% or higher, such as 95.5% or higher, 96% or higher, 96.5% or higher, 97% or higher, 97.5% or higher, 98% or higher, 98.5% or higher, 99% or higher, 99.1% or higher, 99.2% or higher, 99.3% or higher, 99.4% or higher, 99.5% or higher, 99.6% or higher, 99.7% or higher, 99.8% or higher, or 99.9% or higher.

[0122] In some embodiments, amorphous obicetrapibhemicalcium is subjected to a milling process. In some embodiments, the milling process is adapted to enable the production of amorphous obicetrapibhemicalcium in micron size (for example, parameters such as feed rate, venturi pressure, and milling pressure are adapted). Method for preparing ovisetrapib - Step (a) from aspects (a) to (d)

[0123] In step (a) of the method for preparing ovicetrapib according to this disclosure, the compound of formula (II) or a salt thereof is coupled with the compound of formula (III) to form the compound of formula (IV) (for example, as described herein, X 1 Y is a leaving group. 1 (This is a protecting group.) [ka]

[0124] Step (a) of the subject method is to use the compound (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline of formula (II) or a salt thereof: [ka] It starts with this.

[0125] Compounds of formula (II) can be obtained, for example, using the methods disclosed in WO2016 / 024858A1 or WO2007 / 116922A1, both of which are incorporated herein by reference in their entirety. In some embodiments, compounds of formula (II) can be obtained from stable corresponding salts and may be obtained in pure solid form. The solid form may be amorphous or crystalline. In some embodiments, compounds of formula (II) can be obtained from corresponding crystalline salts.

[0126] In some embodiments, the compound of formula (II) obtained in step (a) is a salt of formula (IIA) or (IIB): [ka] (A m- (where is an anion and n is an integer between 1 and 3).

[0127] In some embodiments, the compound of formula (II) obtained in step (a) is a salt of formula (IIA). In some embodiments, the compound of formula (IIA) is used directly in a coupling reaction with the compound of formula (III) without performing a salt decomposition step.

[0128] In some embodiments, the compound of formula (II) obtained in step (a) is a salt of formula (IIB). In some embodiments, the compound of formula (IIB) is used directly in a coupling reaction with the compound of formula (III) without performing a salt decomposition step.

[0129] In some embodiments, the compound of formula (II) in step (a) is obtained from a salt of formula (IIA) or (IIB). In some embodiments, prior to the coupling reaction in step (a), the following: (Pre-a1) Compounds of formula (IIA) or (IIB): [ka] The steps to prepare, (Pre a2) A step of obtaining a compound of formula (II) by salt decomposition of a compound of formula (IIA) or (IIB), The event took place. The reaction in step (pre a2) is carried out in an organic solvent, and the compound of formula (II) is not isolated from the organic solvent; therefore, this method does not involve chromatography.

[0130] In some embodiments, the compound of formula (II) in step (a) is obtained from a salt of formula (IIA). In some embodiments, the compound of formula (II) in step (a) is obtained from a salt of formula (IIB).

[0131] In some embodiments, the salt of formula (IIA) or (IIB) is sulfonate ions (e.g., besylate ions, tosylate ions, napsylate ions, cansylate ions, esyllate ions, edisylate ions, or mesylate ions), sulfate ions (e.g., methyl sulfate ions), halogens (e.g., chloride ions, iodide ions, or bromide ions), acetate ions, aspartate ions, benzoate ions, bicarbonate ions, tartarate ions, carbonate ions, citrate ions, decanoate ions, fumarate ions, gluceptate ions, gluconate ions, gluconate ions. Anion A selected from conate ion, glutamate ion, glycolate ion, hexanoate ion, hydroxynaphthoate ion, isethionate ion, lactate ion, lactobionate ion, malate ion, maleate ion, mandelate ion, mucinate ion, nitrate ion, octanoate ion, oleate ion, pamoate ion, pantothenate ion, phosphate ion, polygalacturonate ion, propionate ion, salicylate ion, stearate ion, succinate ion, tartrate ion, and theoclate ion. m- It is selected from among the salts.

[0132] In some embodiments, the salt of formula (IIA) or (IIB) is an anion A selected from chloride ions, bromide ions, tartaric acid ions, sulfate ions, and sulfonate ions.m- It is selected from among the salts.

[0133] In some embodiments, the salt of formula (IIA) or (IIB) is an anion A selected from chloride ions, bromide ions, tartaric acid ions, and mesylate ions. m- It is selected from among the salts.

[0134] In some embodiments of the salts of formula (IIA) or (IIB), m is 1.

[0135] In some embodiments, the salt is of formula (IIA), and the anion A m- is a mesylate ion, where m is 1. Mesylate (MSA) salts (also referred to herein as Compound 1A shown below) can be obtained by the methods disclosed in WO2016 / 024858A1 or WO2007 / 116922A1, the entirety of which is incorporated herein by reference. [ka]

[0136] In some embodiments, the salt decomposition of the compound of formula (IIA) or (IIB) in step (pre a2) is carried out in a mixture of aqueous sodium hydroxide and an organic solvent selected from toluene, dichloromethane, cyclopentyl methyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, chlorobenzene, and combinations thereof, and this mixture is then heated, and then cooled to separate the system into phases and separate the aqueous phase. In some embodiments, the solvent is toluene. In some embodiments, the reaction mixture is heated to a temperature between 45°C and 60°C, and then cooled to a temperature between 15°C and 40°C.

[0137] In some embodiments, the organic phase obtained after separating the aqueous phase is subjected to one or more washing steps with water, followed by separation of the aqueous phase, such as one or more washing steps with an aqueous sodium chloride solution, then separation of the aqueous phase, followed by one or more washing steps with deionized water, and then separation of the aqueous phase again. Next, the obtained washed organic phase is subjected to distillation as needed to reduce the water content to less than 1000 ppm relative to the weight of the solution. Alternatively, in some embodiments, a small amount of water remains in the organic phase with the compound of formula (II), and the subsequent coupling with the compound of formula (III) proceeds in the presence of this small amount of water.

[0138] In some embodiments, the salt decomposition reaction in step (pre-2a) is carried out with respect to the mesylate (compound 1A) in a mixture of aqueous sodium hydroxide and toluene at a temperature between 45°C and 60°C, and the mixture is then cooled to a temperature between 15°C and 25°C to separate the system and separate the aqueous phase. Next, the toluene phase obtained after the separation of the aqueous phase is subjected to a washing step of one or more times with aqueous sodium chloride, if necessary, followed by the separation of the aqueous phase, followed by a washing step of one or more times with deionized water, followed again by the separation of the aqueous phase, and then the resulting washed toluene phase is distilled under reduced pressure at a temperature between 50°C and 65°C to reduce the water content to less than 1000 ppm relative to the total weight of the solution. Alternatively, a small amount of water remains in the toluene with the compound of formula (II), and the subsequent coupling reaction with the compound of formula (III) proceeds in the presence of this small amount of water.

[0139] As outlined above, in step (a), the compound of formula (II) or a salt thereof (for example, a compound of formula (IIA) or (IIB), such as mesylate 1A) is coupled with the compound of formula (III) to obtain the compound of formula (IV). In some embodiments, this method is carried out in an organic solvent.

[0140] The coupling partner of formula (III) in step (a) is the leaving group (X 1 ) includes X 1 It is understood that any convenient leaving group can be used in this disclosure. In some embodiments, the leaving group (X) in the compound of formula (III) is used. 1 The leaving group (X) in the compound of formula (III) is selected from halogens, carbamates, and substituted sulfonyloxy groups. In some embodiments, the leaving group (X) in the compound of formula (III) is selected from halogens, carbamates, and substituted sulfonyloxy groups. 1 ) is a sulfonyloxy group selected from a methanesulfonyloxy group, a p-toluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group. In some embodiments, the leaving group (X 1 ) is a carbamate. In some embodiments, the leaving group (X 1 ) is a halogen. In certain embodiments, the halogen is a chloride. The coupling partner of formula (III) in step (a) is a protecting group (Y 1 ) also includes. The term “protecting group” refers to any group that, when bonded to a functional group such as a carboxylic acid moiety of a compound (including its intermediates), prevents a reaction from occurring at that functional group, and which can be removed by conventional chemical or enzymatic steps to re-establish the functional group, e.g., the carboxylic acid moiety. The specific removable protecting groups used are not important, and examples of carboxylic acid protecting groups include conventional substituents such as t-butyl esters, methyl esters, ethyl esters, benzyl esters, allyl esters, 1,1-diethylallyl esters, 2,2,2-trifluoro(2,2,2-trifluro)ethyl esters, phenyl esters, 4-methoxybenzyl esters, silyl esters, ortho esters, esters of 2,6-disubstituted phenols (e.g., 2,6-dimethylphenol), and any other groups that are chemically introduced to a carboxylic acid group or similar functional group and subsequently selectively removed by either chemical or enzymatic methods under mild conditions suitable for the properties of the product. Any suitable protecting group for the carboxylic acid moiety (e.g., an ester group) is Y 1It is understood that the appropriate protecting group can be used for the purposes disclosed herein and the selection of an appropriate protecting group can be easily determined by those skilled in the art. Suitable groups for such purposes are described in ProtectiveGroupsin Organic Synthesis, 4 by TWGreene and PGMWuts. th In the field of chemistry, there are publications such as Ed. (John Wiley & Sons, New York, 1999), Protecting Group Chemistry, 1st Ed. (Oxford University Press, 2000) by Jeremy Robertson, and March's Advanced Organic Chemistry: Reactions Mechanisms, and Structure, 8th Ed. (Wiley-Interscience Publication, 2001) by Michael B. Smith. This is discussed in the standard manual. In some embodiments, the protecting group (Y 1 The protecting group (Y) is selected from alkyl groups, substituted alkyl groups, aryl groups, substituted aryl groups, allyl groups, substituted allyl groups, and silyl groups. In some embodiments, the protecting group (Y) is selected from alkyl groups, substituted alkyl groups, aryl groups, substituted aryl groups, allyl groups, substituted allyl groups, and silyl groups. 1 The protecting group (Y) is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluoroethyl, phenyl, 4-methoxybenzyl ester, 2,6-disubstituted phenol, and silyl groups. In some embodiments, the protecting group (Y) is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluoroethyl, phenyl, 4-methoxybenzyl ester, 2,6-disubstituted phenol, and silyl groups. 1 ) is a t-butyl group. In some embodiments, the compound of formula (III) has the following structure 1B: [ka] It is a compound of [the compound].

[0141] In some embodiments of the coupling reaction in step (a), the solvent is selected from toluene, t-butanol, 1,4-dioxane, xylene, N-methyl-2-pyrrolidone, dimethylformamide, water, tetrahydrofuran, and combinations thereof. In some embodiments, the solvent is a mixture of the organic solvent toluene and the organic cosolvent t-butanol.

[0142] If steps (pre-a1) and (pre-a2) are performed before step (a), the compound of formula (II) is already present in the required solvent because the same effective solvent is used in steps (pre-a2) and (a), or because solvent exchange occurs in step (pre-a2). If necessary, additional organic solvents, and for example, organic co-solvents, may be added in step (a). As will be understood by those skilled in the art, organic co-solvents may also be added during solvent exchange in step (pre-a2). In some embodiments, steps (pre-a1) and (pre-a2) are performed before step (a), and the compound of formula (II) is present in toluene.

[0143] The coupling reaction in step (a) is typically a catalytic reaction. In some embodiments, the reaction is a palladium-catalyzed coupling reaction in the presence of a base. Preferred examples of palladium catalysts are, for example, tris(dibenzylideneacetone)dipalladium and Pd(II) acetate. Preferred bases include organic bases (e.g., sodium t-butoxide and potassium t-butoxide) and inorganic bases (e.g., K3PO4, K3PO4·H2O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH, and NaOH).

[0144] In many embodiments, anhydrous K3PO4 is used as the base. In many such embodiments, 90% of the particles have a particle size distribution smaller than about 140–307 microns, including about 160–290 microns, about 180–220 microns, and about 200–210 microns, with 90% of the particles being between about 140–170 microns. In some embodiments, 90% of the particles are less than 205 microns.

[0145] In these embodiments and other embodiments, 50% of the particles are between approximately 35 and approximately 173 microns, including between approximately 35 and approximately 40 microns, or smaller.

[0146] In these embodiments and other embodiments, 10% of the particles are between approximately 7 and approximately 74 microns, including between approximately 7 and approximately 10 microns.

[0147] In some embodiments, the compound of formula (II) is reacted in step (a) with the compound of formula (III) in a solvent (e.g., an organic solvent), using a palladium catalyst and a base. In some embodiments, the reaction mixture further comprises a ligand.

[0148] In some embodiments, the compound of formula (IIA) or (IIB) is reacted in step (a) with the compound of formula (III) in a solvent (e.g., an organic solvent), using a palladium catalyst and a base. In some embodiments, the reaction mixture further comprises a ligand.

[0149] In some embodiments, the salt-hydrolyzed compound of formula (II) is reacted in step (a) with the compound of formula (III) in a solvent (e.g., an organic solvent) using Pd(II) acetate and either (S)-BINAP[(S)-2,2'-bis(diphenylphosphin)-1,1'-binaphthyl] or rac-BINAP as the ligand. In some embodiments, (S)-BINAP is used as the ligand, and the base is selected from sodium t-butoxide, potassium t-butoxide, anhydrous K3PO4, K3PO4·H2O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH, and NaOH.

[0150] In some embodiments, a salt of formula (IIA) or (IIB) is reacted in step (a) with the compound of formula (III) in a solvent (e.g., an organic solvent) using Pd(II) acetate and one of the ligands (S)-BINAP[(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl], (R)-BINAP[(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl] or rac-BINAP. In some embodiments, (S)-BINAP is used as the ligand, and the base is selected from sodium t-butoxide, potassium t-butoxide, anhydrous K3PO4, K3PO4·H2O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH, and NaOH. In some embodiments, the salt of formula (IIA) is compound 1A, which is a mesylate.

[0151] In some embodiments, the reaction in step (a) is carried out at a temperature of 70°C to 80°C for 2 hours or longer, under a nitrogen atmosphere if necessary.

[0152] In some embodiments, the compound of formula (II) or the salt of formula (IIA) is, in step (a), in a nitrogen atmosphere, in a mixture of the organic solvent toluene and the organic cosolvent t-butanol, using acetic acid Pd(II) as a catalyst, (S)-BINAP as a ligand, and anhydrous K3PO4 or K3PO4·H2O as a base, at a temperature between 70°C and 80°C, the compound of formula (III) (X 1 Cl is Y 1 It reacts with t-butyl.

[0153] In some embodiments, the step of washing with water once or more times includes washing once or more times with water, preferably deionized water, then separating the aqueous phase, then washing once or more times with an aqueous HCl solution, then separating the aqueous phase, then washing once or more times with an aqueous sodium chloride solution, then separating the aqueous phase, and finally washing again once or more times with deionized water, then separating the aqueous phase.

[0154] If t-butanol is used as an organic co-solvent in step (a), this organic co-solvent is removed from the organic phase during the washing step.

[0155] If step (a) is carried out in an organic solvent different from the solvent used in step (b), the organic solvent used in step (a) is exchanged for the organic solvent applied in step (b), and thus the compound of formula (IV) remains in solution.

[0156] In some embodiments where the (organic) solvents used in steps (a) and (b) differ, at least a portion of the (organic) solvent used in step (a) is evaporated, for example by using distillation under reduced pressure, and the organic solvent of step (b) is added, so that the compound of formula (IV) remains in solution during solvent exchange. This process can be carried out by continuously evaporating the (organic) solvent used in step (a) and then continuously adding the organic solvent of step (b) until, for example, the amount of the (organic) solvent used in step (a) is below a certain threshold relative to the total amount of solvent. Alternatively, this process can be carried out in batches, with more than one step of evaporating a portion of the (organic) solvent used in step (a) and then adding a portion of the organic solvent used in step (b) until, for example, the amount of the (organic) solvent used in step (a) is below a certain threshold relative to the total amount of solvent.

[0157] In some embodiments, the solvent used in step (a) is a mixture of the organic solvent toluene and the organic cosolvent t-butanol. The t-butanol is removed from the organic phase containing the compound of formula (IV) during the washing step.

[0158] In some embodiments of step (a), the residual organic solvent toluene is replaced with acetonitrile by distilling off a portion of the toluene while adding acetonitrile in two or more steps under reduced pressure at a temperature between 50°C and 65°C, in an amount such that a solvent mixture containing less than 20% by weight of toluene relative to the combined solvent weight is obtained, and thus the compound of formula (IV) remains in the solution. In some embodiments of the compound of formula (IV), Y 1 It is t-butyl. Method for preparing ovisetrapib - Step (b) from aspects (a) to (d)

[0159] In step (b) of the method for preparing the compound of formula (I) according to this disclosure, the compound of formula (IV) is converted to the carbamate of formula (V) in an organic solvent, and subsequently to the solid salt (Y) of formula (VI). 1 It is isolated as, for example, a protecting group as described herein. [ka]

[0160] In some embodiments, the organic solvent used in step (b) is selected from acetonitrile, chlorobenzene, toluene, N-methyl-2-pyrrolidone, xylene, 1,4-dioxane, ethyl acetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, t-butyl methyl ether, and combinations thereof. In some embodiments, the organic solvent is acetonitrile or a mixture of chlorobenzene and dichloromethane.

[0161] As previously described herein, the compound of formula (IV) is already obtained in step (a) in the organic solvent used in step (b), because the same organic solvent is used in steps (a) and (b), or the solvent is exchanged in step (a). In some embodiments of the compounds of formulas (IV), (V), and (VI), Y 1 It is t-butyl.

[0162] In some embodiments, the organic solvent used in step (b) is a mixture of acetonitrile and toluene, wherein the amount of toluene is less than about 20% by weight of the combined weight of the organic solvents.

[0163] In some embodiments, the conversion of the compound of formula (IV) to the corresponding carbamate having formula (V) in step (b) is carried out using excess ethyl chloroformate in the presence of pyridine in acetonitrile containing less than 20% by weight of toluene relative to the combined weight of the organic solvents, at a temperature between 10°C and 20°C.

[0164] If step (b) is carried out in an organic solvent different from the organic solvent used in step (c), the organic solvent used in step (b) is exchanged for the organic solvent applied in step (c), and thus the compound of formula (V) remains in solution.

[0165] In some embodiments where different organic solvents are used in steps (b) and (c), at least a portion of the organic solvent used in step (b) is evaporated, such as by distillation under reduced pressure, and the organic solvent for step (c) is added, such that the compound of formula (V) remains in solution during the organic solvent exchange. This process may be carried out by continuously evaporating the organic solvent used in step (b) and continuously adding the organic solvent for step (c) until, for example, the amount of the organic solvent used in step (b) relative to the total amount of organic solvent is less than a specific threshold. Alternatively, this process may be performed in a batch mode by repeating the steps of evaporating a portion of the organic solvent used in step (b), followed by adding a portion of the organic solvent used in step (c) more than once, until, for example, the amount of the organic solvent used in step (b) relative to the total amount of organic solvent is less than a specific threshold.

[0166] The resulting mixture is preferably treated one or more times with an aqueous solution of sodium chloride and / or HCl, the aqueous phase is then separated, followed by one or more treatments with an aqueous bicarbonate solution, and the aqueous phase is then separated.

[0167] In some embodiments, the conversion of the compound of formula (IV) to the corresponding carbamate of formula (V) in step (b) is carried out in acetonitrile containing excess ethyl chloroformate in the presence of pyridine at a temperature between 10°C and 20°C. This solvent is exchanged for isopropyl acetate in step (b) by distilling off a portion of the acetonitrile under reduced pressure at a temperature of 60°C or lower in two or more steps, with intermediate addition of isopropyl acetate in an amount such that a solution of the compound of formula (V) in isopropyl acetate is obtained. Said solution may be subjected to one or more treatments with an aqueous NaCl / HCl solution, the aqueous phase is then separated, followed by one or more treatments with an aqueous bicarbonate solution, and the aqueous phase may then be separated.

[0168] Next, the compound of formula (V) dissolved in an organic solvent is given by formula (VI)(A n- (where n is an anion and n is an integer between 1 and 3) is converted to the corresponding salt. Next, the solid form of the salt according to formula (VI) is isolated as a solid.

[0169] In some embodiments, the salt of formula (VI) is sulfonate ions (e.g., besylate ions, tosylate ions, napsylate ions, cansylate ions, esyllate ions, edisylate ions, and mesylate ions), sulfate ions (e.g., methyl sulfate ions), halogens, acetate ions, aspartate ions, benzoate ions, bicarbonate ions, tartarate ions, carbonate ions, citrate ions, decanoate ions, fumarate ions, gluceptate ions, gluconate ions, glutamate ions, and glycans. Anion A selected from cholate ion, hexanoate ion, hydroxynaphthoate ion, isethionate ion, lactate ion, lactobionate ion, malate ion, maleate ion, mandelate ion, mucinate ion, nitrate ion, octanoate ion, oleate ion, pamoate ion, pantothenate ion, phosphate ion, polygalacturonate ion, propionate ion, salicylate ion, stearate ion, succinate ion, tartrate ion, and theoclate ion. n- It is selected from among the salts.

[0170] In some embodiments, the salt of formula (VI) is an anion A selected from chloride ions, bromide ions, tartaric acid ions, sulfate ions, and sulfonate ions. n- It is selected from among the salts.

[0171] In some embodiments, the salt of formula (VI) is an anion A selected from chloride ions, bromide ions, tartaric acid ions, and mesylate ions. n- It is selected from among the salts.

[0172] In some embodiments, the salt form of formula (VI) is a mesylate, including its crystalline mesylate, compound 1D: [ka] That is the case.

[0173] In some embodiments of the salt of formula (VI), n is 1.

[0174] The organic solvent used for the conversion from formula (V) to (VI) is not particularly limited, but in some embodiments, it is selected from cyclopentyl methyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof. In some embodiments, isopropyl acetate, or a mixture containing dichloromethane, n-heptane, and isopropyl alcohol is used, such as a mixture of chlorobenzene, dichloromethane, n-heptane, and isopropyl alcohol. It should be noted that the compound of formula (V) has already been obtained in an organic solvent for the solvent exchange described herein.

[0175] Therefore, in some embodiments, the organic solvent used to convert the compound of formula (V) to its corresponding salt of formula (VI) is selected from cyclopentyl methyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof, containing less than 20% by weight of toluene and less than 7% by weight of acetonitrile relative to the combined weight of the solvent. In some embodiments, the solvent is a mixture of isopropyl acetate, toluene, and acetonitrile, containing less than 20% by weight of toluene and less than 7% by weight of acetonitrile relative to the combined weight of the solvent.

[0176] In some embodiments, it is preferable to add an organic co-solvent different from the organic solvent already used in step (b). Exemplary organic co-solvents are selected from cyclopentyl methyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof, such as methyl t-butyl ether. As will be understood by those skilled in the art, the necessity and advantages of using an organic co-solvent depend on the specific organic solvent already used in step (b). In certain cases, the use of a co-solvent may be omitted.

[0177] In some embodiments, the organic solvent for the conversion of the compound of formula (V) to its corresponding salt of formula (VI) includes isopropyl acetate and methyl t-butyl ether as an organic cosolvent.

[0178] Next, an acid is added to form the salt of formula (VI) defined above. In some embodiments, the acid is selected from ditartaric acid, sulfuric acid, sulfonic acid, hydrogen bromide, and hydrogen chloride. In some embodiments, the acid is methanesulfonic acid. In embodiments where the salt of formula (VI) can be obtained in crystalline form, some of the acid required to form the salt of formula (VI) may be added before crystallization, and some may be added during crystallization.

[0179] The solid form of the salt of formula (VI) is isolated by crystallization, filtration, one or more washes of the filtration residue as needed, and drying, if the salt of formula (VI) can be obtained in crystalline form.

[0180] In some embodiments, the compound of formula (V) is converted to the corresponding mesylate of formula (VI) by methanesulfonic acid in an organic solvent mixture of isopropyl acetate and methyl t-butyl ether, which contains less than 20% by weight of toluene and less than 7% by weight of acetonitrile relative to the combined weight of the organic solvent; the mesylate of compound 1D is then crystallized from the organic solvent, followed by filtration, one or more washes of the filtration residue as needed, and drying.

[0181] In some embodiments in which the salt according to formula (VI) can be obtained in crystalline form, crystallization is induced by adding a seed crystal of the salt according to formula (VI).

[0182] In some embodiments in which the salt according to formula (VI) can be obtained in crystalline form, the steps of crystallizing the salt according to formula (VI) and obtaining the crystalline form of the salt according to formula (VI) are carried out by adding the acid necessary to form the salt, stirring the resulting mixture for more than 60 minutes at a temperature of 20°C to 25°C, crystallizing with stirring at a temperature between 15°C and 25°C for more than 120 minutes, then vacuum filtering the resulting slurry (the filtration residue is washed once or more times with the same organic solvent used to crystallize the salt according to formula (VI)), and vacuum drying the crystalline form of the salt according to formula (VI).

[0183] In embodiments, the present invention relates to a salt according to formula (VI), A n- is an anion, and n is an integer between 1 and 3. In some embodiments, the compound is a crystalline mesylate (MSA) salt of formula (VI) (e.g., compound 1D described herein).

[0184] In some embodiments, the step of crystallizing the mesylate of formula (VI) from an organic solvent mixture of isopropyl acetate and methyl t-butyl ether to obtain the crystalline form of the mesylate of compound 1D is carried out by adding methanesulfonic acid necessary to form the salt, stirring the resulting mixture for longer than 60 minutes at a temperature between 15°C and 25°C (e.g., 20°C), and then crystallizing it while stirring at a temperature between 15°C and 25°C for more than 120 minutes. The resulting slurry is subjected to vacuum filtration, and the filtration residue is washed once or multiple times with a mixture of isopropyl acetate and methyl t-butyl ether and dried under vacuum to obtain the crystalline form of the mesylate of compound 1D.

[0185] In some embodiments, the compound of formula (VI) is obtained in a yield of at least 70% based on the number of moles of the compound of formula (II). In some embodiments, the compound of formula (VI) is obtained in a purity of 99% or higher, such as 99.1% or higher, 99.2% or higher, 99.3% or higher, 99.5% or higher, or even higher purity. Process for preparing obicetrapib - Step (c) from embodiments (a) to (d)

[0186] In step (c) of the process according to the present disclosure, alkylation of an isolated salt of formula (VI), or a salt-cleaved derivative thereof (e.g., a compound according to formula (V)), with a compound of formula (VII) gives a compound of formula (VIII):

Chemical Formula

[0187] In some embodiments of step (c), an isolated solid form of a salt according to formula (VI), such as a crystalline form of the salt according to formula (VI) (e.g., compound 1D which is a crystalline mesylate), is reacted directly with the compound of formula (VII) in an organic solvent to form the compound of formula (VIII) (i.e., without a salt cleavage step).

[0188] In some embodiments of step (c), an isolated solid form of a salt according to formula (VI), such as a crystalline form of the salt according to formula (VI) (e.g., compound 1D which is a crystalline mesylate), is subjected to salt cleavage and reacted with the compound of formula (VII) in an organic solvent to form the compound of formula (VIII). Salt cleavage of the compound of formula (VI) provides the compound according to formula (V).

[0189] When the compound of formula (VI) is subjected to a salt decomposition step, the salt decomposition process and subsequent reactions with the compound of formula (V) are carried out in the same organic solvent. In some embodiments, the organic solvent is selected from xylene, n-hexane, toluene, heptane (a mixture of isomers), n-heptane, dichloromethane, chlorobenzene, and combinations thereof. In some embodiments, the organic solvent is toluene or n-heptane.

[0190] In some embodiments, step (c) is carried out in the presence of a base. In some embodiments, step (c) is carried out in the presence of a solid-liquid phase transfer catalyst.

[0191] In some embodiments, the base is selected from alkali metal hydrides, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates, and amines. In some embodiments, the base is selected from alkali metal alkoxides. In some embodiments, the base is sodium t-pentoxide, or a mixture of sodium t-butoxide and potassium t-butoxide.

[0192] In some embodiments, the solid-liquid phase transfer catalyst is selected from t-butylammonium hydrogen sulfate, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, crown ethers, and combinations thereof. In some embodiments, the catalyst is t-butylammonium hydrogen sulfate.

[0193] In some embodiments, the reaction between the compound of formula (V) or (VI) and the compound of formula (VII) takes place at a temperature between 0°C and 25°C (e.g., 5°C to 20°C).

[0194] The coupling partner of formula (VII) in step (c) is the leaving group X 2 Includes. X 2 It is understood that any convenient leaving group can be used in this disclosure. In some embodiments, the leaving group X in the compound of formula (VII) 2The leaving group X in the compound of formula (VII) is selected from halogens and substituted sulfonyloxy groups. In some embodiments, the leaving group X in the compound of formula (VII) is selected from halogens and substituted sulfonyloxy groups. 2 This is a substituted sulfonyloxy group selected from a methanesulfonyloxy group, a p-toluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group. In some embodiments, the leaving group X 2 is a halogen. In certain embodiments, the halogen is a bromide. In some embodiments, the compound of formula (VII) has the following structure 1E: [ka] It is a compound of [the compound].

[0195] In some embodiments, the salt decomposition of the compound of formula (VI) and the subsequent reaction with the compound of formula (VII) in step (c) are carried out in toluene as an organic solvent in the presence of a base and a catalyst at a temperature of 5°C to 25°C. In some embodiments, the salt decomposition of the compound of formula (VI) and the subsequent reaction with the compound of formula (VII) in step (c) are carried out in toluene as an organic solvent in the presence of sodium t-pentoxide as a base and t-butylammonium hydrogen sulfate as a catalyst, with stirring, for about 1 to 8 hours at a temperature between 5°C and 25°C. In some embodiments of the compound of formula (VI), Y 1 It is t-butyl.

[0196] In some embodiments, the alkylation of the compound of formula (VI) with the compound of formula (VII) in step (c) (i.e., without an additional salt decomposition step) is carried out in toluene as an organic solvent in the presence of a base and a catalyst at a temperature of 5°C to 25°C. In some embodiments, the alkylation of the compound of formula (VI) with the compound of formula (VII) in step (c) is carried out in toluene as an organic solvent in the presence of sodium t-pentoxide as a base and t-butylammonium hydrogen sulfate as a catalyst, with stirring, for about 1 to 8 hours at a temperature between 5°C and 25°C.

[0197] In some embodiments, step (c) is the step of preparing crystalline 1D, the step of salt-decomposing this compound, and the step of obtaining the compound (X) of formula (VII) after salt-decomposition. 2 The process includes the step of reacting (where is Br) in toluene as an organic solvent at a temperature between 5°C and 25°C for about 1 to 8 hours, with stirring, in the presence of sodium t-pentoxide as a base and t-butylammonium hydrogen sulfate as a catalyst.

[0198] In some embodiments, step (c) is to convert crystalline 1D into compound (X) of formula (VII). 2 The process includes the step of reacting (where is Br) in toluene as an organic solvent at a temperature between 5°C and 25°C for about 1 to 8 hours, with stirring, in the presence of sodium t-pentoxide as a base and t-butylammonium hydrogen sulfate as a catalyst.

[0199] In some embodiments of step (c), the base is the last reagent added to the reaction mixture. Without being bound by any particular theory, the inventors have found that by adding the base as the last reagent, the equivalent amounts of both the base and the compound of formula (VII) used in the reaction mixture can be reduced. Reducing the equivalent amount of the compound of formula (VII) can, in turn, reduce the risk of carrying over impurities associated with formula (VII) to the final product.

[0200] Therefore, step (c) results in the formation of the compound of formula (VIII) in an organic solvent. In some embodiments of the compound of formula (VIII), Y 1is t-butyl. In some embodiments, the reaction mixture is subjected to a step of washing with water once or more times in step (c) to remove impurities, followed by separation of the aqueous phase and, if necessary, one or more filtration steps to obtain a washed reaction mixture containing the compound of formula (VIII) in the organic solvent. In some embodiments, the reaction mixture containing the compound of formula (VIII) in the organic solvent is concentrated by distilling off a portion of the organic phase to obtain a concentrated reaction mixture containing the compound of formula (VIII) in the organic solvent. In some embodiments, the organic solvent contains 30 to 40% by weight of the compound of formula (VIII) relative to the weight of the reaction mixture. In some embodiments, the organic solvent contains 34 to 37% by weight of the compound of formula (VIII) relative to the weight of the reaction mixture.

[0201] The steps of washing with water once or more times, filtering once or more times as needed, and concentrating are preferably performed together to obtain a washed and concentrated reaction mixture containing the compound of formula (VIII) in an organic solvent. In some cases, the organic solvent contains 30-40% by weight of the compound of formula (VIII). In some embodiments, the organic solvent contains 34-37% by weight of the compound of formula (VIII) relative to the weight of the reaction mixture.

[0202] In some embodiments, the step of washing with water once or more times includes the step of washing with an aqueous acetic acid solution once or more times.

[0203] In some embodiments, a reaction mixture containing the compound of formula (VIII) in toluene as an organic solvent is subjected to the following steps: step (c) is to wash the mixture once or more times with an aqueous acetic acid solution, then to separate the aqueous phase, and then to distill off a portion of the toluene, usually at a temperature of 75°C to 90°C under reduced pressure, to obtain a washed and concentrated reaction mixture containing the compound of formula (VIII) in toluene at a concentration of 30 to 40% by weight relative to the weight of the reaction mixture. In some embodiments, the concentrated mixture contains the compound of formula (VIII) at a concentration of 34 to 37% by weight relative to the weight of the reaction mixture.

[0204] If step (c) is carried out in an organic solvent different from the organic solvent used in step (d), the organic solvent used in step (c) is exchanged in step (c) for the organic solvent applied in step (d), and thus the compound of formula (VIII) remains in solution.

[0205] In some embodiments where the organic solvents used in steps (c) and (d) differ, at least a portion of the organic solvent used in step (c) is evaporated, preferably by distillation under reduced pressure, and the organic solvent in step (d) is added so that the compound of formula (VIII) remains in solution during the organic solvent exchange. This process can be carried out by continuously evaporating the organic solvent used in step (c) and continuously adding the organic solvent in step (d) until, for example, the amount of the organic solvent used in step (c) is below a certain threshold relative to the total amount of the organic solvent. Alternatively, this process can be carried out in batches, with more than one step of evaporating a portion of the organic solvent used in step (c) and then adding a portion of the organic solvent used in step (d) until, for example, the amount of the organic solvent used in step (c) is below a certain threshold relative to the total amount of the organic solvent. Method for preparing the compound of formula (I) - Step (d) from aspects (a) to (d)

[0206] In step (d) of the method according to this disclosure, the compound of formula (VIII) is converted to ovicetrapib in a first organic solvent (Y 1 (For example, these are protecting groups described herein.) [ka]

[0207] The choice of the first organic solvent used in step (d) is not particularly limited. In some embodiments, the first organic solvent is neither an ether nor an ester. In some embodiments, the first organic solvent is toluene or a mixture of n-heptane and acetic acid. As previously described herein, the compound of formula (VIII) is already obtained in step (c) in the first solvent used in step (d), since the same organic solvent is used in steps (c) and (d), or the solvent is exchanged in step (c).

[0208] Therefore, in some embodiments, a first organic solvent as previously defined herein, containing 30 to 40% by weight of the compound of formula (VIII), such as 34 to 37% by weight, relative to the weight of the reaction mixture, is supplied in step (d).

[0209] In some embodiments, toluene containing 30-40% by weight of the compound of formula (VIII), such as 34-37% by weight, relative to the weight of the reaction mixture, is supplied in step (d) as the first organic solvent.

[0210] Any convenient protecting group for the carboxylic acid, such as the ester moiety, is used in the compound of formula (VIII) Y. 1 It can be used as such. As disclosed herein, the selection of an appropriate protecting group for a carboxylic acid can be easily determined by those skilled in the art. In some embodiments of formula (VIII), the protecting group (Y 1 ) is selected from alkyl groups, substituted alkyl groups, aryl groups, substituted aryl groups, allyl groups, substituted allyl groups, and silyl groups. In some embodiments of formula (VIII), the protecting group (Y 1 The protecting group is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluoroethyl, phenyl, 4-methoxybenzyl ester, 2,6-disubstituted phenol, and silyl groups. In some embodiments of the compounds of formula (VIII), the protecting group Y 1t-butyl is used. In some embodiments, the conversion of the compound of formula (VIII) to ovicetrapib is carried out by contacting the compound of formula (VIII) with acetic acid (AcOH) and dry HCl with stirring in a first organic solvent such as toluene or a mixture of n-heptane and acetic acid. In some embodiments, the reaction mixture is heated to a temperature between 40°C and 55°C, and the resulting mixture is maintained at this temperature with stirring for at least 3 hours.

[0211] Obisetrapib can be isolated from the resulting mixture using techniques known to those skilled in the art.

[0212] In some embodiments, step (d) involves washing the resulting mixture containing ovicetrapib with water one or more times. In some embodiments, the one or more water washing steps in step (d) are carried out as follows: (AA) Cool the reaction mixture containing ovicetrapib to a temperature between 15°C and 25°C, then add the mixture of n-heptane, acetonitrile, and water, and stir the resulting mixture at this temperature for longer than 15 minutes. (BB) The system obtained in step (AA) is separated into an organic phase and an aqueous phase, and both phases are separated. (CC) Add a mixture of n-heptane, acetonitrile, toluene, and water to the aqueous phase obtained in step (BB), and then stir the resulting system for longer than 15 minutes at a temperature between 15°C and 25°C. (DD) Step (CC) The system obtained is separated into an organic phase and an aqueous phase, and both phases are separated. (EE) Combine the organic phase obtained in step (BB) and the organic phase obtained in step (DD), add water, and stir the resulting system at a temperature between 15°C and 25°C for longer than 15 minutes. (FF) The system obtained in step (EE) is separated into an organic phase and an aqueous phase, and both phases are separated. (GG) Add water to the organic phase obtained in step (FF), and stir the resulting system for longer than 15 minutes at a temperature between 15°C and 25°C. The system obtained in step (GG) (HH) is separated into an organic phase and an aqueous phase, and both phases are separated. (II) Add an aqueous solution of trisodium citrate dihydrate to the organic phase obtained in step (HH), and then stir the resulting mixture at a temperature between 15°C and 25°C for longer than 15 minutes. (JJ) The system obtained in step (II) is separated into an organic phase and an aqueous phase, and both phases are separated. (KK) Add water to the organic phase obtained in step (JJ), and stir the resulting system for longer than 15 minutes at a temperature between 15°C and 25°C, and The system obtained in step (LL) (KK) is subjected to phase separation into an organic phase and an aqueous phase, and both phases are separated.

[0213] Steps (AA) to (LL) in this embodiment result in the washed compound of formula (I) being brought into an organic solvent mixture containing n-heptane, acetonitrile, and a first organic solvent. In some embodiments, the first solvent is toluene.

[0214] In some embodiments, the first organic solvent is not yet predominantly cyclopentyl methyl ether, and the organic solvent mixture is replaced with CPME in a later step (MM), so that ovicetrapib remains in solution.

[0215] Therefore, in some embodiments, step (LL) is followed by step (MM), in which at least a portion of the solvent in the organic solvent mixture obtained in step (LL) is evaporated by means of distillation under reduced pressure, and cyclopentyl methyl ether is added, so that ovicetrapib remains in the solution during solvent exchange. In some embodiments, the method yields a cyclopentyl methyl ether solution of ovicetrapib at a concentration between 30 and 40% by weight relative to the weight of the solution. In some embodiments, the concentration of ovicetrapib in cyclopentyl methyl ether is 33 to 37% by weight relative to the weight of the solution, the first organic solvent is less than 1% by weight, and n-heptane is less than 1% by weight relative to the weight of the solution.

[0216] This process can be carried out by continuously evaporating the solvent in the organic solvent mixture obtained in step (LL) and continuously adding cyclopentyl methyl ether until, for example, the amount of a specific solvent in the organic solvent mixture is below a certain threshold relative to the total amount of organic solvent. Alternatively, this process can be carried out in batches of more than one step, in which a portion of the solvent in the organic solvent mixture obtained in step (LL) is evaporated, followed by the addition of cyclopentyl methyl ether until, for example, the amount of a specific solvent in the organic solvent mixture is below a certain threshold relative to the total amount of solvent.

[0217] In some embodiments, the first organic solvent is toluene, and step (LL) is followed by step (MM), in which at least a portion of the n-heptane, acetonitrile, and toluene in the organic solvent mixture obtained in step (LL) is evaporated by distillation under reduced pressure (vacuum) at a temperature of 45°C or below, with the intermediate addition of cyclopentyl methyl ether, so that ovicetrapib remains in the solution during solvent exchange, yielding a cyclopentyl methyl ether solution of ovicetrapib having a concentration between 30 and 40% by weight. In some embodiments, the concentration of ovicetrapib in cyclopentyl methyl is 33 to 37% by weight of the solution, and it contains less than 0.5% by weight of toluene, less than 0.5% by weight of acetonitrile, and less than 2.7% by weight of n-heptane. Method for preparing crystalline ovicetrapib HCl - Steps (e) to (f) added to aspects (a) to (d)

[0218] In some embodiments of the subject method, steps (e) to (f) follow step (d), in which ovicetrapib is treated with HCl in a suitable solvent. Such a solvent may be an aqueous solvent or an organic solvent. In some embodiments, the use of an organic solvent yields crystalline ovicetrapib HCl.

[0219] In some embodiments, the organic solvent used in step (e) includes a mixture of the solvent and the antisolvent. In some embodiments, the solvent is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether, N-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, 1,2-difluorobenzene, toluene, hexafluoroisopropanol, and water. In some embodiments, the antisolvent is selected from n-heptane, n-hexane, n-pentane, and cyclohexane. In some embodiments, HCl has sufficient solubility in the antisolvent so that the antisolvent can be used as a suitable solvent. In some embodiments, the organic solvent used in step (e) includes a mixture of cyclopentyl methyl ether and n-heptane. In some embodiments, the organic solvent used in step (e) further includes toluene.

[0220] In some embodiments, step (e) includes the steps of preparing ovicetrapib in a mixture of cyclopentyl methyl ether and n-heptane, raising the temperature between 35°C and 40°C while stirring, adding dry HCl to the cyclopentyl methyl ether, and raising the temperature again between 50°C and 55°C, then adding further n-heptane as an antisolvent. At this point, a small amount of the reaction mixture can be extracted and cooled to a temperature between 10°C and 15°C to obtain a slurry of crystalline ovicetrapib HCl crystals in a mixture of cyclopentyl methyl ether and n-heptane (hereinafter referred to as the "seed crystal slurry"). If necessary, all or part of the crystalline ovicetrapib HCl seed crystal slurry can then be added back to the reaction mixture as seed crystals. The seed assists in nucleation but is not necessary, and therefore the method described herein can be carried out without seed crystal addition. Next, the resulting reaction mixture is cooled to a temperature between 5°C and 15°C (e.g., 10°C to 15°C), and then crystalline ovicetrapib HCl is crystallized from the system while stirring. In some embodiments, the crystalline ovicetrapib HCl is crystallized for 12 hours or longer, followed by filtration (e.g., through a filter dryer), one or more washes as needed with a mixture of cyclopentyl methyl ether and n-heptane, and drying. In some cases, the wet filter cake of crystalline ovicetrapib HCl is dried under vacuum using a stepwise temperature range of 25°C to 30°C, 30°C to 40°C, 40°C to 50°C, and then 50°C to 55°C, such as 25°C, 35°C, 46°C, and 54°C.

[0221] Therefore, in some embodiments, the method for preparing crystalline ovicetrapib HCl involves the addition of seed crystals (e.g., as a seed crystal slurry). Seed crystals of crystalline ovicetrapib HCl can be formed as a slurry by extracting a small amount of the reaction mixture after adding dry HCl and the antisolvent n-heptane in cyclopentyl methyl ether, following step (i) described above, and cooling to a temperature between 10°C and 15°C to obtain a slurry of crystalline ovicetrapib HCl crystals in cyclopentyl methyl ether and n-heptane.

[0222] In some embodiments, the organic solvent used in step (e) includes a mixture of cyclopentyl methyl ether and n-heptane. Thus, in one embodiment, step (e) includes preparing ovicetrapib in a mixture of cyclopentyl methyl ether and n-heptane, raising the temperature to 35°C to 45°C while stirring, adding dry HCl to the cyclopentyl methyl ether, and raising the temperature again to 50°C to 55°C, adding further n-heptane as an antisolvent, adding seed crystals of crystalline ovicetrapib HCl as needed (for example, as a seed crystal slurry prepared as described herein), cooling to a temperature between 5°C and 15°C (e.g., 10°C to 15°C), and then crystallizing crystalline ovicetrapib HCl from the system while stirring. In some embodiments, crystalline ovicetrapib HCl is crystallized for at least 12 hours, then filtered, followed by one or more washes as needed with a mixture of cyclopentyl methyl ether and n-heptane, and drying. In some embodiments, crystalline ovicetrapib HCl is dried under vacuum. In some embodiments, crystalline ovicetrapib HCl is dried in a vacuum drying cabinet for 10 hours or longer at a pressure of 25 mbar and a temperature of 55°C. In some embodiments, after the drying procedure, crystalline ovicetrapib HCl contains less than 0.1% by weight of residual cyclopentyl methyl ether.

[0223] In some embodiments described earlier in this specification, step (MM) of step (d) yields a solution of cyclopentyl methyl ether, the first organic solvent used in step (d) at a concentration between 30 and 40% by weight, such as 33 to 37% by weight, and ovicetrapib in n-heptane at a concentration between 30 and 40% by weight, such as 33 to 37% by weight, relative to the weight of the solution. In some embodiments described earlier in this specification, step (MM) of step (d) yields a solution of cyclopentyl methyl ether, toluene at a concentration between 1% by weight, such as 30 to 40% by weight, such as 33 to 37% by weight, and ovicetrapib in n-heptane at a concentration between 1% by weight, relative to the weight of the solution. These solutions may be advantageous to use in step (e) after the addition of n-heptane. As will be understood by those skilled in the art, n-heptane may also be added in step (d).

[0224] Therefore, in some embodiments, step (e) is the step of preparing a cyclopentyl methyl ether solution of ovicetrapib at a concentration between 30 and 40% by weight, such as 33 to 37% by weight, relative to the weight of the solution (where the first organic solvent used in step (such as toluene) is less than 1% by weight and n-heptane is less than 1% by weight), adding n-heptane, raising the temperature to 35°C to 45°C while stirring, adding dry HCl to the cyclopentyl methyl ether, and raising the temperature again to 50°C to 55°C. The process includes the steps of: adding an additional n-heptane as an antisolvent; adding a seed crystal of crystalline ovicetrapib HCl (for example, as a seed crystal slurry prepared as described herein) as needed; cooling to a temperature between 5°C and 15°C (e.g., 10°C to 15°C); then crystallizing crystalline ovicetrapib HCl from the system while stirring for at least 12 hours, and subsequently filtering; washing once or more times with a mixture of cyclopentyl methyl ether and n-heptane; and drying. In some cases, the wet filter cake of crystalline ovicetrapib HCl is dried under vacuum using a stepwise temperature range of 25°C to 30°C, 30°C to 40°C, 40°C to 50°C, and then 50°C to 55°C, such as 25°C, 35°C, 46°C, and 54°C.

[0225] In some embodiments, step (f) is as follows: (aa) A step of preparing crystalline ovicetrapib HCl, (bb) A step in which crystalline ovicetrapib HCl is dissolved in ethanol while stirring. In some embodiments, between 15°C and 25°C, (cc) Add an aqueous NaOH solution to the solution obtained in step (bb), and stir the resulting mixture for at least 4 hours at a temperature of 20°C to 25°C to obtain a solution of the sodium salt of ovicetrapib. (dd) If necessary, filter the solution obtained in step (cc), (ee) Prepare a CaCl2 solution by adding deionized water to CaCl2 while stirring, then add ethyl acetate as a cosolvent, and stir the resulting mixture for 10 to 30 minutes. (ff) Cool the CaCl2 solution obtained in step (ee) to a temperature between 8°C and 12°C, and at that temperature, add it to the solution obtained in step (dd) (or (cc)) via a filter while stirring. (gg) A step of stirring the slurry obtained from step (ff) for about 1 to about 10 hours. In some embodiments, the slurry is stirred at a temperature between 8°C and 12°C. (hh) A step to isolate the solid from the slurry obtained in step (gg) by filtration. In some embodiments, the isolation step is performed at a temperature between 8°C and 12°C. (ii) A step of washing the filtration residue obtained in step (hh) with water one or more times. In some embodiments, the washing is carried out at a temperature between 8°C and 12°C, and (jj) A step to obtain amorphous obicetrapib hemicalcium by drying the washed residue obtained in step (ii) in a vacuum or the like at a temperature between 40°C and 50°C for more than 16 hours (e.g., 200 hours or longer). Includes.

[0226] In some embodiments of the subject method, crystalline ovicetrapib HCl is isolated in step (f) with a purity of 98% or higher, such as 98.5% or higher, 99% or higher, 99.5% or higher, or even higher.

[0227] Another embodiment of the present disclosure relates to crystalline obisetrapib HCl obtained or obtainable by the methods defined herein.

[0228] Another embodiment of this disclosure relates to crystalline obisetrapib HCl.

[0229] In some embodiments, crystalline ovicetrapib HCl, including crystalline ovicetrapib HCl, is hygroscopic, so it is stored at a controlled room temperature and under a nitrogen atmosphere to protect it from moisture and prevent the formation of an amorphous solid. Method for preparing amorphous ovicetrapib hemicalcium - Steps (g) to (h) added to aspects (a) to (f)

[0230] In some embodiments of the method described in the subject, steps (g) to (h) follow step (f), and crystalline ovicetrapib HCl is converted to amorphous ovicetrapib hemicalcium (formula IB): [ka] .

[0231] In some embodiments, step (g), which is the preparation of amorphous ovicetrapib hemicalcium, is steps (g1) to (g3) described below: (g1) In an organic solvent, a step is taken to convert the crystalline ovicetrapib HCl from step (f) to ovicetrapib. (g2) The step of treating ovicetrapib in an organic solvent with aqueous sodium hydroxide to form the sodium salt of ovicetrapib, and (g3) The sodium salt of ovicetrapib is treated with aqueous calcium chloride to form amorphous ovicetrapib hemicalcium. Includes, The compounds in steps (g1) and (g2) are not isolated.

[0232] Therefore, in some embodiments, step (g1) is as follows: (aa) Step (f) is defined as a step of preparing crystalline obisetrapib HCl, (bb) A step in which crystalline ovicetrapib HCl is dissolved in a mixture of water and isopropyl acetate while stirring. In some embodiments, step (bb) is performed at a temperature between 15°C and 25°C. (cc) A step of separating the phases and subjecting the obtained organic phase to a step of washing with water once or more times thereafter, wherein the aqueous phase is separated after each washing step to obtain a washed organic phase, and (dd) The washed organic phase obtained from step (cc) is subjected to two or more distillations at a temperature of 50°C or below (e.g., 30°C or below) (with intermediate addition of ethanol) to obtain an ethanol solution of the ovicetrapib compound. This includes: In some embodiments, step (g2) is as follows: (ee) Add an aqueous NaOH solution to the solution obtained in step (dd), and stir the resulting mixture for at least 4 hours at a temperature between 20°C and 25°C to obtain a solution of the sodium salt of ovicetrapib, and (ff) A step in which the solution obtained in step (ee) is filtered as needed. Includes.

[0233] In some embodiments, step (g3) is as follows: (gg) Prepare a CaCl2 solution by adding deionized water to CaCl2 while stirring, then add ethyl acetate as a cosolvent, and stir the resulting mixture for 10 to 30 minutes. (hh) The CaCl2 solution obtained in step (gg) is cooled to a temperature of 8°C to 12°C, and at that temperature, while stirring, it is added through a filter to the solution obtained in step (ff) or (ee). (ii) A step of stirring the slurry obtained from step (hh) for about 1 to 10 hours. In some embodiments of step (ii), the stirring is carried out at a temperature between 8°C and 12°C. (jj) A step of isolating the solid from the slurry obtained in step (ii) by filtration. In some embodiments of step (jj), the isolation is carried out at a temperature between 8°C and 12°C. (kk) A step of washing the filtration residue obtained in step (jj) with water, one or more times. In some embodiments of step (kk), the washing is performed at a temperature between 8°C and 12°C, and (ll) The washed residue obtained in step (kk) is dried in a vacuum or the like at a temperature of 40°C to 50°C for more than 16 hours (such as 50 hours, 100 hours, 150 hours or 200 hours, or longer) to obtain amorphous ovicetrapibhemicalcium (sometimes referred to as compound 3 herein). Includes.

[0234] In some embodiments, step (g) is as follows: (aa) Step (f) is defined as a step of preparing crystalline obisetrapib HCl, (bb) A step in which crystalline ovicetrapib HCl is dissolved in ethanol while stirring. In some embodiments, between 15°C and 25°C, (cc) Add an aqueous NaOH solution to the solution obtained in step (bb), and stir the resulting mixture for at least 4 hours at a temperature of 20°C to 25°C to obtain a solution of the sodium salt of ovicetrapib. (dd) If necessary, filter the solution obtained in step (cc), (ee) Prepare a CaCl2 solution by adding deionized water to CaCl2 while stirring, then add ethyl acetate as a cosolvent, and stir the resulting mixture for 10 to 30 minutes. (ff) The CaCl2 solution obtained in step (ee) is cooled to a temperature between 8°C and 12°C, and at that temperature, while stirring, it is added to the solution obtained in step (dd) or (cc) via a filter. (gg) A step of stirring the slurry obtained from step (ff) for about 1 to 10 hours. In some embodiments, the slurry is stirred at a temperature between 8°C and 12°C. (hh) A step of isolating the solid from the slurry obtained in step (gg) by filtration. In some embodiments, the isolation is performed at a temperature between 8°C and 12°C. (ii) A step of washing the filtration residue obtained in step (hh) with water one or more times. In some embodiments, the washing is carried out at a temperature between 8°C and 12°C, and (jj) A step to dry the washed residue obtained in step (ii) under vacuum or the like at a temperature between 40°C and 50°C for more than 16 hours (such as 50 hours, 100 hours, 150 hours or 200 hours, or longer) to obtain the amorphous hemicalcium salt of formula (IB). Includes.

[0235] In some embodiments, amorphous ovicetrapib hemicalcium is stored in a sealed container at a temperature below 30°C and protected from light.

[0236] In some embodiments, amorphous ovicetrapib hemicalcium is subjected to a subsequent reprocessing procedure. In some embodiments, amorphous ovicetrapib hemicalcium is dissolved in ethanol (such as twice the weight of ethanol relative to amorphous ovicetrapib hemicalcium) at a temperature of 25°C to 50°C, then cooled to 10°C to 15°C, then filtered and placed in a mixture of aqueous calcium chloride solution and ethyl acetate, which has also been cooled to 10°C to 15°C, then filtered and washed with water, and further reprocessed by drying under vacuum at 45°C or below for 20 hours or longer.

[0237] In many embodiments of this disclosure, amorphous obi-cetrapib hemi-calcium is processed to achieve a particle size distribution. In many embodiments, such processing is performed by milling. Examples of milling include hammer milling, ball milling, and jet milling. In other embodiments, spray drying may be used to achieve a particle size distribution. Thus, in some embodiments of this disclosure, spray-dried amorphous obi-cetrapib hemi-calcium is obtained. An example of jet-milled amorphous obi-cetrapib hemi-calcium is presented in Example 14.

[0238] In many embodiments of this disclosure, amorphous obi-cetrapib hemicalcium that has not been milled is provided. In many embodiments of this disclosure, amorphous obi-cetrapib hemicalcium that has been milled is provided.

[0239] In many embodiments, the particle size distribution of amorphous ovicetrapib hemicalcium is such that 90% of the particles have a diameter of about 15 microns or less. In these embodiments and other embodiments, 90% of the particles have a diameter of about 14 microns or less, 13 microns or less, 12 microns or less, 11 microns or less, 10 microns or less, 9 microns or less, 8 microns or less, 7 microns or less, 6 microns or less, 5 microns or less, 4 microns or less, or 3 microns or less.

[0240] In some embodiments, 90% of the particles have a diameter between approximately 6 and 15 microns.

[0241] In these embodiments and other embodiments, the particle size distribution of amorphous ovicetrapibhemicalcium is such that 50% of the particles have a diameter of approximately 5 microns or less, for example, 4 microns or less or 3 microns or less.

[0242] In these embodiments and other embodiments, the particle size distribution of amorphous ovicetrapibhemicalcium is such that 10% of the particles have a diameter of about 2 microns or less.

[0243] The amorphous ovicetrapib hemicalcium of this disclosure can be prepared with high chemical purity by the method of this disclosure. Such levels of purity include purity above 98.0%, such as 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%, or higher. The highest levels of purity, such as purity above 99.8% or 99.9%, can be achieved even more readily by using a method in which crystalline ovicetrapib HCl is used as an intermediate.

[0244] As summarized above, amorphous calcium salts of ovicetrapib, including amorphous ovicetrapib hemicalcium, are also provided herein. Novel intermediates for use in the synthesis of ovicetrapib and its salts are also provided.

[0245] The term "pharmaceutically acceptable" indicates that a substance does not possess properties that would cause a reasonably sensible physician to avoid administering the substance to a patient, taking into account the disease or condition being treated and the individual route of administration. For example, such substances are generally required to be substantially sterile, for instance, for injectable preparations.

[0246] The term "carrier" refers, in no particular way, to a fluidity enhancer, diluent, adjuvant, excipient, or vehicle to which a compound is administered together. Examples of carriers are described herein and in Remington: The Science and Practice of Pharmacy (Remington: The Science and Practice of Pharmacy, 23rd Edition, ISBN-13: 978-0128200070).

[0247] The term “effective dose” or “therapeutic effective dose” means the amount sufficient to perform a treatment when administered to a mammal requiring such treatment as defined herein. The therapeutic effective dose varies depending on the patient being treated, the patient’s weight and age, the severity of the disease, the method of administration, etc., and this can be readily determined by those skilled in the art.

[0248] The term "solvate" refers to a solid-state complex, such as an adduct, formed between an organic compound and a solvent molecule. Solvates can be held together by hydrogen bonds, van der Waals forces, or other non-covalent interactions. Solvates can be channel solvates, in that varying amounts of solvent can be present in channels within the solid structure.

[0249] The term “treatment” or “to treat” includes, to the extent relating to a disease or condition, preventing the onset of a disease or condition, inhibiting a disease or condition, eliminating a disease or condition, and / or reducing one or more symptoms of a disease or condition.

[0250] Unless specifically stated otherwise, if a compound can exhibit other tautomers, positional isomers, and / or stereoisomers, all other isomers are intended to be included within the scope of the subject matter of this application. For example, if a compound is described as having a particular optical isomer D- or L-, both optical isomers are intended to be included herein. For example, if a compound is described as having one of two tautomers, both tautomers are intended to be included herein. Thus, the compounds provided herein may be pure as enantiomers, or mixtures of stereoisomers or diastereomers. The compounds provided herein may contain a chiral center. Such a chiral center may be in either a (R) or (S) configuration, or a mixture thereof. The chiral center of the compounds provided herein may undergo epimerization in vivo. Thus, those skilled in the art will recognize that, in the case of a compound that undergoes epimerization in vivo, administration of the (R) form of the compound is equivalent to administration of the (S) form of the compound.

[0251] This disclosure also encompasses all suitable isotopic variants of the compounds of this disclosure, whether radioactive or not. An isotopic variant of a compound of this disclosure is understood to mean a compound in which at least one atom in the compound of this disclosure is replaced with another atom having the same atomic number but a different atomic mass than that which is normally or primarily naturally occurring. Examples of isotopes that may be incorporated into the compounds of this disclosure are: 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131These are isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine, and iodine, such as I. For example, in the case of testing the mechanism of action or the distribution of active compounds in the body, the compounds according to this disclosure, in particular specific isotopic variants of compounds incorporating one or more radioactive isotopes, may be advantageous. 3 H, 14 C and / or 18 Compounds labeled with 1F isotopes are suitable for this purpose. Furthermore, the incorporation of an isotope, such as deuterium, can result in certain therapeutic benefits, such as an extension of the half-life in the body or a reduction in the required dose of the active ingredient, as a result of greater metabolic stability of the compound. In some embodiments, the hydrogen atoms of the compounds described herein may be replaced by deuterium atoms. In certain embodiments, unless otherwise specified, “deuterated” as applied to a chemical group means a chemical group that isotopically enriched with deuterium in amounts substantially greater than its natural abundance. Isotopic variants of the compounds according to this disclosure can be prepared by using certain reagents and / or corresponding isotopic modifications of the starting compounds, for example, by various methods including those described below and in the examples.

[0252] Therefore, any of the embodiments described herein are intended to include single stereoisomers, mixtures of stereoisomers, and / or isotopes of the compound.

[0253] Unless otherwise specified, the terms “about” or “approximately” mean an error that is permissible for a particular value as determined by those skilled in the art, and which depends in part on the method by which the value was measured or determined. In certain embodiments, the terms “about” or “approximately” mean within one, two, or three standard deviations. In certain embodiments, the terms “about” or “approximately” mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.25%, 0.2%, 0.1%, or 0.05% of a given value or range. Unless otherwise specified, the term “about” means within plus or minus 10% of the explicitly stated value, rounded up or down to the nearest integer.

[0254] Accordingly, the subject method is described by reference to certain embodiments discussed above. It is recognized that these embodiments are readily subject to various modifications and alternative forms well known to those skilled in the art.

[0255] This disclosure may be further described by one or more of the following non-limiting clauses.

[0256] Clause 1. Amorphous calcium salt of ovicetrapib.

[0257] Clause 2. Amorphous ovicetrapib hemicalcium.

[0258] Clause 3. Stable amorphous ovicetrapib hemicalcium.

[0259] Clause 4. Substantially pure amorphous ovicetrapib hemicalcium.

[0260] Clause 5. Amorphous ovicetrapibhemicalcium salts of Clauses 2-4 that substantially do not contain any crystalline salts of ovicetrapibhemicalcium.

[0261] Clause 6. Amorphous obicetrapib hemicalcium of Clauses 2-5 having substantially the same X-ray powder diffraction pattern as the X-ray powder diffraction pattern of Figure 1.

[0262] Clause 7. Amorphous obicetrapib hemicalcium according to Clauses 2-5, having an X-ray powder diffraction pattern including one or more X-ray powder diffraction peaks at approximately 3.4°(2θ), approximately 7.0°(2θ), and approximately 9.2°(2θ).

[0263] Clause 8. Amorphous ovicetrapib hemicalcium according to Clauses 2-7, which does not exhibit birefringence.

[0264] Clause 9. Amorphous obicetrapib hemicalcium of Clauses 2-8 having a glass transition temperature between approximately 107°C and approximately 112°C.

[0265] Clause 10. Amorphous obicetrapib hemicalcium according to Clause 9, the glass transition temperature of which is measured by modulated differential scanning calorimetry.

[0266] Clause 11. Measurement by modulated differential scanning calorimetry using an open sample pan, amorphous obicetrapib hemicalcium as in Clause 10.

[0267] Clause 12. Amorphous obicetrapib hemicalcium of Clause 11, wherein the opening is a pinhole.

[0268] Clause 13. Amorphous ovicetrapib hemicalcium of Clauses 8-12, wherein the glass transition temperature is between approximately 110°C and approximately 112°C.

[0269] Clause 14. Amorphous obicetrapib hemicalcium of Clauses 2-13 having a glass transition temperature of less than approximately 100°C when measured by differential scanning calorimetry using a sealed sample pan.

[0270] Clause 15. Amorphous obicetrapib hemicalcium of Clause 14, having a glass transition temperature between approximately 70°C and approximately 92°C, as measured by differential scanning calorimetry using a sealed sample pan.

[0271] Clause 16. Amorphous ovicetrapib hemicalcium of Clauses 2-15, having a weight loss of less than approximately 1% when heated to approximately 200°C.

[0272] Clause 17. Amorphous ovicetrapib hemicalcium of Clause 16, wherein the weight loss is between approximately 0.8% and approximately 0.95%.

[0273] Clause 18. Amorphous ovicetrapib hemicalcium of Clause 17, wherein the weight loss is between approximately 0.84% ​​and approximately 0.92%.

[0274] Clause 19. Amorphous ovicetrapib hemicalcium of Clauses 2-18 having a moisture content of less than approximately 5%.

[0275] Clause 20. Amorphous obicetrapib hemicalcium of Clause 19, having a moisture content of less than approximately 4%.

[0276] Clause 21. Amorphous ovicetrapib hemicalcium of Clause 20, having a water content of less than approximately 3%.

[0277] Clause 22. Amorphous ovicetrapib hemicalcium of Clause 19, having a moisture content between approximately 0.5% and approximately 1.5%.

[0278] Clause 23. Amorphous ovicetrapib hemicalcium of Clauses 2-22, which is a bulk form or formulated composition having a particle size distribution in which approximately 90% of the particles have a diameter of approximately 15 microns or less.

[0279] Clause 24. Amorphous ovicetrapib hemicalcium of Clause 23, wherein approximately 90% of the particles have a diameter between approximately 6 microns and approximately 15 microns.

[0280] Clause 25. Amorphous obicetrapib hemicalcium of Clause 24, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 14 microns or less.

[0281] Clause 26. Amorphous obicetrapib hemicalcium of Clause 25, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 13 microns or less.

[0282] Clause 27. Amorphous obicetrapib hemicalcium of Clause 26, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 12 microns or less.

[0283] Clause 28. Amorphous ovicetrapib hemicalcium of Clause 27, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 11 microns or less.

[0284] Clause 29. Amorphous obicetrapib hemicalcium of Clause 28, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 10 microns or less.

[0285] Clause 30. Amorphous obicetrapib hemicalcium of Clause 29, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 9 microns or less.

[0286] Clause 31. Amorphous obicetrapib hemicalcium of Clause 30, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 8 microns or less.

[0287] Clause 32. Amorphous obicetrapib hemicalcium of Clause 31, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 7 microns or less.

[0288] Clause 33. Amorphous obicetrapib hemicalcium of Clause 32, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 6 microns or less.

[0289] Clause 34. Amorphous obicetrapib hemicalcium of Clause 33, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 5 microns or less.

[0290] Clause 35. Amorphous obicetrapib hemicalcium of Clause 34, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 4 microns or less.

[0291] Clause 36. Amorphous ovicetrapib hemicalcium of Clause 35, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 3 microns or less.

[0292] Clause 37. Amorphous ovicetrapib hemicalcium of Clauses 2-36, in the form of a bulk form or a formulated composition having a particle size distribution in which approximately 50% of the particles have a diameter of approximately 5 microns or less.

[0293] Clause 38. Amorphous obicetrapib hemicalcium of Clause 37, having a particle size distribution in which approximately 50% of the particles have a diameter of approximately 4 microns or less.

[0294] Clause 39. Amorphous ovicetrapib hemicalcium of Clause 38, having a particle size distribution in which approximately 50% of the particles have a diameter of approximately 3 microns or less.

[0295] Clause 40. Amorphous ovicetrapib hemicalcium of Clauses 2-39, in the form of a bulk form or a formulated composition having a particle size distribution in which about 10% of the particles have a diameter of about 2 microns or less.

[0296] Clause 41. Amorphous ovicetrapib hemicalcium of Clauses 2-40 having a chemical purity of at least 98.0%.

[0297] Clause 42. Amorphous ovicetrapib hemicalcium of Clause 41 having a chemical purity of at least 99.0%.

[0298] Clause 43. Amorphous ovicetrapib hemicalcium of Clause 42 having a chemical purity of at least 99.5%.

[0299] Clause 44. Amorphous ovicetrapib hemicalcium of Clause 43 having a chemical purity of at least 99.6%.

[0300] Clause 45. Amorphous ovicetrapib hemicalcium of Clause 44 having a chemical purity of at least 99.7%.

[0301] Clause 46. Amorphous ovicetrapib hemicalcium of Clause 45 having a chemical purity of at least 99.8%.

[0302] Clause 47. Amorphous ovicetrapib hemicalcium of Clause 46 having a chemical purity of at least 99.9%.

[0303] Clause 48. Solid state in Figure 17 13 The solid state is virtually identical to the C-NMR spectrum. 13 Amorphous ovicetrapibhemicalcium of clauses 2-47 having a 1C-NMR spectrum.

[0304] Clause 49. Solid state where no peak exists at approximately 22.1 ppm. 13 Amorphous ovicetrapibhemicalcium with 1C-NMR spectra, clauses 2-48.

[0305] Clause 50. Solid state where no peak exists at approximately 29.5 ppm. 13 Amorphous ovicetrapibhemicalcium of clauses 2-49 having a 1C-NMR spectrum.

[0306] Clause 51. Unmilled amorphous ovicetrapib hemicalcium.

[0307] Clause 52. Mill-ground amorphous ovicetrapib hemicalcium.

[0308] Clause 53. Amorphous ovicetrapib hemicalcium is milled and ground, as per Clauses 2-50.

[0309] Clause 54. Amorphous ovicetrapib hemicalcium is jet-milled, according to Clauses 2-50 or 53.

[0310] Clause 55. Amorphous ovicetrapib hemicalcium spray-dried, according to Clauses 2-50 or 53-54.

[0311] Clause 56. Amorphous ovicetrapib hemicalcium prepared by a synthetic method, wherein the intermediate in the method comprises crystalline ovicetrapib HCl.

[0312] Clause 57. Amorphous ovicetrapib hemicalcium according to Clauses 2-56, wherein amorphous ovicetrapib hemicalcium is prepared by a synthetic method, the intermediate in the method comprising crystalline ovicetrapib HCl.

[0313] Clause 58. Obisetrapib HCl.

[0314] Clause 59. Crystalline ovicetrapib HCl.

[0315] Clause 60. Amorphous ovicetrapib HCl compound.

[0316] Clause 61. Solvates of ovicetrapib HCl according to Clauses 58-60.

[0317] Clause 62. Obisetrapib HCl of Clauses 58-61, wherein the weight percentage of HCl is between approximately 0.01% and approximately 8%.

[0318] Clause 63. A composition comprising any one of the crystalline ovicetrapib HCl specified in Clauses 58 to 62.

[0319] Clause 64. Crystalline ovicetrapib HCl is the solvate of crystalline ovicetrapib HCl according to Clauses 58-60 or 62-63.

[0320] Clause 65. Crystalline ovicetrapib HCl of Clause 64, wherein the solvate comprises ovicetrapib and hydrochloric acid.

[0321] Clause 66. Crystalline ovicetrapib HCl of Clause 65, wherein the solvate contains an organic solvent.

[0322] Clause 67. Crystalline ovicetrapib HCl according to Clause 66, wherein the solvate comprises a solvent having sufficient solubility to dissolve enough HCl to produce crystalline ovicetrapib HCl.

[0323] Clause 68. A solvate of any one of Clauses 61 or 64-67, wherein the solvent of the solvate is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether (CPME), N-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, 1,2-difluorobenzene, toluene, and hexafluoroisopropanol.

[0324] Clause 69. Crystalline ovicetrapib HCl of Clause 68, wherein the solvent is CPME.

[0325] Clause 70. Crystalline obicetrapib HCl of any one of Clauses 58-59 or 61-69, having an X-ray powder diffraction pattern substantially identical to the X-ray powder diffraction pattern in Figure 19.

[0326] Clause 71. Crystalline ovicetrapib HCl having an X-ray powder diffraction pattern containing a peak at approximately 9.8°(2θ), according to either Clause 58-59 or 61-69.

[0327] Clause 72. Crystalline ovicetrapib HCl of any one of Clauses 58-59, 61-69, or 71, having an X-ray powder diffraction pattern including one or more peaks at approximately 8.1°(2θ), approximately 9.8°(2θ), approximately 13.8°(2θ), approximately 16.7°(2θ), and approximately 19.5°(2θ).

[0328] Article 73. Salt according to formula (VI): [ka] (In the formula, Y 1 (where is a protecting group, An- is an anion, and n is an integer between 1 and 3).

[0329] Clause 74. The compound is a mesylate salt of the following structure (Compound 1D): [ka] The salt is as per Article 73.

[0330] Clause 75. Crystalline mesylate of compound 1D of Clause 74.

[0331] Clause 76. A crystalline mesylate of compound 1D of Clause 75 having a powder diffraction pattern substantially identical to one of the four X-ray powder patterns described in Figure 20.

[0332] Clause 77. A crystalline mesylate of compound 1D of Clause 75 having an X-ray powder diffraction pattern including one or more peaks at approximately 5.2°(2θ) and approximately 9.1°(2θ).

[0333] Clause 78. A crystalline mesylate salt of Compound 1D according to any one of Clauses 75 to 77, which has an X-ray powder diffraction pattern comprising one or more peaks at about 9.1° (2θ), about 15.9° (2θ), about 16.5° (2θ), about 17.2° (2θ), about 18.6° (2θ) and about 19.2° (2θ).

[0334] Clause 79. A method for preparing obicetrapib, comprising: (a) a step of preparing a compound of formula (IV) by coupling a compound of formula (II) or a salt thereof with a compound of formula (III);

Chemical Formula

Chemical Formula

Chemical Formula

[0335] Clause 80. The compound of formula (II) in step (a) is, prior to step (a), the following: (Pre-a1) Compounds of formula (IIA) or (IIB): [ka] The steps to prepare, (Pre a2) A step of obtaining a compound of formula (II) by salt decomposition of a compound of formula (IIA) or (IIB). A method obtained by applying Article 79, A method wherein the reaction in step (pre a2) is carried out in an organic solvent, the compound of formula (II) is not isolated from the organic solvent under certain circumstances, and the method does not require chromatography.

[0336] Article 81. Salts of formula (IIA) or (IIB) include sulfonate ions, sulfate ions, halogens, acetate ions, aspartate ions, benzoate ions, bicarbonate ions, tartarate ions, carbonate ions, citrate ions, decanoate ions, fumarate ions, gluceptate ions, gluconate ions, glutamate ions, glycolate ions, hexanoate ions, hydroxynaphthoate ions, isethionate ions, lactate ions, lactobionate ions, malate ions, maleate ions, mandelate ions, mucinate ions, nitrate ions, octanoate ions, oleate ions, pamoate ions The method according to Clause 80, wherein the salt is selected from an anion Am- selected from on, pantothenate ion, phosphate ion, polygalacturonate ion, propionate ion, salicylate ion, stearate ion, succinate ion, tartrate ion and theoclate ion, the sulfonate ion may be besylate ion, tosylate ion, napsylate ion, cansylate ion, esylate ion, edisylate ion or mesylate ion, the sulfate ion may be methyl sulfate ion, and the halogen may be chloride ion, iodide ion or bromide ion.

[0337] Article 82. Anion A m-The method of Clause 81, wherein the salt formed with is selected from chloride, bromide, bitartrate, sulfate and sulfonate.

[0338] Clause 83. Anion A m- The method of Clause 82, wherein the salt formed with is selected from chloride, bromide, bitartrate and mesylate.

[0339] Clause 84. Y in the compounds of formulae (III) to (VI) and (VIII) 1 The method according to any one of Clauses 79 to 83, wherein is selected from an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an allyl group, a substituted allyl group and a silyl group.

[0340] Clause 85. Y in the compounds of formulae (III) to (VI) and (VIII) 1 The method of Clause 84, wherein is selected from tert-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluoroethyl, phenyl, 4-methoxybenzyl ester, 2,6-disubstituted phenol and a silyl group.

[0341] Clause 86. Y in the compounds of formulae (III) to (VI) and (VIII) 1 The method of Clause 85, wherein is tert-butyl.

[0342] Clause 87. The salt of formula (VI) is selected from sulfonate ions, sulfate ions, halogens, acetate ions, aspartate ions, benzoate ions, bicarbonate ions, bitartrate ions, carbonate ions, citrate ions, decanoate ions, fumarate ions, gluceptate ions, gluconate ions, glutamate ions, glycolate ions, hexanoate ions, hydroxynaphthoate ions, isethionate ions, lactate ions, lactobionic ions, malate ions, maleate ions, mandelate ions, mucinate ions, nitrate ions, octanoate ions, oleate ions, pamoate ions, pantothenate ions, phosphate ions, polygalacturonate ions, propionate ions, salicylate ions, stearate ions, succinate ions, tartrate ions, and theoclate ions, anion A n- A method according to any one of the claims 79 to 86, selected from salts of the following, wherein the sulfonate ion may be besylate ion, tosylate ion, napsylate ion, cansylate ion, esyllate ion, edisylate ion or mesylate ion, the sulfate ion may be methyl sulfate ion, and the halogen may be chloride ion, iodide ion or bromide ion.

[0343] Article 88. Anion A n- The method of Clause 87, wherein the salt is selected from chlorides, bromides, tartrates, sulfates, and sulfons.

[0344] Article 89. Anion A n- The method of Clause 87, wherein the salt is selected from chlorides, bromides, tartrates, and mesylates.

[0345] Clause 90. The salt form of formula (VI) is the mesylate of compound 1D: [ka] The method of Article 87.

[0346] Clause 91. The method of Clause 90, wherein the mesylate is crystalline.

[0347] Article 92. X in the compound of formula (III) 1 However, one of the methods described in clauses 79 to 91, selected from halogens, carbamates, and substituted sulfonyloxy groups.

[0348] Article 93. X in the compound of formula (III) 1 The method of Article 92, wherein the halogen is.

[0349] Article 94. The method of Article 93, wherein the halogen is a chloride.

[0350] Article 95. X in a compound of formula (VII) 2 However, one of the methods described in clauses 79 to 94, selected from halogens and substituted sulfonyloxy groups.

[0351] Article 96. X in the compound of formula (III) 2 The method of Article 95, wherein the halogen is.

[0352] Article 97. The method of Article 96, wherein the halogen is a bromide.

[0353] Article 98. A method for preparing an amorphous hemicalcium salt of ovicetrapib, (i) A step of treating ovicetrapib with HCl to obtain a crystalline ovicetrapib HCl compound, (ii) A step to isolate the crystalline ovicetrapib HCl compound, (iii) A step of preparing an amorphous hemicalcium salt of ovicetrapib from the crystalline ovicetrapib HCl compound isolated in step (ii), and (iv) Step to isolate the amorphous hemicalcium salt of ovicetrapib. Methods that include...

[0354] Clause 99. The crystalline obisetrapib HCl compound isolated in step (ii) is a compound of formula (IH): [ka] (In the formula, y varies from 0.002 to 1.5) The methods of Article 98, including those of Article 98.

[0355] Clause 100. The preparation of the amorphous hemicalcium salt of formula (I) in step (iii) is as follows: (iii-1) In one or more suitable solvents selected from organic solvents and aqueous solvents, the crystalline ovicetrapib HCl compound from step (ii) is converted to obtain ovicetrapib. (iii-2) The step of treating ovicetrapib in an organic solvent with aqueous sodium hydroxide to form the sodium salt of ovicetrapib, and (iii-3) A step in which the sodium salt of ovicetrapib is treated with aqueous calcium chloride to form an amorphous hemicalcium salt of ovicetrapib. Methods under Article 98 or 99, including, A method in which the compounds in steps (iii-1) and (iii-2) are not isolated under certain circumstances.

[0356] Clause 101. The method according to any one of Clauses 98-100, wherein the amorphous hemicalcium salt of ovicetrapib is amorphous ovicetrapib hemicalcium.

[0357] Clause 102. The amorphous calcium salt of ovicetrapib is isolated with at least 99% chemical purity by any one method of Clauses 98-101.

[0358] Clause 103. The method of Clause 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.1%.

[0359] Clause 104. The method of Clause 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.2%.

[0360] Clause 105. The method of Clause 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.3%.

[0361] Clause 106. The method of Clause 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.4%.

[0362] Clause 107. The method of Clause 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.5%.

[0363] Clause 108. The method of Clause 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.6%.

[0364] Clause 109. The method of Clause 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.7%.

[0365] Clause 110. The method of Clause 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.8%.

[0366] Clause 111. The method of Clause 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.9%.

[0367] Clause 112. The method according to any of the provisions of Clauses 102 to 111, wherein the amorphous calcium salt of ovicetrapib is amorphous ovicetrapib hemicalcium.

[0368] Clause 113. A pharmaceutical composition comprising one amorphous salt of ovicetrapib calcium according to any one of Clauses 1 to 57, and one or more pharmaceutically acceptable carriers.

[0369] Clause 114. The pharmaceutical composition of Clause 113, wherein the amorphous salt of ovicetrapib calcium is amorphous ovicetrapib hemicalcium.

[0370] Article 115. A method for treating a subject who has a cardiovascular disease or who is at increased risk of developing such a disease, comprising the step of administering a therapeutically effective amount of a pharmaceutical composition according to Article 113 or 114 to the subject.

[0371] Clause 116. Amorphous calcium salt of ovicetrapib, prepared by any one of the methods described in Clauses 79-112.

[0372] Clause 117. The amorphous calcium salt of Clause 116, which is amorphous ovicetrapibhemicalcium.

[0373] Clause 118. A method for preparing an amorphous ovicetrapib calcium salt, comprising the steps of: treating ovicetrapib with an acid to form a salt, solvate, composition or combination thereof; isolating a salt, solvate, composition or combination thereof; and treating a salt, solvate, composition or combination thereof with a calcium source to prepare an amorphous ovicetrapib hemicalcium salt.

[0374] Clause 119. The method of Clause 118, wherein the calcium source is calcium chloride.

[0375] Clause 120. Salts, solvates, compositions, or combinations thereof comprising ovicetrapib and free acids.

[0376] Article 121. The salt of Article 120.

[0377] Clause 122. The solvate of Clause 120.

[0378] Clause 123. Composition of Clause 120.

[0379] Article 124. Free acids include sulfonic acid, sulfuric acid, halogenated acid, acetic acid, aspartic acid, benzoic acid, bicarbonate, tartaric acid, carbonic acid, citric acid, decanoic acid, fumaric acid, and gluceptic acid. A salt, solvate, composition or combination thereof of the sulfonic acid of Clause 120, selected from gluconic acid, glutamic acid, glycolic acid, hexanoic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, mucinic acid, nitric acid, octanoic acid, oleic acid, pamoic acid, pantothenic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, succinic acid, tartric acid and theoclic acid, wherein the sulfonic acid may be benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, ethanedisulfonic acid or methanesulfonic acid, the sulfuric acid may be methylsulfonic acid, and the halogenated acid may be HCl, HBr or HI.

[0380] Clause 125. The method of Clause 118, wherein the calcium source is a calcium halide salt.

[0381] Clause 126. The method of Clause 118, wherein the calcium source is a soluble calcium salt.

[0382] Clause 127. The method of Clause 118, wherein the calcium source is a calcium salt.

[0383] Clause 128. Obisetrapib hydrochloride according to Clause 58 or 59, comprising a chloride ion hydrogen-bonded to at least one protonated nitrogen on the pyrimidine ring of ovisetrapib.

[0384] Clause 129. Obicetrapib hydrochloride of Clause 59 or 128, having an asymmetric unit comprising four cationic ovicetrapib moieties, two neutral ovicetrapib molecules, four chloride anions, and at least one solvent molecule.

[0385] Clause 130. Obisetrapib hydrochloride of Clause 129, wherein the asymmetric unit contains two solvent molecules.

[0386] Clause 131. Obisetrapib hydrochloride of Clause 129, wherein the asymmetric unit contains three solvent molecules.

[0387] Clause 132. Obisetrapib hydrochloride according to any one of Clauses 129-132, wherein the solvent molecule is selected from heptane and cyclopentyl methyl ether.

[0388] Clause 133. The following unit cell parameters: [Table 14] Obisetrapib hydrochloride having any one of the provisions 128-132.

[0389] Clause 134. Crystalline ovicetrapib hydrochloride of form A.

[0390] Crystalline ovicetrapib hydrochloride of form A of form A of form 134, having an X-ray powder diffraction pattern including a peak at approximately 8.6°(2θ), two peaks between approximately 9.7°(2θ) and approximately 10.4°(2θ), and two peaks between approximately 8.6°(2θ) and 9.0°(2θ).

[0391] Clause 136. Crystalline ovicetrapib hydrochloride of form A of Clause 134, having an X-ray powder diffraction pattern substantially identical to that of the X-ray powder diffraction pattern in Figure 22.

[0392] Clause 137. Crystalline ovicetrapib hydrochloride of form B.

[0393] Clause 138. Crystalline ovicetrapib hydrochloride of form B of Clause 136, having an X-ray powder diffraction pattern with peaks at approximately 6.5°(2θ), approximately 8.8°(2θ), and approximately 11.0°(2θ).

[0394] Clause 139. Crystalline ovicetrapib hydrochloride of form B of Clause 137, having an X-ray powder diffraction pattern substantially identical to that of the X-ray powder diffraction pattern in Figure 23.

[0395] Clause 140. Crystalline ovicetrapib hydrochloride of form C.

[0396] Clause 141. Crystalline ovicetrapib hydrochloride of form C of Clause 140, having an X-ray powder diffraction pattern substantially identical to that of the X-ray powder diffraction pattern in Figure 24.

[0397] Clause 142. Crystalline ovicetrapib hydrochloride of form D.

[0398] Clause 143. Crystalline ovicetrapib hydrochloride of form D of Clause 142, having an X-ray powder diffraction pattern substantially identical to that of the X-ray powder diffraction pattern in Figure 25.

[0399] Clause 144. Crystalline ovicetrapib hydrochloride of Clause 59 having an X-ray powder diffraction pattern with a peak between approximately 4.3°(2θ) and approximately 4.7°(2θ). [Examples]

[0400] The examples in this section are presented illustratively and are not limiting. It should be understood that the examples may represent only a subset of embodiments, and the following examples are illustrative and not limiting. All substituents are as previously defined unless otherwise specified. Reagents and starting materials are readily available to those skilled in the art. Specific synthesis steps for each of the described pathways can be combined in various ways, or in conjunction with steps from different schemes, to prepare the compounds described herein. [ka]

[0401] Referring to Scheme 1, amorphous ovicetrapibhemicalcium (compound 3) was prepared by six chemical steps and three isolations from (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline mesylate (compound 1A), t-butyl-4-(2-chloropyrimidine-5-yloxy)-butyrate (compound 1B), and 3,5-bis(trifluoromethyl)benzyl bromide (compound 1E). Compound 1A was coupled with compound 1B via a palladium-catalyzed reaction to produce a solution of (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidine-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1C), which could not be isolated. When this was reacted directly with excess ethyl chloroformate in the presence of pyridine, (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidine-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester was produced, which was isolated as a crystalline mesylate (compound 1D). When compound 1D, a crystalline mesylate, was alkylated with 3,5-bis(trifluoromethyl)benzyl bromide (compound 1E) under strongly basic conditions, a toluene solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-t-butoxycarbonylpropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester (compound 1F) was produced. Next, when compound 1F was cleaved with tert-butyl acid, a solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester (compound 1) was produced.Next, compound 1 was converted to compound 2, which is the solvate of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester (compound 2). Finally, compound 2 was converted to amorphous hemicalcium salt (compound 3) and milled to the target particle size. Compound 2 is crystalline ovicetrapib HCl, and compound 3 is amorphous ovicetrapib hemicalcium. The FT-IR spectrum of the milled amorphous ovicetrapib hemicalcium can be seen in Figure 4. The solution state corresponds to the chemical structure of ovicetrapib hemicalcium. 1 The 1H-NMR spectrum can be seen in Figure 5.

[0402] Each step in the manufacturing process of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester (compound 1), intermediate HCl (compound 2), and the corresponding amorphous calcium salt (compound 3) is described in more detail in Examples 1 to 16 below.

[0403] Examples 1-3, 5, 7, 9, and 11-12 describe the manufacturing steps in a method for preparing amorphous obicetrapib hemicalcium (compound 3), while Examples 4, 6, 8, 10, and 13 present additional methods for preparing the indicated compounds. The methods in these examples sometimes represent more than one batch of the indicated compound being prepared.

[0404] Examples 14-15 describe a method for milling amorphous ovicetrapibhemicalcium (compound 3), and Example 16 describes a method for preparing crystalline ovicetrapibhemicalcium. (Example 1) Preparation of (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (free base of compound 1A) [ka]

[0405] In a reaction vessel equipped with a reflux condenser, (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1A) (62 kg, 182 mol, 1.00 equivalent) was added along with toluene (375 L). The resulting slurry was stirred at 52°C, and 1 M aqueous sodium hydroxide solution (322 L, 5.2 vol) was added. The reaction mixture was stirred until all solids were dissolved, and then cooled to 20°C. Stirring was stopped, and the reaction mixture was separated into two phases. The lower aqueous phase was drained, and aqueous sodium chloride solution (310 L, 5.0 vol) was added. The reaction mixture was then stirred at 20°C for 30 minutes. Stirring was stopped again, and the reaction mixture was separated into two phases. The lower aqueous phase was drained, and deionized water (310 L, 5.0 vol) was added. The reaction mixture was then stirred at 20°C for 30 minutes. The stirring was stopped again, and the reaction mixture was separated into two phases. The lower aqueous phase was separated. Next, the resulting organic solution was distilled under vacuum at an internal temperature of 65°C or below. Distillation was continued until a final visual volume of 4.0 volumes (250 L) was reached. Next, the reaction vessel was cooled to 20°C to obtain a toluene solution of (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1A-free base) containing a small amount of water. Compound 1A-free base was not isolated and was used directly in Example 2. (Example 2) Preparation of (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidine-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1C) [ka]

[0406] To a reaction vessel ("Vessel A") containing (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1A - free base) in toluene containing <1000 ppm of water derived from the previous step, additional toluene (107 L, 1.5 vol) was added. Next, t-butyl-4-(2-chloropyrimidine-5-yloxy)-butyrate (compound 1B) (54.6 kg, 200 mol, 1.10 equivalents) was added to Vessel A along with t-BuOH (122 L, 1.55 vol). The reaction mixture was stirred and nitrogen was blown over it. Meanwhile, palladium acetate (410 g, 1.8 mol, 1 mol%) was added to a second reaction vessel ("Vessel B") under nitrogen. To container B, (S)-BINAP (2.48 kg, 4.0 mol, 2.2 mol%) and toluene (107 L, 1.5 vol) were added, and the resulting mixture was stirred to form a red / orange Pd-BINAP solution. The orange / red Pd-BINAP solution from reaction container B was transferred to container A. K3PO4 (85 kg, 400 mol, 2.20 equivalents) was added to container A, and the resulting reaction mixture was heated to an internal temperature of 72°C and stirred for at least 2 hours. Next, the mixture was cooled to 20°C, deionized water (124 L) was carefully added, and the mixture was stirred for 30 minutes. Next, stirring was stopped and the layers separated into two phases. The lower aqueous phase was separated, and an aqueous solution of 1 M HCl (123 L) was added while stirring. After 30 minutes, stirring was stopped again, and the layers separated into two phases. The lower aqueous phase was separated, and while stirring, an aqueous solution of sodium chloride (326 kg, 5.26 vol) was added. After 30 minutes, stirring was stopped again, and the layers were separated into two phases. The lower aqueous phase was separated, and while stirring, deionized water (248 L, 4.0 vol) was added. After 30 minutes, stirring was stopped again, and the layers were separated into two phases. The lower aqueous phase was separated. Next, the resulting reaction mixture was treated with ethylenediamine (1.60 kg, 0.15 equivalents) and stirred at 20°C for 80 minutes. Next, this reaction mixture was filtered through a charcoal cartridge, and the filtrate was returned to a clean container. Next, the mixture was distilled under partial vacuum at an internal temperature of 60°C or below. Distillation was continued until approximately 2.50 vol (155 L) remained, as visually observed in the reactor, and then acetonitrile (394 L, 5.0 vol) was added.Next, the mixture was distilled under vacuum at an internal temperature of 60°C or below. Distillation was continued until the volume reached approximately 2.50 volumes (155 L) by visual inspection in the reactor, and then the contents were cooled to 20°C. Next, acetonitrile (394 L, 5.0 volumes, until it reached approximately 11 volumes by visual inspection (approximately 620 L)) was added to the reaction vessel to obtain (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidine-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1C) dissolved in acetonitrile. Compound 1C was not isolated and was used directly in Example 3. (Example 3) Preparation of (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidine-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester as crystalline mesylate (compound 1D) [ka]

[0407] (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidine-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1C) was cooled to an internal temperature of <10°C in acetonitrile (approximately 620 L), and pyridine (72 L, 900 mol, 4.9 equivalents) was added. Next, while maintaining the internal temperature of the reactor contents at <10°C, ethyl chloroformate (136 L, 1428 mol, 7.84 equivalents) was added from a dropping funnel. The internal temperature of the reaction mixture was then linearly raised to 20°C over 3.5 hours. Next, this mixture was distilled under vacuum at an internal temperature of 60°C or less. Distillation was continued until the volume was approximately 2.50 liters (155 L) as observed visually. Next, isopropyl acetate (471 L, 6.6 vol) was added to the reaction vessel, and distillation was continued under vacuum at an internal temperature of 60°C or lower until approximately 2.50 vol (155 L) remained, as observed visually. Then, isopropyl acetate (471 L, 6.6 vol), 1 M hydrochloric acid (307 L, 5.0 vol) and 26% aqueous sodium chloride (63 L, 1.2 vol) were added to the reaction vessel. The resulting mixture was stirred for 30 minutes, and then separated into two phases. The lower aqueous phase was separated, and saturated aqueous sodium bicarbonate (132 L, 2.3 vol) was added. The resulting mixture was stirred for 30 minutes, and then separated into two phases. The aqueous phase was separated, and the residual mixture was distilled under vacuum at or below 60°C until the total volume reached approximately 4.0 volumes (250 L) by visual observation. The (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidine-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester (the corresponding free base of compound 1D) in isopropyl acetate was obtained relative to the weight of the solution.

[0408] Additional isopropyl acetate (86 L, 1.4 vol) and methyl t-butyl ether (MTBE, 593 L, 9.6 vol) were added to the corresponding free base of compound 1D in the isopropyl acetate, and the jacket temperature was set to 20°C. Next, methanesulfonic acid (MsOH, 17.6 kg, 1.0 equivalent relative to mmol of compound (the corresponding free base of compound 1D)) was added to this reaction mixture over 60 minutes. The resulting slurry was then stirred for 8 hours. The slurry was then filtered under vacuum at 20°C. Next, the solid cake was washed with 75 / 25 v / v isopropyl acetate (78 L, 1.1 vol) and methyl t-butyl ether solution (236 L, 2.8 vol), and then dried under vacuum at 20°C to obtain the isolated (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidine-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester as crystalline mesylate (compound 1D) in 74% yield relative to the number of moles of compound 1A. The purity of the obtained crystalline compound 1D was >99%. (Example 4) Further preparation of compound 1C and compound 1D

[0409] Multiple batches of compound 1C and compound 1D were prepared using the preparations generally described below. In some preparations, seed crystal addition was performed with compound 1D, for example, as further discussed below, while in others it was not.

[0410] Pd(OAc)2 and (S)-BINAP were dissolved in toluene and stirred to form the corresponding Pd-BINAP-complex (which changed color to red) ("catalyst solution"). Toluene, compound 1B, compound 1A, and K3PO4 were added to the reactor and stirred. The target water content was approximately 6%. The catalyst solution was added to the mixture in the reactor, and the reaction mixture was heated to 70-75°C and stirred.

[0411] The solution was washed with HCl, brine, and water, followed by phase separation. EDA and toluene were then added, and the solution was stirred for approximately 90 minutes. To remove palladium, the solution was passed through a cartridge equipped with activated carbon (Begerow, F-9120). After this, the solvent was replaced from toluene to acetonitrile (MeCN) by distillation to obtain compound 1C.

[0412] Pyridine was added to a solution of compound 1C and cooled to below 10°C before the addition of ethyl chloroformate. Ethyl chloroformate was added to the solution of compound 1C in one or two doses while controlling the temperature to 10°C NMT. ​​The reaction mixture was then stirred at 17–27°C for approximately 1 hour to convert compound 1C to the free base of compound 1D (compound 1D-FB). Solvent exchange from acetonitrile to isopropyl acetate (iPrOAc) was performed by distillation, and the organic phase was washed with HCl (1M), brine, and aqueous NaHCO3 (NaOH may be used), and then the volume was reduced by distillation.

[0413] Methanesulfonic acid (MsOH) and MTBE were added to an iPrOAc solution of compound 1D-FB and stirred. In some cases, seed crystals of compound 1D prepared previously were added, but this was not necessary. Crystallization of compound 1D occurred afterward, regardless of whether seed crystals were added or not. The solid product was filtered, washed with MTBE / iPrOAc (75 / 25), and dried on the filter. (Example 5) Preparation of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-tbutoxycarbonylpropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2Hquinoline-1-carboxylate ethyl ester (compound 1F) [ka]

[0414] In a reaction vessel at 5°C, (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidine-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester as crystalline mesylate (compound 1D) (42 kg) and toluene (465 kg, 12.7 vol) were added. Next, tetrabutylammonium bisulfate (3.5 kg, 0.16 equivalents) and sodium tert-pentoxide (34.5 kg, 4.8 equivalents) were added, and the resulting reaction mixture was stirred for 10 minutes and degassed with nitrogen. Next, 3,5-bis(trifluoromethyl)benzyl bromide (compound 1E) (28 kg, 1.41 equivalents) was added to this reaction mixture, and stirring was continued at 5°C for 6.5 hours. Next, the reaction mixture was treated with a 1N acetic acid solution (320 kg) and stirred at 20°C for approximately 30 minutes. After this time, stirring was stopped and the mixture was separated into two phases. The lower aqueous phase was discarded, and the reaction mixture was concentrated under vacuum at an internal temperature of 60°C or below until approximately 3.3 volumes (137 L) remained, yielding a toluene solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-tbutoxycarbonylpropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2Hquinoline-1-carboxylate ethyl ester (compound 1F) in 36.8% by weight relative to the weight of the solution, in 97% yield relative to the number of moles of compound 1D. (Example 6) Further preparation of compound 1F

[0415] Compound 1E was added to a toluene solution containing compound 1D and tetrabutylammonium bisulfate. Sodium tert-pentoxide was added to the toluene under cooling. The resulting reaction mixture was quenched with dilute acetic acid. The aqueous layer was separated, and the product in the toluene layer was treated with charcoal and concentrated under vacuum (compound 1F). (Example 7) (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester (compound 1) [ka]

[0416] A 37 wt% solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-tbutoxycarbonylpropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2Hquinoline-1-carboxylate ethyl ester (compound 1F) in toluene (128.4 kg of 37 wt solution, equivalent to 47.5 kg of compound 1F) was diluted to 32 wt% with further toluene and then mixed with acetic acid (253 kg, 5.33 wt) and 6M HCl (109.9 kg, 2.32 wt, prepared in situ using 66.1 kg of concentrated HCl and 43.8 kg of water). The resulting reaction mixture was vigorously stirred and heated at 48°C for 3 hours. Next, the reaction mixture was cooled to 21°C, and then n-heptane (159.8 kg, 3.36 wt), acetonitrile (73.8 kg, 1.55 wt), and water (170 kg, 3.58 wt) were added. The resulting mixture was stirred for 34 minutes and then separated into two phases. The lower aqueous phase was then further treated with water (90 kg, 1.89 wt), n-heptane (95 kg, 2.00 wt), acetonitrile (38 kg, 0.80 wt), and toluene (42 kg, 0.88 wt), stirred again for 20 minutes, and then the organic phase was separated and the lower aqueous phase was drained. Next, the combined organic phase was treated with water (240 kg, 5.05 wt) and stirred for a further 30 minutes before separating into two phases. The lower aqueous phase was discarded, and the upper organic phase was treated with 5% w / w trisodium citrate dihydrate (34 kg, 0.72 wt) and water (205 kg, 4.32 wt). The resulting mixture was vigorously stirred for 30 minutes, then separated into two phases, after which the lower aqueous phase was discarded. The residual organic phase was again treated with water (240 kg, 5.05 wt) and stirred for 30 minutes before separating the two phases and draining the lower aqueous phase. Next, the organic phase was concentrated under vacuum to approximately 3 volumes (approximately 149 L) while maintaining an internal temperature of 50°C or below. The reaction mixture was diluted with cyclopentyl methyl ether (CPME, 250 kg, 5.26 wt) and stirred. Next, this solution was concentrated under vacuum to approximately 3 volumes (approximately 165 L) while maintaining an internal temperature of 50°C or below. Then, CPME (250 kg, 5.26 wt) was added, and this mixture was concentrated under vacuum to approximately 2.5 volumes (approximately 124 L) while maintaining an internal temperature of 50°C or below, to obtain a cyclopentyl methyl ether (CMPE) solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester (compound 1, free base form) containing 1 wt% toluene and less than 1 wt% n-heptane relative to the weight of the solution. (Example 8) Further preparation of compound 1

[0417] Compound 1F (in solution in toluene) was mixed with acetic acid and 6M aqueous HCl. The two-phase mixture was vigorously stirred at 45-50°C and then cooled to 20°C. After the addition of water, acetonitrile, and n-heptane, the mixture was extracted and the layers were separated.

[0418] The aqueous layer from the first extraction was diluted with water and extracted a second time with acetonitrile, n-heptane, and toluene. The two resulting organic extracts were combined. The organic phase was washed with water, and a 5% sodium citrate solution was added to bring the pH to ≥3.5. After washing with water, the organic layer was treated with activated carbon. Solvent exchange from toluene and n-heptane to CPME was performed by repeated vacuum distillation and addition of CPME to obtain compound 1. (Example 9) (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl hydrochloride (compound 2) [ka]

[0419] A cyclopentyl methyl ether (CPME) solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester (compound 1, free base form, 115.6 kg, 59.2 mol) derived from the previous step was added to a clean reaction vessel under nitrogen at a jacket temperature of 22°C. After dilution with CPME (27.8 kg / 0.58 wt), n-heptane (54.8 kg, 1.15 wt) was added, raising the internal reaction temperature to 39°C. Next, while maintaining the internal reaction temperature at 39°C, 3.0 M HCl (17.6 kg, 0.37 wt) in CPME was added at a constant rate. After the addition of HCl was completed, the internal temperature was raised to 52°C. Next, while maintaining the internal reaction temperature at 51°C, additional n-heptane (133.2 kg, 2.80 wt) was added at a constant rate. The reaction mixture was heated to 55°C and then cooled to 49°C. A fixed amount of the reaction mixture was taken out and cooled to 11°C at a linear cooling rate until a slurry containing crystals of compound 2 (hereinafter referred to as "seed crystal slurry") in CPME / n-heptane was formed. Next, at 49°C, the seed crystal slurry of compound 2 in CPME / n-heptane (169 g, 0.43 wt%) was added, and this temperature was maintained for 105 minutes. Next, the opaque reaction mixture was cooled to 11°C at a linear cooling rate over 12 hours. Next, the reaction mixture was filtered under vacuum at 11°C to collect a solid wet HCl intermediate (compound 2). Next, a mixture of CPME and n-heptane (56.6 kg of CPME and 179 kg of n-heptane) was added to the reaction vessel and cooled to 11°C. Then, half of the mixture was poured into a filter dryer as a chromatographic washing and passed through. The other half was passed through a filter as a slurry washing. Compound 2 was further purified by recrystallization according to the following procedure without removing it from the filter dryer.

[0420] Compound 2 in cyclopentyl methyl ether (CPME) (77.6 kg) was added to a filter dryer containing compound 2 and heated to 25°C. Next, the dissolved compound 2 was transferred to a reaction vessel with a jacket temperature set to 25°C under nitrogen and the internal temperature was raised to 38°C. 3.1 M HCl (6.4 kg) in CPME was added, resulting in a total of 1.07 equivalents of HCl, based on assays of compound 1 in crude compound 2 and HCl in crude compound 2. Next, n-heptane (139.4 kg) was added and the internal reaction temperature was raised to 51°C. Next, at 50°C, seed crystal slurry of compound 2 in CPME / n-heptane (291 g, 0.87 wt%) was added and this temperature was maintained for 105 minutes. Next, the opaque reaction slurry was cooled to 11°C at a linear cooling rate over 12 hours. Next, the slurry was filtered under vacuum at 9°C using a filter dryer. Then, 20 vol% of CPME in n-heptane (57.4 kg of CPME, 180 kg of n-heptane) was added to the reaction vessel and cooled to 11°C. Next, half of the mixture was poured into the filter dryer as chromatography washings and passed through. The other half was passed through the filter dryer as slurry washings. Next, the wet filter cake was dried under vacuum at stepwise jacket temperatures of 25, 35, 46, and 54°C to obtain compound 2 in 64% yield (from compound 1F) with a purity of 99.6 area% and residual solvents of 0.3% w of CPME and <0.1% w of n-heptane. (Example 10) Further preparation of compound 2

[0421] Compound 1 in solution was further diluted with n-heptane and heated to 40°C. At this temperature, approximately 3M HCl (1.1 meq for compound 1F) in CPME was added. This solution was further heated to 48-53°C, and a second volume of n-heptane was added. For seed crystal addition of compound 2 as needed, this clear solution was cooled to 53°C (seed crystal addition is optional but preferred under manufacturing conditions). If seed crystals were added, the solution was salt-decomposed at 53°C and then cooled to 10°C over 12 hours.

[0422] The color of the resulting filtered compound 2 can be improved by performing a crystallization aging procedure (a procedure involving repeated heating and cooling cycles). The suspension of the product was filtered, washed once with cold CPME / n-heptane (20:80 vol.), and then dried under vacuum. (Example 11) (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester (compound 3) [ka]

[0423] (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl hydrochloride (compound 2, 35.0 kg, 48.4 mol) was added to isopropyl acetate (IPAC, 214 kg, 6.11 wt) in an inert reactor, and the mixture was stirred at 22°C until dissolution was achieved. Deionized water (245 kg, 7.00 wt) was added, and the reaction mixture was stirred at 23°C for 35 minutes. Then, stirring was stopped, the phases were separated, and the lower aqueous phase was removed. The process of adding deionized water (245 kg, 7 wt), stirring, and removing the lower aqueous phase was repeated three more times. Next, the organic phase was concentrated under reduced pressure to approximately 71 L (approximately 2 volumes) while maintaining an internal temperature of 55°C or below. Next, ethanol (115 kg, 3.29 wt) was added, and the reaction mixture was concentrated under reduced pressure to approximately 78 L (approximately 2 vol) while maintaining an internal temperature of 55°C or below. The process of adding ethanol (115 kg, 3.29 wt) and concentrating was repeated two more times. Next, the reaction mixture was cooled to 25°C and charred using a cartridge. The cartridge was then rinsed with ethanol (100 kg, 2.86 wt), concentrated under vacuum at 55°C or below to 147 L (approximately 3.8 vol), and then 35 L of EtOH (1.0 vol) was added to obtain the free base form of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester (compound 1) in ethanol. Next, a 14% by weight NaOH solution (15.8 kg, 1.13 equivalents) was added to a reaction vessel containing compound 1 in ethanol, while maintaining a reaction temperature of 20°C. The reaction mixture was stirred at 20°C for 5 hours to achieve complete conversion.

[0424] 34% by weight calcium chloride (aqueous solution) (10.8 kg) was added to an inert reactor. Next, deionized water (336 L, 9.61 by weight per compound) and ethyl acetate (15 kg, 0.43 by weight per compound) were added, and the mixture was stirred for 30 minutes to obtain "Solution B".

[0425] Next, solution B was cooled to 9°C while being stirred. Then, solution A (see above) was added to solution B via a filter over 90 minutes while maintaining the temperature at 10°C. Next, the container of solution A was rinsed with additional ethanol (50 kg, 1.43 wt per compound 1) and transferred to solution B. The resulting slurry was stirred at 9°C for 1 hour. Next, the solid was collected by filtration and rinsed with deionized water (2 × 175 kg, 5 wt per compound 1). Next, this solid was dried under vacuum at 50°C for 21 hours to obtain 27.6 kg of amorphous ovicetrapib hemicalcium (compound 3) containing <1 wt% water (77% yield, relative to the number of moles of compound 2). Compound 3 was reworked as described in Example 12 below. (Example 12) Reworking Compound 3

[0426] Compound 3 (27.6 kg) was dissolved in ethanol (55.2 kg, 2 wt relative to Compound 3) at 45-48°C, and then cooled to 11°C. The solution was filtered and placed in a pre-cooled (approximately 10°C) mixture of CaCl2 aqueous solution (33-35 wt% of 8.2 kg, 0.3 wt), water (262 kg, 9.5 wt), and ethyl acetate (12.6 kg, 0.46 wt). The resulting suspension was filtered and washed with water (2 × 5 wt, 138 kg per washing step), and the solid was dried under vacuum while maintaining an internal temperature of 45°C or below for 23 hours to obtain 24.8 kg (91% yield) of amorphous hemicalcium salt (compound 3) of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidine-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate ethyl ester with a purity of 97.5 wt% and >99.9 area%. (Example 13) Further preparation of compound 3

[0427] Compound 2 was neutralized and dissolved in aqueous NaOH in EtOH. This solution was filtered through activated carbon. The solution was concentrated by vacuum distillation. For saponification of the ester, aqueous NaOH solution was added to obtain the sodium salt of compound 1 in the solution, and the ester was formed in this step and the previous step.

[0428] Next, a mixture of aqueous CaCl2 solution and dimethyl phosphate was prepared in a second container. Then, the sodium salt of compound 1 from the first container was added to this mixture, thereby precipitating compound 3. If necessary, the suspension may be heated to 25°C NMT and then cooled to 8°C. The solid compound 3 was filtered off at 8°C, washed with water, and dried under vacuum. (Example 14) Milling of reworked compound 3

[0429] Compound 3 was jet-milled using an 8-inch spiral mill. The feed rate, venturi pressure, and mill pressure were adjusted within the ranges listed below to produce micron-sized Compound 3 in accordance with the particle size acceptance criteria (D90 = 6~15 μm). Feeding rate: 17~20kg / hour Mill pressure: 20 PSI / 1.4 bar Venturi pressure: 100 PSI / 6.9 bar Processing gas: Nitrogen Analysis: Mastersizer 3000. (Example 15) Milling of another compound 3 preparation The particle size distribution was adjusted to the target parameter d90: 6-15 microns by micronization using a spiral jet mill, an 8-inch jet mill, and 8005 and KT4 LIW feeders. Three samples were milled using jet mills, and the following results were obtained: d90: 8 microns, 8 microns and 9 microns d50: 4 microns, 3 microns, and 4 microns d10: 2 microns, 1 micron, 1 micron (Example 16) Crystalline ovicetrapibhemicalcium

[0430] 2 g of amorphous ovicetrapib hemicalcium was added to acetonitrile (ACN) / methyl tert-butyl ketone (MIBK) (200 mg / ml in a 6:1 ratio), and the sample was heated to 50°C for 5 minutes until all solids were dissolved. Next, the sample was placed in a water bath and cooled from 50°C to 5°C at 0.9°C / min over 48 hours. The sample was maintained at 5°C for 3 days, and then transferred to -20°C for 30 minutes before isolation of the solid. The solid was air-dried for 2 hours before further characterization. This process resulted in the formation of crystalline ovicetrapib hemicalcium. (Example 17) Polarized light microscopy (PLM)

[0431] Polarized light microscope images were captured at room temperature using a Nikon DS-Fi2 upright microscope. The sample (2 mg) was mounted on a glass slide and covered with a single drop of silicone oil using a coverslip for analysis. The sample was not protected from light. (Example 18) X-ray powder diffraction (XRPD)

[0432] In a silicon zero-background holder, a panalytical beam of Cu radiation generated using an Empyran tube and a fine-focus source is used. X'Pert 3 XRPD was performed using a powder diffractometer. Before analysis, a silicon standard (NIST SRM 640d) was analyzed to confirm that the Si 111 peak position matched the NIST-certified position. Approximately 5-10 mg of sample was placed in a silicon zero-background holder, and the sample was manually flattened using an aluminum spatula to minimize variations in overall sample height. This holder was then mounted on the analytical instrument. The XRPD parameters used are listed in Table 10. [Table 10] (Example 19) X-ray powder diffraction pattern

[0433] A PANalytical X-ray powder diffractometer was used under the following measurement conditions, data was acquired using DataViewer, and the data was evaluated using X'Pert High Score Plus: X-ray tube Cu LFF HR Configuration Transparent type X-ray mirror, Focused X-ray mirror W / Si Solar slit 0.02rad Detector Pixel 1D Detector effective length: 1.69° Divergent slit fixed Divergence slit size 1 / 2° X-ray tube excitation 40mA, 40kV 2-theta range: 2° to 40° Measurement mode: Continuous Time per step: 300 seconds Step size 0.013° (2-theta) Rotation speed: 1 revolution per second (Example 20) X-ray powder diffraction pattern

[0434] The diffraction pattern shown in Figure 3 was measured using a Malvern PANalytical Empyrean powder diffractometer in transmission mode. The sample was prepared as a thin layer between two Kapton foils and measured in continuous mode. The detector measured from approximately 2°(2θ) to 40°(2θ). Signal peaks can be observed at approximately 3.4°(2θ), 7.0°(2θ), and 9.2°(2θ). The peak at approximately 5.6°(2θ) is attributed to the Kapton foil. (Example 21) X-ray powder diffraction method for crystalline ovicetrapib HCl / compound 1D

[0435] The diffraction patterns were measured using a Thermo Fisher Scientific ARL Equinox 1000 powder diffractometer. The diffractometer was used with a copper source and monochromatic Cu It is equipped with a germanium (111) monochromator that emits Kα1 radiation, and a position-sensitive gas ionization detector.

[0436] The sample was measured in reflection mode using an aluminum sample holder without any further preparation (i.e., grinding). The detector simultaneously measured over the entire angular range from approximately 2°(2θ) to 120°(2θ). In the case of HCl ovicetrapib, a discernible signal useful for phase identification was observed up to approximately 45°(2θ). The diffractometer temperature was typically maintained at approximately 30°C during the measurement. (Example 22) X-ray powder diffraction method for crystalline ovicetrapib HCl

[0437] The Rigaku SmartLab X-ray diffractometer was configured with a Bragg-Brentano reflection setup, equipped with a beam stop and knife edge to reduce incident beam and air scattering. The data acquisition parameters are shown in Table 11. [Table 11] (Example 23) FT-IR spectroscopy

[0438] The FTIR spectra of amorphous obicetrapib hemicalcium samples are shown in Figure 4. The FTIR spectra were acquired using a Bruker Tensor 27 spectrometer equipped with a Platinum ATR-QL-Diamond unit. Mill-ground samples were placed in the ATR unit without any pretreatment. (Example 24) 1 H-NMR spectroscopy

[0439] The NMR spectrum of a solution prepared from a sample of amorphous ovicetrapibhemicalcium is shown in Figure 5. The NMR spectrum was obtained using a 600 MHz AVANCE NEO Bruker, with tetramethylsilane (TMS) used as an internal standard for the chemical shift at 0.0 ppm, and in deuterated MeOH as the solvent. The spectral shifts are consistent with the chemical structure. (Example 25) Modulated differential scanning calorimetry (mDSC)

[0440] A sample containing an mDSC thermogram is shown in Figure 12, and Figure 14 shows the sample prepared using a T-zero aluminum pan with a pinhole. The gradient rate was set at 2°C / min, modulated by ±0.5°C every 60 seconds, from 25°C to 225°C. The instrument used was a TA Q2500 DSC from TA Instruments. (Example 26) Modulated differential scanning calorimetry (mDSC)

[0441] Using a TA Instruments DSC2500, the sample was heated at a starting temperature of 25°C, modulating by ±0.5°C every 60 seconds up to 225°C. A T-zero aluminum pan and a T-zero airtight lid with an additionally perforated and enlarged factory pinhole were used for this test. An integrated thermogram (showing reversible heat flow) derived from the sample is included in Figure 13. The sample showed a glass transition with a Tg of approximately 111°C. (Example 27) Methods for evaluating stability

[0442] The stability of ovicetrapib in crystalline and amorphous forms was investigated at 70°C / 75% relative humidity (RH). The solid was placed in a 4.0 ml glass vial without a stopper (open condition) and stored at 70°C / 75% RH. At time points of day 1 (24 hours) and day 7, the sample was withdrawn from the stability chamber. The physical stability of the solid was analyzed by XRPD, and its chemical purity by HPLC. The sample taken at each time point was dissolved in methanol and then analyzed by HPLC. To minimize the influence of adsorption of potential analytes on the filter, the first 0.5 mL of supernatant that passed through the filter was discarded before taking the sample for HPLC analysis. The purity of each sample was determined based on the peak area % and compared to the sample at T=0. (Example 28) Method used to evaluate dynamic solubility in biolilevant medium

[0443] The dynamic solubility of ovicetrapib in crystalline and amorphous forms was investigated in biorelevant medium, including simulated intestinal fluid under feeding conditions (FeSSIF) at pH 5.0 and simulated fasting conditions (FaSSIF) at pH 6.5, at 37°C. The solid was magnetically stirred in a shaker bath at 600 RPM, and samples were withdrawn using a 1.0 ml syringe at T=15, 30, 60, 90, and 120 minutes. Solubility was measured using the HPLC method provided by the client. The compound was added to a 4.0 ml glass vial at approximately 20.0 mg / ml. The sample was stirred in a vortex mixer for approximately 5 minutes to confirm the presence of undissolved excess powder. Samples taken at each time point were centrifuged at 1200 RPM, filtered through a 0.45 μm polytetrafluoroethylene (PTFE) filter, diluted with methanol, and then analyzed by HPLC. To minimize the influence of potential analytes adsorbed onto the filter, the first 0.5 mL of supernatant that passed through the filter was discarded before collecting the sample for HPLC analysis.

[0444] While the present invention has been specifically shown and described with reference to preferred embodiments and various alternative embodiments, it will be understood by those skilled in the art that various modifications of form and detail can be made in these embodiments without departing from the spirit and scope of the invention. (Example 29) Preparation of crystalline ovicetrapib hydrochloride form A

[0445] Obicetrapib HCl (approximately 43 mg, prepared in accordance with the disclosure herein) was combined with CPME / heptane (1:7) (0.8 mL) in a 1-drum vial, and the mixture was magnetically stirred at room temperature. After 2 weeks, the solid was separated by centrifugation, and the residual liquid was removed by pipette. The sample was dried in a vacuum desiccator for approximately 30 minutes to obtain approximately 25 mg of form A. (Example 30) Preparation of crystalline ovicetrapib hydrochloride form B

[0446] Obisetrapib HCl (approximately 84 mg, prepared in accordance with the disclosure herein) was dissolved in 3.5 mL of toluene. After stirring at room temperature, approximately 1 molar equivalent of hydrochloric acid (116 μL, 1 M solution in diethyl ether) was added to the above solution. Next, heptane (4 mL) was added to the mixture, and a cloudy solution was obtained within a few minutes. After stirring overnight, the suspension was filtered under vacuum, and the solid was dried briefly on the filter under reduced pressure to obtain approximately 40 mg of Form B (weighed after 26 days of ambient storage). (Example 31) Preparation of crystalline ovicetrapib hydrochloride form C

[0447] Obisetrapib HCl (approximately 84 mg, prepared in accordance with the disclosure herein) was dissolved in 1.0 mL of isopropyl acetate. After stirring at room temperature, approximately 1 molar equivalent of hydrochloric acid (116 μL, 1 M solution in diethyl ether) was added to the above solution. Next, heptane (6 mL) was added to the mixture to obtain a cloudy solution. After stirring overnight, the suspension was filtered under vacuum, and the solid was dried briefly on the filter under reduced pressure to obtain approximately 25 mg of Form C (weighed after 26 days of ambient storage). (Example 32) Preparation of crystalline ovicetrapib hydrochloride form D

[0448] Obicetrapib HCl (approximately 46 mg, prepared in accordance with the disclosure herein) was combined with butyl acetate / heptane (1:5) (0.6 mL) in a 1-drum vial, and the mixture was magnetically stirred at room temperature. After 2 weeks, the solid was separated by centrifugation, and the residual liquid was removed by pipette. The sample was dried in a vacuum desiccator for approximately 30 minutes to obtain approximately 15 mg of form D. (Example 33) Preparation of single crystal samples

[0449] Obicetrapib HCl (approximately 10 mg, prepared according to the disclosure herein) was dissolved in a mixture of cyclopentyl methyl ether and heptane (1:8) (0.232 mL) at approximately 60°C. The resulting solution was cooled to 50–55°C and allowed to stand overnight. The following day, some needle-shaped solids were observed on the side of the vial. A temperature cycling experiment was performed using continuous heating and cooling: the sample was heated to 55–60°C, then cooled to 45–50°C, and held at that temperature for several hours. After approximately 5 days, aggregated, long, blade-like particles were observed under a microscope and found to be of sufficient size and quality. (Example 34) Solution of single crystal structure

[0450] Formula [4(C) has approximate dimensions of 0.02 × 0.09 × 0.28 mm 32 H 32 F9N4O5)·2(C 32 H 31 F9N4O5)·C6H 12 O·C7H 16 Colorless, long-blade shaped single crystals of Example 33 containing ·4(Cl)·[+solvent]] were mounted in a random orientation on a Mitegen micromesh mount. Data was acquired from the shock-cooled single crystals at 150(2)K using a Bruker AXS D8 Quest quad-axis diffractometer equipped with an I-mu-S microsource X-ray tube, employing a laterally stepped multilayer (Goebel) mirror as a monochromator and a PhotonIII_C14 charge-accumulating photon counting pixel array detector. The diffractometer was CuK αRadiation (λ=1.54178 Å) was used. All data were integrated using SAINT V8.40B and multi-scan absorption correction was applied using SADABS 2016 / 2 (Bruker, SAINT, V8.40B, Bruker AXS Inc., Madison, Wisconsin, USA; L. Krause, R. Herbst-Irmer, GM Sheldrick, D. Stalke, J.Appl.Cryst. 2015, 48, 3-10, doi:10.1107 / S1600576714022985). The structure was solved using the dual method with SHELXT and F using SHELXL-2019 / 2. 2 The model was refined using the complete matrix least squares method (GMSheldrick, Acta Cryst. 2015, A71, 3-8, doi:10.1107 / S2053273314026370; GMSheldrick, Acta Cryst. 2015, C71, 3-8, doi:10.1107 / S2053229614024218). All non-hydrogen atoms were refined using anisotropic displacement parameters. Hydrogen atoms bonded to carbon, hydroxyl H atoms in carboxylic acids, and H atoms in planar (sp2 hybridized) NH groups were refined isotropically with respect to the computational position using the riding model. Regarding further details of hydrogen atom treatment, methyl CH3 and hydroxyl H atoms were rotated but not tilted to best fit the experimental electron density. The Uiso value was bound to 1.5 times the Ueq of the pivot atom for methyl and hydroxyl groups, and to 1.2 times for all other hydrogen atoms.

[0451] The asymmetrical part of the structure consists of six major organic molecules, four chloride anions, and several solvating molecules (methylcyclopentyl ether and heptane). Four of the six major fragments are cationic, and two are neutral molecules ("free bases"). Protonation is present on the "N3" nitrogen atom of the pyrimidine ring for all four cations, all four N-H+ units are ionized, and all four chloride anions are ionized; that is, two associate with two N-H+ units, and the others associate with the carboxyl moiety. Equivalent positions for the two free base molecules are not protonated, and no close contact with potential H-bond acceptors is observed.

[0452] Extensive disorder is observed throughout the structure, and some fragments exhibit very large thermal vibrations. This is even more pronounced in the case of the two free base molecules (residues 5 and 6), particularly their bis(trifluoromethyl)benzene moieties. The solvated molecules are also extensively disordered, exhibiting very large thermal vibrations, which are only partially resolved.

[0453] All six major ovicetrapib molecules (cations and free bases) were bound to have similar geometric shapes. Small disordered regions were bound to have similar geometric shapes as well-defined, disorder-free fragments of other molecules (using the SAME command in Shelxl). All CF bond distances and all FCF angles were bound to be similar to one another. The carbon atoms of the major and secondary parts of the bis(trifluoromethyl)benzene moieties of residues 1, 2, and 3, as well as the mono(trifluoromethyl)benzene moiety of residue 3, were bound to be close to a plane (using the FLAT command in Shelxl). The latter atomic displacement parameters ("ADP") were bound to be close to isotropic. The Uij components of ADP for atoms closer than 2.0 Å to each other were bound to be similar. The position of one N-H+ H atom (H3A_3) was refined. The hydroxyl H atoms of the carboxylic acid groups were rotated. Some were further bound based on consideration of hydrogen bonding. In the first refinement cycle, a mild decay factor was applied. In the final refinement cycle, some hydroxyl H atoms were set to rest on the O atoms they possessed (H4_1, H4_4, H4B_1), and their decay factors were removed.

[0454] The irregularity was refined for the following fragments, and the occupancy rate was refined as follows according to the above conditions: • The bis(trifluoromethyl)benzene moiety of residue 1 (cation). Occupancy: 0.589(14)~0.411(14). • The bis(trifluoromethyl)benzene moiety of residue 2 (cation). Occupancy: 0.534(11)~0.466(11). • The bis(trifluoromethyl)benzene and mono(trifluoromethyl)benzene moieties of residue 2 (cation). Occupancy: 0.598(11)~0.402(11) and 0.492(19)~0.492(19). • 4-(pyrimidine-2-yloxy)butanoic acid fragment at residue 6 (free base). Occupancy: 0.493(11)~0.507(11).

[0455] The methylcyclopentyl ether solvated molecule was refined to be completely occupied. Bond distances and angles were constrained to the expected target values, and the Uij components of ADP with respect to atoms closer than 2.0 Å to each other were constrained to be similar. ADP was constrained to be close to isotropic. The heptane solvated molecule was refined to be disordered in two directions. Bond distances and angles were constrained to the expected target values, and the Uij components of ADP with respect to atoms closer than 2.0 Å to each other were constrained to be similar. Mild anti-damping constraints were applied to avoid close contact with atoms of the main molecule. According to these conditions, the occupancy was refined to 0.460(13) to 0.540(13).

[0456] The structure is further 980 Å 3 It includes the solvent-accessible void volume. Two main void spaces (333 Å each) 3 ) likely contains indistinct and highly irregular solvated molecules. The large electron density peak is likely due to solvent-accessible voids (Å). 3 No electron density peaks were observed (less than 0.70 electrons per atom), and the remaining electron density peaks were not aligned in a recognizable pattern. Instead, the structure factor was extended by the inverse Fourier transform using the SQUEEZE routine implemented in the Platon program (AL Spek J. Appl. Cryst. 2003, 36, 7-13) (P. vander Sluis, & AL Spek, Acta Cryst. 1990, A46, 194-201). This explains that there are 229 electrons in this volume, meaning that approximately one heptane molecule (100.2 electrons / heptane) exists in each of the two large void spaces.

[0457] Flack's x-parameter was determined using Parsons' method, employing 4528 quotients [(I+)-(I-)] / [(I+)+(I-)], and refined to 0.046(17) (S. Parsons, H. Flack, T. Wagner, Acta Cryst. 2013, B69, 249-259). (Example 35) X-ray powder diffraction pattern

[0458] The Rigaku SmartLab X-ray diffractometer was configured with a Bragg-Brentano reflection setup, equipped with a beam stop and knife edge to reduce incident beam and air scattering. The data acquisition parameters are shown in the table below (Table 12). This method has not been validated. [Table 12] (Example 36) Calculated X-ray powder diffraction pattern

[0459] The X-ray powder diffraction pattern was calculated from the solution of the single crystal structure of Example 34. The pattern was obtained using Mercury 3.3 (Build) from the Cambridge Crystallographic Data Centre (CCDC). It was generated using commercially available software called RC5).

[0460] The table of peaks associated with the calculated patterns is shown in Table 13 below. [Table 13-1] [Table 13-2] [Table 13-3]

[0461] All references, granted patents, and patent applications cited within the body of this Specified Publication are incorporated herein by reference in their entirety for all purposes. In embodiments of the present invention, for example, the following items are provided. (Item 1) Amorphous calcium salt of ovicetrapib. (Item 2) Amorphous ovicetrapib hemicalcium. (Item 3) Stable amorphous ovicetrapib hemicalcium. (Item 4) Essentially pure amorphous ovicetrapib hemicalcium. (Item 5) Amorphous ovicetrapibhemicalcium salts as described in items 2-4, substantially free of any crystalline salts of ovicetrapibhemicalcium. (Item 6) Amorphous obicetrapib hemicalcium described in items 2-5, having substantially the same X-ray powder diffraction pattern as the X-ray powder diffraction pattern in Figure 1. (Item 7) Amorphous obicetrapib hemicalcium as described in items 2-5, having an X-ray powder diffraction pattern including one or more X-ray powder diffraction peaks at approximately 3.4°(2θ), approximately 7.0°(2θ), and approximately 9.2°(2θ). (Item 8) The amorphous ovicetrapib hemicalcium described in items 2-7, wherein the amorphous ovicetrapib hemicalcium does not exhibit birefringence. (Item 9) Amorphous ovicetrapib hemicalcium as described in items 2-8, having a glass transition temperature between approximately 107°C and 112°C. (Item 10) Amorphous obicetrapib hemicalcium as described in item 9, wherein the glass transition temperature is measured by modulated differential scanning calorimetry. (Item 11) The measurement by modulated differential scanning calorimetry uses an open sample pan and is amorphous obicetrapib hemicalcium as described in item 10. (Item 12) Amorphous obicetrapib hemicalcium as described in item 11, with a pinhole opening. (Item 13) Amorphous ovicetrapibhemicalcium as described in items 8-12, wherein the glass transition temperature is between approximately 110°C and approximately 112°C. (Item 14) Amorphous obicetrapib hemicalcium as described in items 2-13, having a glass transition temperature of less than approximately 100°C as measured by differential scanning calorimetry using a sealed sample pan. (Item 15) Amorphous obicetrapib hemicalcium, as described in item 14, having a glass transition temperature between approximately 70°C and approximately 92°C, as measured by differential scanning calorimetry using a sealed sample pan. (Item 16) Amorphous ovicetrapib hemicalcium as described in items 2-15, which exhibits a weight loss of less than approximately 1% when heated to approximately 200°C. (Item 17) Amorphous ovicetrapib hemicalcium as described in item 16, wherein the weight loss is between approximately 0.8% and approximately 0.95%. (Item 18) Amorphous ovicetrapib hemicalcium as described in item 17, wherein the weight loss is between approximately 0.84% ​​and approximately 0.92%. (Item 19) Amorphous ovicetrapib hemicalcium as described in items 2-18, having a water content of less than approximately 5%. (Item 20) Amorphous ovicetrapib hemicalcium as described in item 19, having a water content of less than approximately 4%. (Item 21) Amorphous ovicetrapib hemicalcium as described in item 20, having a water content of less than approximately 3%. (Item 22) Amorphous ovicetrapib hemicalcium as described in item 19, having a moisture content between approximately 0.5% and approximately 1.5%. (Item 23) Amorphous ovicetrapib hemicalcium as described in items 2-22, which is a bulk form or formulated composition having a particle size distribution in which approximately 90% of the particles have a diameter of approximately 15 microns or less. (Item 24) Amorphous ovicetrapib hemicalcium as described in item 23, with approximately 90% of the particles having a diameter between approximately 6 microns and approximately 15 microns. (Item 25) Amorphous obicetrapib hemicalcium as described in item 24, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 14 microns or less. (Item 26) Amorphous obicetrapib hemicalcium as described in item 25, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 13 microns or less. (Item 27) Amorphous ovicetrapib hemicalcium as described in item 26, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 12 microns or less. (Item 28) Amorphous obicetrapib hemicalcium as described in item 27, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 11 microns or less. (Item 29) Amorphous obicetrapib hemicalcium as described in item 28, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 10 microns or less. (Item 30) Amorphous obicetrapib hemicalcium as described in item 29, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 9 microns or less. (Item 31) Amorphous obicetrapib hemicalcium as described in item 30, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 8 microns or less. (Item 32) Amorphous obicetrapib hemicalcium as described in item 31, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 7 microns or less. (Item 33) Amorphous obicetrapib hemicalcium as described in item 32, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 6 microns or less. (Item 34) Amorphous ovicetrapib hemicalcium as described in item 33, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 5 microns or less. (Item 35) Amorphous obicetrapib hemicalcium as described in item 34, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 4 microns or less. (Item 36) Amorphous ovicetrapib hemicalcium as described in item 35, having a particle size distribution in which approximately 90% or more of the particles have a diameter of approximately 3 microns or less. (Item 37) Amorphous ovicetrapib hemicalcium as described in items 2-36, in bulk form or in the form of a formulated composition, having a particle size distribution in which approximately 50% of the particles have a diameter of approximately 5 microns or less. (Item 38) Amorphous ovicetrapib hemicalcium as described in item 37, having a particle size distribution in which approximately 50% of the particles have a diameter of approximately 4 microns or less. (Item 39) Amorphous ovicetrapib hemicalcium as described in item 38, having a particle size distribution in which approximately 50% of the particles have a diameter of approximately 3 microns or less. (Item 40) Amorphous ovicetrapib hemicalcium as described in items 2-39, in bulk form or in the form of a formulated composition, having a particle size distribution in which approximately 10% of the particles have a diameter of approximately 2 microns or less. (Item 41) Amorphous ovicetrapib hemicalcium as described in items 2-40, having a chemical purity of at least 98.0%. (Item 42) Amorphous ovicetrapib hemicalcium as described in item 41, having a chemical purity of at least 99.0%. (Item 43) Amorphous ovicetrapib hemicalcium as described in item 42, having a chemical purity of at least 99.5%. (Item 44) Amorphous ovicetrapib hemicalcium as described in item 43, having a chemical purity of at least 99.6%. (Item 45) Amorphous ovicetrapib hemicalcium as described in item 44, having a chemical purity of at least 99.7%. (Item 46) Amorphous ovicetrapib hemicalcium as described in item 45, having a chemical purity of at least 99.8%. (Item 47) Amorphous ovicetrapib hemicalcium as described in item 46, having a chemical purity of at least 99.9%. (Item 48) Solid state (Figure 17) 13 The solid state is virtually identical to the C-NMR spectrum. 13 Amorphous ovicetrapibhemicalcium, as described in items 2-47, having a 1C-NMR spectrum. (Item 49) In the solid state, there is no peak at approximately 22.1 ppm. 13 Amorphous obicetrapib hemicalcium, as described in items 2-48, having a 1C-NMR spectrum. (Item 50) In the solid state, there is no peak at approximately 29.5 ppm. 13 Amorphous ovicetrapibhemicalcium, as described in items 2-49, having a 1C-NMR spectrum. (Item 51) Unground amorphous ovicetrapib hemicalcium. (Item 52) Mill-ground amorphous ovicetrapib hemicalcium. (Item 53) Amorphous ovicetrapib hemicalcium as described in items 2-50, wherein the amorphous ovicetrapib hemicalcium is milled. (Item 54) Amorphous ovicetrapib hemicalcium as described in items 2-50 or 53, wherein the amorphous ovicetrapib hemicalcium is jet-milled. (Item 55) Amorphous ovicetrapib hemicalcium as described in items 2-50 or 53-54, wherein the amorphous ovicetrapib hemicalcium is spray-dried. (Item 56) Amorphous ovicetrapib hemicalcium prepared by a synthesis method, wherein the intermediate in the method contains crystalline ovicetrapib HCl. (Item 57) The amorphous obisetrapib hemicalcium described in items 2 to 56, wherein the amorphous obisetrapib calcium is prepared by a synthetic method, and the intermediate in the method contains crystalline obisetrapib HCl. (Item 58) Obisetrapib HCl. (Item 59) Crystalline ovicetrapib HCl. (Item 60) Amorphous ovicetrapib HCl compound. (Item 61) The solvate of ovicetrapib HCl as described in items 58-60. (Item 62) Obisetrapib HCl as described in items 58-61, wherein the weight percentage of HCl is between approximately 0.01% and approximately 8%. (Item 63) A composition comprising crystalline ovicetrapib HCl as described in any one of items 58 to 62. (Item 64) The crystalline ovicetrapib HCl described in items 58-60 or 62-63, wherein the crystalline ovicetrapib HCl is a solvate. (Item 65) The crystalline ovicetrapib HCl according to item 64, comprising the solvate ovicetrapib and hydrochloric acid. (Item 66) The crystalline ovicetrapib HCl described in item 65, wherein the solvate contains an organic solvent. (Item 67) The crystalline obisetrapib HCl according to item 66, wherein the solvate comprises a solvent having sufficient solubility to dissolve enough HCl to produce crystalline obisetrapib HCl. (Item 68) The solvate according to any one of items 61 or 64-67, wherein the solvent of the solvate is selected from methanol, ethanol, isopropanol, acetic acid, acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether, N-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, 1,2-difluorobenzene, toluene, and hexafluoroisopropanol. (Item 69) The crystalline obisetrapib HCl described in item 68, wherein the solvent is CPME. (Item 70) Crystalline obisetrapib HCl according to any one of items 58-59 or 61-69, having an X-ray powder diffraction pattern substantially identical to that of the X-ray powder diffraction pattern in Figure 19. (Item 71) Crystalline ovicetrapib HCl according to any one of items 58-59 or 61-69, having an X-ray powder diffraction pattern with a peak at approximately 9.8°(2θ). (Item 72) Crystalline ovicetrapib HCl according to any one of items 58-59, 61-69, or 71, having an X-ray powder diffraction pattern including one or more peaks at approximately 8.1°(2θ), approximately 9.8°(2θ), approximately 13.8°(2θ), approximately 16.7°(2θ), and approximately 19.5°(2θ). (Item 73) Salts according to formula (VI): [ka] [In the formula, Y1 is a protecting group, A n- [where n is an anion and n is an integer between 1 and 3]. (Item 74) The compound is a mesylate salt with the following structure (compound 1D): [ka] The salt described in item 73. (Item 75) A crystalline mesylate of compound 1D, as described in item 74. (Item 76) A crystalline mesylate of compound 1D described in item 75, having a powder diffraction pattern substantially identical to one of the four X-ray powder patterns shown in Figure 20. (Item 77) A crystalline mesylate of compound 1D as described in item 75, having an X-ray powder diffraction pattern including one or more peaks at approximately 5.2°(2θ) and approximately 9.1°(2θ). (Item 78) A crystalline mesylate of compound 1D described in items 75-77, having an X-ray powder diffraction pattern containing one or more peaks at approximately 9.1°(2θ), approximately 15.9°(2θ), approximately 16.5°(2θ), approximately 17.2°(2θ), approximately 18.6°(2θ), and approximately 19.2°(2θ). (Item 79) A method for preparing ovicetrapib, (a) A step of preparing the compound of formula (IV) by coupling the compound of formula (II) or a salt thereof with the compound of formula (III): [ka] [where, X 1 is a leaving group, Y 1 [is a protecting group] (b) The step of preparing the carbamate of formula (V) from the compound of formula (IV) and isolating it as a solid salt of formula (VI): [ka] [In the formula, Y1 is a protecting group, and A n- [where n is an anion and n is an integer between 1 and 3] (c) The compound of formula (VI) is optionally subjected to salt decomposition and alkylated with the compound of formula (VII) to obtain the compound of formula (VIII): [ka] [where, X 2 is a leaving group, Y 1 is a protecting group, and (d) The step of converting the compound of formula (VIII) to ovicetrapib. Includes, A method wherein reaction steps (a) to (d) are carried out in an organic solvent, compounds (IV), (V), and (VIII) are not isolated from the organic solvent under certain circumstances, and the method does not require chromatography. (Item 80) The compound of formula (II) in step (a) is, prior to step (a), the following: (Pre-a1) Compounds of formula (IIA) or (IIB): [ka] The steps to prepare, (Pre a2) A step of obtaining the compound of formula (II) by salt decomposition of the compound of formula (IIA) or (IIB). Obtained by applying, The method according to item 79, wherein the reaction in step (pre a2) is carried out in an organic solvent, the compound of formula (II) is not isolated from the organic solvent under certain circumstances, and the method does not require chromatography. (Item 81) Anion A is an anion in which the salt of formula (IIA) or (IIB) is selected from sulfonate ions, sulfate ions, halogens, acetate ions, aspartate ions, benzoate ions, bicarbonate ions, bitartrate ions, carbonate ions, citrate ions, decanoate ions, fumarate ions, gluceptate ions, gluconate ions, glutamate ions, glycolate ions, hexanoate ions, hydroxynaphthoate ions, isethionate ions, lactate ions, lactobionate ions, malate ions, maleate ions, mandelate ions, mucinate ions, nitrate ions, octanoate ions, oleate ions, pamoate ions, pantothenate ions, phosphate ions, polygalacturonate ions, propionate ions, salicylate ions, stearate ions, succinate ions, tartrate ions, and theoclate ions. m- The method according to item 80, wherein the sulfonate ion is selected from salts of the following, and the sulfonate ion may be besylate ion, tosylate ion, napsylate ion, cansylate ion, esyllate ion, edisylate ion, or mesylate ion, the sulfate ion may be methyl sulfate ion, and the halogen may be chloride ion, iodide ion, or bromide ion. (Item 82) Anion A m- The method according to item 81, wherein the salt is selected from chlorides, bromides, tartrates, sulfates, and sulfons. (Item 83) Anion A m- The method according to item 82, wherein the salt is selected from chlorides, bromides, tartrates, and mesylates. (Item 84) Y in the compounds of formulas (III) to (VI) and (VIII) 1 The method according to any one of items 79 to 83, wherein the group is selected from alkyl groups, substituted alkyl groups, aryl groups, substituted aryl groups, allyl groups, substituted allyl groups, and silyl groups. (Item 85) Y in the compounds of formulas (III) to (VI) and (VIII) 1The method according to item 84, wherein the group is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluoroethyl, phenyl, 4-methoxybenzyl ester, 2,6-disubstituted phenol, and silyl group. (Item 86) Y in the compounds of formulas (III) to (VI) and (VIII) 1 However, the method described in item 85 is t-butyl. (Item 87) Anion A is selected from the following salts of formula (VI): sulfonate ion, sulfate ion, halogen, acetate ion, aspartate ion, benzoate ion, bicarbonate ion, bitartrate ion, carbonate ion, citrate ion, decanoate ion, fumarate ion, gluceptate ion, gluconate ion, glutamate ion, glycolate ion, hexanoate ion, hydroxynaphthoate ion, isethionate ion, lactate ion, lactobionic acid ion, malate ion, maleate ion, mandelate ion, mucinate ion, nitrate ion, octanoate ion, oleate ion, pamoate ion, pantothenate ion, phosphate ion, polygalacturonate ion, propionate ion, salicylate ion, stearate ion, succinate ion, tartrate ion, and theoclate ion. n- The method according to any one of items 79 to 86, selected from salts of the following, wherein the sulfonate ion may be besylate ion, tosylate ion, napsylate ion, cansylate ion, esyllate ion, edisylate ion or mesylate ion, the sulfate ion may be methyl sulfate ion, and the halogen may be chloride ion, iodide ion or bromide ion. (Item 88) Anion A n- The method according to item 87, wherein the salt is selected from chlorides, bromides, tartrates, sulfates, and sulfons. (Item 89) Anion A n- The method according to item 87, wherein the salt is selected from chlorides, bromides, tartrates, and mesylates. (Item 90) The salt form of formula (VI) is the mesylate of compound 1D: [ka] The method described in item 87. (Item 91) The method according to item 90, wherein the mesylate is crystalline. (Item 92) X in the compound of formula (III) 1 The method according to any one of items 79 to 91, wherein the halogen, carbamate, and substituted sulfonyloxy groups are selected. (Item 93) X in the compound of formula (III) 1 The method described in item 92, wherein the halogen is used. (Item 94) The method according to item 93, wherein the halogen is a chloride. (Item 95) X in the compound of formula (VII) 2 The method according to any one of items 79 to 94, wherein the halogen and substituted sulfonyloxy groups are selected. (Item 96) X in the compound of formula (III) 2 The method described in item 95, wherein the halogen is... (Item 97) The method according to item 96, wherein the halogen is a bromide. (Item 98) A method for preparing the amorphous hemicalcium salt of ovicetrapib, (i) A step of treating ovicetrapib with HCl to obtain a crystalline ovicetrapib HCl compound. (ii) The step of isolating the crystalline obisetrapib HCl compound. (iii) A step of preparing an amorphous hemicalcium salt of ovicetrapib from the crystalline ovicetrapib HCl compound isolated in step (ii), and (iv) Step to isolate the amorphous hemicalcium salt of ovicetrapib. Methods that include... (Item 99) The crystalline obisetrapib HCl compound isolated in step (ii) is a compound of formula (IH): [ka] [In the formula, y varies from 0.002 to 1.5] The method described in item 98, including the method described in item 98. (Item 100) The preparation of the amorphous hemicalcium salt of formula (I) in step (iii) is as follows: (iii-1) In one or more suitable solvents selected from organic solvents and aqueous solvents, the crystalline ovicetrapib HCl compound from step (ii) is converted to obtain ovicetrapib. (iii-2) The step of treating the ovicetrapib in the organic solvent with aqueous sodium hydroxide to form the sodium salt of ovicetrapib, (iii-3) The step of treating the sodium salt of ovicetrapib with aqueous calcium chloride to form the amorphous hemicalcium salt of ovicetrapib. Includes, The method according to item 98 or 99, wherein the compound in steps (iii-1) and (iii-2) is not isolated in some circumstances. (Item 101) The method according to any one of items 98 to 100, wherein the amorphous hemicalcium salt of ovicetrapib is amorphous ovicetrapib hemicalcium. (Item 102) The method according to any one of items 98 to 101, wherein the amorphous calcium salt of ovicetrapib is isolated with at least 99% chemical purity. (Item 103) The method according to item 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.1%. (Item 104) The method according to item 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.2%. (Item 105) The method according to item 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.3%. (Item 106) The method according to item 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.4%. (Item 107) The method according to item 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.5%. (Item 108) The method according to item 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.6%. (Item 109) The method according to item 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.7%. (Item 110) The method according to item 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.8%. (Item 111) The method according to item 102, wherein the amorphous calcium salt of ovicetrapib is isolated with a purity of at least 99.9%. (Item 112) The method according to any one of items 102 to 111, wherein the amorphous calcium salt of ovicetrapib is amorphous ovicetrapib hemicalcium. (Item 113) A pharmaceutical composition comprising an amorphous salt of ovicetrapib calcium as described in any one of items 1 to 57, and one or more pharmaceutically acceptable carriers. (Item 114) The pharmaceutical composition according to item 113, wherein the amorphous salt of ovicetrapib calcium is amorphous ovicetrapib hemicalcium. (Item 115) A method for treating a subject suffering from a cardiovascular disease or a subject at increased risk of developing such a disease, comprising the step of administering a therapeutically effective amount of a pharmaceutical composition described in item 113 or 114 to the subject. (Item 116) Amorphous calcium salt of ovicetrapib, prepared by the method described in any one of items 79 to 112. (Item 117) Amorphous ovicetrapibhemicalcium, an amorphous calcium salt as described in item 116. (Item 118) A method for producing an amorphous ovicetrapib calcium salt, comprising the steps of: treating ovicetrapib with an acid to form a salt, solvate, composition or combination thereof; isolating the salt, solvate, composition or combination thereof; and treating the salt, solvate, composition or combination thereof with a calcium source to produce an amorphous ovicetrapib hemicalcium salt. (Item 119) The method according to item 118, wherein the calcium source is calcium chloride. (Item 120) A salt, solvate, composition, or combination thereof containing ovicetrapib and a free acid. (Item 121) Salt as described in item 120. (Item 122) The solvate described in item 120. (Item 123) The composition described in item 120. (Item 124) The free acid is selected from sulfonic acid, sulfuric acid, halogenated acid, acetic acid, aspartic acid, benzoic acid, bicarbonate, tartaric acid, carbonic acid, citric acid, decanoic acid, fumaric acid, glyceptic acid, gluconic acid, glutamic acid, glycolic acid, hexanoic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, mucinic acid, nitric acid, octanoic acid, oleic acid, pamoic acid, pantothenic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, and theoclic acid, and the sulfonic acid may be benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, ethanedisulfonic acid, or methanesulfonic acid, the sulfuric acid may be methylsulfonic acid, and the halogenated acid may be HCl, HBr, or HI, as described in item 120, the salt, solvate, composition or combination thereof. (Item 125) The method according to item 118, wherein the calcium source is a calcium halide salt. (Item 126) The method according to item 118, wherein the calcium source is a soluble calcium salt. (Item 127) The method according to item 118, wherein the calcium source is a calcium salt. (Item 128) Obisetrapib hydrochloride as described in item 58 or 59, comprising a chloride ion hydrogen-bonded to at least one protonated nitrogen on the pyrimidine ring of ovisetrapib. (Item 129) Obisetrapib hydrochloride as described in item 59 or 128, having an asymmetric unit comprising four cationic obisetrapib moieties, two neutral obisetrapib molecules, four chloride anions, and at least one solvent molecule. (Item 130) The ovicetrapib hydrochloride described in item 129, wherein the aforementioned asymmetric unit contains two solvent molecules. (Item 131) The ovicetrapib hydrochloride described in item 129, wherein the aforementioned asymmetric unit contains three solvent molecules. (Item 132) Obisetrapib hydrochloride according to any one of items 129 to 131, wherein the solvent molecule is selected from heptane and cyclopentyl methyl ether. (Item 133) The following unit cell parameters: [Table 15] Obisetrapib hydrochloride as described in any one of items 128 to 132, having the properties of: (Item 134) Crystalline ovicetrapib hydrochloride of form A. (Item 135) Crystalline ovicetrapib hydrochloride of form A as described in item 134, having an X-ray powder diffraction pattern including a peak at approximately 8.6°(2θ), two peaks between approximately 9.7°(2θ) and approximately 10.4°(2θ), and two peaks between approximately 8.6°(2θ) and approximately 9.0°(2θ). (Item 136) Crystalline ovicetrapib hydrochloride of form A described in item 134, having an X-ray powder diffraction pattern substantially identical to that of the X-ray powder diffraction pattern in Figure 22. (Item 137) Crystalline ovicetrapib hydrochloride of form B. (Item 138) Crystalline ovicetrapib hydrochloride of form B as described in item 136, having an X-ray powder diffraction pattern with peaks at approximately 6.5°(2θ), approximately 8.8°(2θ), and approximately 11.0°(2θ). (Item 139) Crystalline ovicetrapib hydrochloride of form B described in item 137, having an X-ray powder diffraction pattern substantially identical to that of the X-ray powder diffraction pattern in Figure 23. (Item 140) Crystalline ovicetrapib hydrochloride of form C. (Item 141) Crystalline ovicetrapib hydrochloride of form C described in item 140, having an X-ray powder diffraction pattern substantially identical to that of the X-ray powder diffraction pattern in Figure 24. (Item 142) Crystalline ovicetrapib hydrochloride of form D. (Item 143) Crystalline ovicetrapib hydrochloride of form D described in item 142, having an X-ray powder diffraction pattern substantially identical to that of the X-ray powder diffraction pattern in Figure 25. (Item 144) Crystalline ovicetrapib hydrochloride as described in item 59, having an X-ray powder diffraction pattern with a peak between approximately 4.3°(2θ) and approximately 4.7°(2θ).

Claims

【Request Item 1】 Cardiovascular disease.

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