Enantioselective process for preparing tetrahydroquinoline derivatives

Abstract

Provided herein is an improved manufacturing process for tetrahydroquinoline derivatives via a one-pot highly enantioselective Povarov process. Also provided is the manufacture of a new crystalline form of benzyl ((2R,4S)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4- yl)carbamate, and the use of the same in an improved manufacturing process of obicetrapib and salts thereof.

Description

ENANTIOSELECTIVE PROCESS FOR PREPARING TETRAHYDROQUINOLINE DERIVATIVES1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No.63 / 726,000 filed November 27, 2024, and U.S. Provisional Application No. 63 / 922,025 filed November 20, 2025, which are hereby incorporated by reference in their entirety.2. INTRODUCTION

[0002] 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 decrease these atherogenic LDL-C levels has resulted in a marked reduction of CVD-related morbidity and mortality: every 1 mmol / L decrease in LDL-C results in an estimated 22% reduction of CVD events and a 10% reduction of all-cause mortality. Notwithstanding these impressive benefits, a large residual disease burden persists that has a large impact on both individual patients as well as on global healthcare costs. Novel therapeutics are required to reduce further this residual CVD risk in patients.

[0003] One route which reduces LDL-C and elevates high-density lipoprotein cholesterol (HDL-C) levels is to inhibit Cholesterol Ester Transfer Protein (CETP). CETP is a plasma protein secreted primarily by liver and adipose tissue. CETP mediates the transfer of cholesteryl esters from HDL to apolipoprotein B (Apo B)-containing particles (mainly LDL and very low density lipoprotein VLDL) in exchange for triglycerides, thereby decreasing the cholesterol content in HDL in favor of that in VLDL. Hence, CETP inhibition has been hypothesized to retain cholesteryl esters in HDL-C and decrease the cholesterol content of the atherogenic Apo B fraction.

[0004] Clinical studies have shown that obicetrapib also known as ((27?,45)-4-{[3,5 bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester), or a pharmaceutically acceptable salt thereof is a potent CETP- inhibitor. The structure of obicetrapib is set forth below:

[0005] Compared to other known CETP -inhibitors, only a relatively low dose of obicetrapib is needed to reach near complete CETP inhibition. Typically, repeated daily dosages (once a day) as low as 2.5 mg of the compound of obicetrapib have proven to be already sufficient to reach near complete CETP inhibition. These are considerably lower dosages than had to be used for other CETP-inhibitors. Moreover, clinical studies have also shown that obicetrapib is well tolerated and that it does not lead to serious side effects.

[0006] While processes have been described previously for the manufacture of obicetrapib, (see, e.g., WO 2005 / 095409A2 and US Pat. Nos. 7,872,126 and 8,158,640, Examples 1 and 177-180; WO 2007 / 116922 Al and US Pat. No. 8,084,611; and WO 2016 / 024858 and US Patent No. 10,112,904), these processes have relatively low yield and are not particularly suitable for carrying out on an industrial scale. A process for the manufacture of an improved solid form of obicetrapib and an alternative manufacture of the same with improved yield, purity, and stability is described in W02024 / 009144 and US Patent No. 12,006,305. These references are incorporated herein by reference in their entirety.

[0007] The previously described methods for the manufacture of obicetrapib have made use of intermediate compound (IB):

[0008] The current methods for preparing compound (IB), such as described in US Patent No.10,112,904, involves three steps, and a chiral resolution step to obtain the desired enantiomer of compound (IB).

[0009] For carrying out the manufacture of obicetrapib on an industrial scale there is a need for further improved manufacturing processes which involve less processing steps, improved intermediates having high enantiopurity, and improved overall yield.3. SUMMARY OF THE DISCLOSURE

[0010] The present disclosure provides for an improved manufacturing process for obicetrapib.

[0011] The present disclosure provides a crystalline intermediate of Formula (VA) useful in the manufacturing process for obicetrapib.

[0012] The present disclosure further provides an improved process for the synthesis of (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (Compound IB), via intermediate compound of Formula (VA), which is prepared in high enantiopurity, without the need for any optical resolution steps.

[0013] The present disclosure provides methods for the manufacture of tetrahydroquinoline derivatives via a one-pot highly enantioselective Povarov process, the manufacture of a crystalline compound of Formula (VA), and the manufacture of obicetrapib (e.g., as the amorphous hemicalcium salt), including intermediates, such as the crystalline compound of Formula (VA).4. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] These and other features, aspects, and advantages of the present disclosure will become better understood with regard to the following description, and accompanying drawings where:

[0015] Figure 1 is an x-ray powder diffraction pattern of crystalline CbzDIAM.

[0016] Figure 2 is a peak-picked x-ray powder diffraction pattern of crystalline CbzDIAM.

[0017] Figure 3 is a differential scanning calorimetry thermogram of crystalline CbzDIAM.5. DETAILED DESCRIPTION

[0018] Provided herein is an enantiopure crystalline compound of Formula (VA) used in the preparation of obicetrapib:

[0019] Formula (VA) may also be referred to as CbzDIAM and crystalline Formula (VA) may be referred to as crystalline CbzDIAM. Also, provided herein are enantiopure crystalline compounds of Formula (V) used in the preparation of obicetrapib:pHNwherein P is a protecting group (e.g., as described herein); R1is H, optionally substituted (C1-6)alkyl, optionally substituted (C1-6)alkylhalide, halide, hydroxy, or optionally substituted (C1-6)alkoxy; and R2is H or optionally substituted(Ci-6)alkyl.

[0020] Crystalline compounds such as crystalline Compound of Formula (VA), for example, may be characterized by x-ray powder diffraction. An x-ray powder diffraction pattern is an x-y graph with °29 (diffraction angle) on the x-axis and intensity on the y-axis. The peaks are usually represented and referred to by their position on the x-axis rather than the intensity of peaks on the y-axis because peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255-257 (2003)). Thus, intensity is not typically used to characterize solid forms. The data from x-ray powder diffraction may be used in multiple ways to characterize crystalline forms. For example, the entire x-ray powder diffraction pattern output from a diffractometer may be used to characterize a crystalline compound of Formula (VA). A smaller subset of such data, however, may also be, and typically is, suitable for characterizing such compounds. For example, a collection of one or more peaks from such a pattern may be used to so characterize these compounds. When the phrase “one or more peaks” of a list of peaks from an x-ray powder diffraction pattern are provided, what is generally meant is that any combination of the peaks listed may be used for characterization. Further, the fact that other peaks are present in the x-ray powder diffraction pattern, generally does not negate or otherwise limit that characterization.

[0021] In addition to the variability in peak intensity, there may also be variability in the position of peaks on the x-axis. This variability can, however, typically be accounted for when reporting the positions of peaks for purposes of characterization. Such variability in the position of peaks along the x-axis may derive from several sources (e.g., sample preparation, particle size, moisture 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 may operate using different parameters and these may lead to slightly different diffraction patterns from the same crystalline solid. Due to such sources of variability, it is common to recite x-ray diffraction peaks using the word “about” prior to the peak value in °29. Forpurposes of data reported herein, that value is generally ±0.2°29 are intended to be reported with such a variability whenever disclosed herein whether the word “about” is present or not. Variability may, in some instances, be higher depending on instrumentation conditions including how well instruments are maintained.

[0022] In some embodiments, crystalline compound of Formula (VA) may be further characterized by an x-ray powder diffraction pattern substantially the same as the x-ray powder pattern as that of Figure 1.

[0023] In some embodiments of the disclosure, there is provided a method of preparing an enantiopure compound of Formula (I) or a salt thereof:wherein:R1is H, optionally substituted (C1-6)alkyl, optionally substituted (C1-6)alkylhalide, halide, hydroxy, or optionally substituted (C1-6)alkoxy; andR2is H or optionally substituted(C1-6)alkyl;comprising the steps of:i) reacting the amine of Formula (II)with an aldehyde according to Formula (III)oH^R2(ill); anda compound of formula (IV)H (IV),wherein P is an amine protecting group,in the presence of a solvent and a chiral catalyst to form an enantiopure compound of formula (V) or a salt thereofH (V); andii) removing the protecting group in the compound of Formula (V) to form an enantiopure compound of formula (I).

[0024] In some embodiments, the method of forming an enantiopure compound of Formula (I) does not require any chiral resolution steps, or any purification steps using chromatography, such as column chromatography to achieve the enantiopurity and chemical purity levels described herein.

[0025] In some embodiments of the disclosure, there is provided a method of preparing a crystalline compound of Formula (VA) or a salt thereof:HN O''3'comprising the steps of:a) reacting the amine of Formula (IIA)with an aldehyde according to Formula (IIIA)(IIIA); anda compound of formula (IVA)in the presence of a solvent and a chiral catalyst to form an enantiopure compound of formula (VA); andb) crystallization of the enantiopure compound of formula (VA) to form a crystalline compound of formula (VA).

[0026] In some embodiments, the method further comprises preparing an enantiopure compound of Formula (IB), wherein the method comprises:c) converting the compound of Formula (VA) to an enantiopure compound of Formula (IB) or a salt thereof:'2

[0027] In some embodiments, the method of forming an enantiopure compound of Formula (VA) and (IB) does not require any chiral resolution steps, or any purification steps using chromatography, such as column chromatography to achieve the enantiopurity and chemical purity levels described herein.

[0028] In some embodiments, there is provided a method of preparing obicetrapib, the method comprising the steps of:a) reacting an amine of Formula (IIA)with an aldehyde according to Formula (IIIA)(IIIA); anda compound of formula (IVA)in the presence of a solvent and a chiral catalyst to form an enantiopure compound of formula (VA)(VA);b) crystallization of the enantiopure compound of formula (VA) to form a crystalline compound of formula (VA) or a salt thereof;c) converting the compound of Formula (VA) to an enantiopure compound of Formula (IB):d) crystallization of the compound of Formula (IB) as a salt;(e) preparing a compound of Formula (VII), by coupling a compound of Formula (IB) or a salt thereof, with a compound of Formula (VI):(f) preparing a carbamate of Formula (VIII) from the compound of Formula (VII) and isolating as a solid salt form of Formula (IX):(VIII) (IX)where Y1is a protecting group, An' is an anion and n is an integer from 1-3;(g) optionally desalting the compound of Formula (IX) and alkylating with a compound of Formula (X) to provide a compound of Formula (XI):C(X) where X2is a leaving group and Y1is a protecting group; and(h) deprotection of the compound of Formula (XI) to provide obicetrapib (1),1wherein the reaction steps (a)-(h) are performed in an organic solvent, compounds (VII), (IX), and (XI) are optionally not isolated from the organic solvent, and wherein the method does not require chromatography.

[0029] The reactions in steps (a)-(d) of the subject methods are performed in an organic solvent, and the methods do not require any chiral resolution steps. The subject methods also do not need to comprise purification steps using chromatography, such as column chromatography to achieve the chemical purity levels described herein.

[0030] Further, the reactions in steps (e)-(h) of the subject method are performed in a solvent, and compounds of Formulae (VII), (VIII) and (XI) do not need to be isolated from their respective solvents if they are to be processed further to end products. This means that any solvent swap between reaction steps (x) and (x+1) takes places by evaporating at least part of the solvent used in step (x) and by gradually adding the solvent of step (x+1), such that the compound remains in solution during the solvent swap. The intermediate compound of Formula (IX) may be isolated from the solvent as a salt in solid form, such that it can be washedto remove impurities. This isolation step ensures sufficient purity of downstream products. The subject process does not need to comprise purification steps using chromatography, such as column chromatography to achieve the chemical purity levels described herein.Method of Preparing tetrahydroquinoline derivatives of Formula (I)

[0031] In some embodiments, there is provided improved methods for the synthesis of enantiopure tetrahydroquinoline derivatives of Formula (I) or a salt thereof:wherein:R1is H, optionally substituted (C1-6)alkyl, optionally substituted (C1-6)alkylhalide, halide, hydroxy, or optionally substituted (C1-6)alkoxy; andR2is H or optionally substituted(C1-6)alkyl;

[0032] The improved process for the synthesis of enantiopure compounds of Formula (I) is carried out in two synthetic steps and does not involve any chiral resolution steps or column chromatography.

[0033] In step (i) of the process for preparing a compound of Formula (I) according to the present disclosure, the compound of Formula (II), is reacted with an aldehyde of Formula (III) and a compound of Formula (IV) in the presence of a solvent and a chiral catalyst to form an enantiopure compound of Formula (V) (where P is an amine protecting group, e.g., as described herein). In some embodiments of step (i), the amount of the aldehyde of Formula (III) present in the reaction mixture is greater that of the amount of the compound of Formula (IV). In some embodiments of step (i), the amount of the aldehyde of Formula (III) present in the reaction mixture is at least twice the amount of the compound of Formula (IV). In some embodiments of step (i), the ratio of reagent (II): (III): (IV) is 1: 3: 1.2. In some embodiments of step (i), the ratio of reagent (II): (III): (IV) is 1: 2.5: 1.1. In some embodiments of step (i), the ratio of reagent (II): (III): (IV) is 1: 2.5: 1.2. In some embodiments of step (i), the ratio of reagent (II): (III): (IV) is 1: 1.5: 1.2. In some embodiments of step (i), the ratio of reagent (II): (III): (IV) is 1: 1.5: 1.o chiral catalystH(III) (IV)

[0034] In step (i) of the process, use is made of a so-called three component Povarov reaction. A key step in the process is the formation of an enantiopure Povarov product according to Formula (V) where, P is an amine protecting group; R1is H, optionally substituted (C1-6)alkyl, optionally substituted (C1-6)alkylhalide, halide, hydroxy, or optionally substituted (C1-6)alkoxy; and R2is H or optionally substituted(Ci-6)alkyl.

[0035] In some embodiments, the enantiopure Povarov product of Formula (V) is the 2R,4S-enantiomer having the Formula (VB):HN

[0036] In some embodiments, the compound of Formula (VB) is obtained with greater than 99% enantiopurity, such as greater than 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or greater than 99.9%. In some embodiments, the compound of Formula (VB) is obtained in 99.9% enantiomeric excess (e.e.) or more, such as 99.91% e.e., 99.92% e.e., 99.93% e.e., 99.94% e.e., 99.95% e.e., 99.96% e.e., 99.97% e.e., 99.98% e.e., or 99.99% e.e.

[0037] In some embodiments, the compound of Formula (VB) has a purity of 98% or more, such as 98.5% or more, 99% or more, 99.5% or more, or even more. In some embodiments, the compound of Formula (VB) has a purity of 99.9%.

[0038] In some embodiments of step (i), the chiral catalyst is a chiral Bronsted acid catalyst. In some embodiments, the chiral Bronsted acid catalyst comprises any one of:wherein:R is H, alkyl, cycloalkyl, heterocyclyl, heteroaryl, halogen, alkoxy, aryl, NO2, silyl, where any of the R groups are optionally further substituted;Ar is an optionally substituted aryl or an optionally substituted heteroaryl group; and BArF24is tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.

[0039] In some embodiments, the chiral Bronsted acid catalyst comprises any one of:wherein:each R is independently H, alkyl, cycloalkyl, heterocyclyl, heteroaryl, halogen, alkoxy, aryl, NO2, silyl, where any of the R groups are optionally further substituted;Tf is triflate (-OSO2CF3); andeach RAis (-)-menthyl.

[0040] In some embodiments of step (i), the chiral catalyst is a weakly acidic species, such as a diol, or a (thio)urea.

[0041] In some embodiments, the chiral catalyst is a chiral carboxylic acid. In some embodiments, the chiral carboxylic acid catalyst is selected from a catalyst disclosed in Min et al, Chem. Soc. Rev., 2017, 46, 5889-5902.

[0042] In some embodiments, the chiral catalyst is a tartaric acid, or a derivative thereof.

[0043] In some embodiments, the chiral catalyst is a N-protected amino acid, such as an N-protected proline derivative (e.g., a A-formyl-a'-aryl-L-proline derivative, or an N-acyl-L-proline derivative).

[0044] In some embodiments, the chiral catalyst is an a-hydroxy carboxylic acid.

[0045] In some embodiments, the chiral catalyst is an axially chiral dicarboxylic acid. In some embodiments, the chiral catalyst is an axially chiral hydroxyl carboxylic acid.

[0046] In some embodiments, the chiral catalyst is a chiral borylbenzoic acid.

[0047] In some embodiments, the chiral catalyst is a conjugate-base-stabilized chiral carboxylic acid.

[0048] In some embodiments, the chiral catalyst is a phosphoric acid.

[0049] In some embodiments of step (i), the chiral catalyst is a BINOL derived chiral catalyst. In some embodiments, the chiral catalyst is a chiral BINOL-based phosphoric acid catalyst (e.g., (R)-TRIP, (S)-TRIP, (R)-TiPSY, (S)-TiPSY etc.). In some embodiments, the chiral BINOL-based phosphoric acid catalyst is selected from a catalyst disclosed in Parmar, Chem. Rev. 114, 9047-9153 (2014).

[0050] In some embodiments of step (i), the chiral catalyst is one of the following BINOL-phosphoric acid (PA) catalysts:RR PA 1, R = H PA 10, R = H PA 20, R = CF3PA 2, R = SiPh3PA 11, R =fBu PA21, R = SFsPA 3, R = Si(4-tBuC6H4)3PA 12, R = F PA 22, R = Ph PA 4, R = adamanthyl PA 13, R = Cl PA 23, R = 2,4,6-(Me)3C6H2PA 5, R = 1 -naphthyl PA 14, R = OMe PA 6, R = 2-naphthyl PA 15, R = NO2PA 7, R = 9-anthracenyl PA 16, R - Ph PA 8, R = 9-phenanthryl PA 17, R = 3,5-(CF3)2C6H3PA 9, R = 1-pyrenyl PA 18, R = 2,3,4,5,6-F5C6PA 19, R = 2-naphthylPA 24, R = Me PA 26, R1= Me, R2= OMe PA 30, R = / Pr, X = I PA 25, R = / Pr PA 27, R1= / Pr, R2= tBu PA 31, R = / Pr, X = NO2PA 28, R1= / Pr, R2= 4-tBuC6H4PA 32, R = Pr, X = Si( / Pr)3PA 29, R1= / Pr, R2= 9-anthracenyl PA 33, R = / Pr, X = C8H17

[0051] In some embodiments, the catalyst is (R)-3,3'-Bis(2,4,6-triisopropylphenyl)-l,l'-binaphthyl-2,2'-diyl hydrogenphosphate (R)-TRIP:CH3CH3(R)-TRIP

[0052] In some embodiments of step (i), the chiral catalyst loading is 1 mol% or less, such as 0.9 mol% or less, 0.8 mol% or less, 0.7 mol% or less, 0.6 mol% or less, 0.5 mol% or less, or even less. In some embodiments of step (i), the chiral catalyst loading is 0.5 mol% or less, such as 0.4 mol% or less, 0.3 mol% or less, 0.2 mol% or less, 0.1 mol% or less, 0.09 mol% or less, 0.08 mol% or less, 0.07 mol% or less, 0.06 mol% or less, or even less. In some embodiments of step (i), the catalyst loading is 0.1 mol%. In some embodiments of step (i), the catalyst loading is 0.05 mol%.

[0053] In some embodiments, step (i) is carried out in a suitable solvent. Such solvent may be an organic solvent. In some embodiments, the organic solvent used in step (i) comprises a mixture of a solvents. In some embodiments, the solvent is selected from one or more of methanol, ethanol, isopropanol, 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-diflurobenzene, toluene, and hexafluoroisopropanol. In some embodiments, the solvent is isopropyl acetate (IP AC). In some embodiments, the solvent is tetrahydrofuran (THF).

[0054] In some embodiments, step (i) further includes the addition of a dehydrating agent. Any convenient dehydrating agent may find use in step (i). In some embodiments, the dehydrating agent comprises molecular sieves. In some embodiments, the dehydrating agent is 3 A molecular sieve powder. In some embodiments, the molecular sieves are added to the solventand the pH is adjusted to between 9.5-10.5 before addition of one or more of the reagents in step (i). In some embodiments, the pH is adjusted to between 9.5-10.4, 9.5-10.3, 9.5 to 10.2, 9.5-10.1 or 9.5-10.0. In some embodiments, the pH is adjusted to between 9.6-10.5, 9.7-10.5, 9.8-10.5, 9.9-10.5, or 10.0-10.5. In some embodiments, the pH is adjusted to between 9.7-10.1.

[0055] In some embodiments, the reaction in step (i) is conducted at a temperature from -25 °C to 20 °C. In some embodiments, the reaction in step (i) is conducted at a temperature from -15 °C to 20 °C. In some embodiments, the reaction in step (i) is conducted at about -5 °C. In some embodiments, the reaction in step (i) is conducted at -5 °C. In some embodiments, the reaction in step (i) is conducted at a temperature of -5 °C or less. In some embodiments, step (i) comprises simultaneously adding a compound of Formula (II) and a compound of Formula (IV) to a compound of Formula (III) at -5 °C or less in the presence of a chiral catalyst (e.g., (R)-TRIP), ensuring that the temperature stays at -5 ° C or less. The reaction mixture held at -5 ° C or less until a compound of Formula (V) is obtained, or as deemed complete by an in process control (IPC) assay. In some embodiments, the reaction mixture is held at -5 ° C or less for at least 1 hour, then warmed up to about 20 ° C.

[0056] In some embodiments, the reaction in step (i) is conducted at a temperature from -10 °C to -20 °C. In some embodiments, step (i) involves forming a solution of a compound of Formula (III), optionally containing a desiccant, and cooling to -15 °C, then simultaneously adding a solution containing a compound of Formula (II) and a chiral catalyst (e.g., (R)-TRIP), and a separate solution of a compound of Formula (IV). The reaction mixture is held at a temperature from -15 °C to -20 °C for two hours until a compound of Formula (V) is obtained, or as deemed complete by an in process control (IPC) assay. In some embodiments, the solutions of the compounds of Formula (III), (II) and (IV) comprise isopropyl acetate (IP AC) as solvent. In some embodiments, the solution of the compound of Formula (III) is made by first adding molecular sieves to a solvent (e.g., IP AC), adjusting the pH to between 9.5 and 10.5 (such as 9.7 to 10.1), then adding the compound of Formula (III). In some embodiments, the compound of Formula (IV) is a solution in IP AC, and the solution is filtered and dried azeotropically to remove residual water before addition to the solution of the compound of Formula (III). In some embodiments, the solution containing the compound of Formula (II) and the chiral catalyst, and the solution of Formula (IV) are simultaneously added to the solution of a compound of Formula (III) over a period of 2 hours or more, such as 2.5 hours or more, 3 hours or more, 3.5 hours or more, 4 hours or more, 4.5 hours or more, 5 hours or more, 5.5 hours or more, 6 hours or more, 6.5 hours or more, 7 hours or more, 7.5 hours or more, 8hours or more, 8.5 hours or more, 9 hours or more, 9.5 hours or more, 10 hours or more, 10.5 hours or more, 11 hours or more, 11.5 hours or more, or 12 hours or even more. In some embodiments, the solution containing the compound of Formula (II) is added over a time period that is at least twice the addition time for the solution of Formula (IV) to the solution of the compound of Formula (III). In some embodiments, the solution of Formula (II) and the chiral catalyst is added over 2 hours or more, and the solution of Formula (IV) is added over 4 hours or more to the solution of the compound of Formula (III). In some embodiments, the solution of Formula (II) and the chiral catalyst is added over 3 hours or more, and the solution of Formula (IV) is added over 6 hours or more to the solution of the compound of Formula (III). In some embodiments, the solution of Formula (II) and the chiral catalyst is added over 6 hours or more, and the solution of Formula (IV) is added over 12 hours or more to the solution of the compound of Formula (III).

[0057] In some embodiments, the compound of Formula (V) formed in step (i) is subjected to a crystallization step. In some embodiments, the compound of Formula (V) is crystallized in a mixture of isopropyl acetate and a non-polar solvent. In some embodiments, the non-polar solvent comprises one or more alkanes. In some embodiments, the non-polar solvent comprises heptane. In some embodiments, the non-polar solvent is an alkane. In some embodiments, the non-polar solvent is heptane. In some embodiments, the non-polar solvent is n-heptane. In some embodiments, the ratio of non-polar solvent to IP AC is from 1:4 to 1:10. In some embodiments, the ratio of non-polar solvent to IP AC is 1:4. In some embodiments, the ratio of non-polar solvent to IP AC is 1:5. In some embodiments, the ratio of non-polar solvent to IP AC is 1:6. In some embodiments, the ratio of non-polar solvent to IP AC is 1:7. In some embodiments, the ratio of non-polar solvent to IP AC is 1:8. In some embodiments, the ratio of non-polar solvent to IP AC is 1:9. In some embodiments, the ratio of non-polar solvent to IP AC is 1:10.

[0058] In step (ii) of the process, the protecting group (P) is removed from the compound of Formula (V) to obtain an enantiopure compound of Formula (I). It will be understood that any convenient protecting group for an amino moiety may find use in the present disclosure for P, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis, 4thEd., by T. W. Greene and P. G. M. Wuts (John Wiley & Sons, New York, 1999), in Protecting Group Chemistry, 1st Ed., by Jeremy Robertson (Oxford University Press, 2000); and in March's Advanced Organicchemistry: Reactions Mechanisms, and Structure, 8th Ed., by Michael B. Smith (Wiley-Interscience Publication, 2001). In some embodiments of Formula (V), P is an amine protecting group selected from benzyloxycarbonyl (Cbz), tertiary butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), and formyl (CHO).

[0059] In some embodiments of Formula (V), P is a Cbz group, and step (ii) proceeds via a hydrogenation reaction (e.g., by catalytic hydrogenation with a palladium catalyst and hydrogen gas) to obtain the compound of Formula (I). In some embodiments, the hydrogenation reaction is carried out by treatment with palladium on carbon (Pd-C) catalyst and hydrogen gas. In some embodiments, the hydrogenation reaction is carried out by treatment with palladium on alumina (Pd / Al2O3) catalyst and hydrogen gas. In some embodiments, the catalyst loading is 5% or less, such as 4% or less, 3% or less, or even less.

[0060] In some embodiments of Formula (V), P is a Boc group, and step (ii) proceeds via treatment with an acid (e.g., trifluoroacetic acid, or hydrochloric acid) to obtain the compound of Formula (I).

[0061] In some embodiments of Formula (V), P is a Fmoc group, and step (ii) proceeds via treatment with a secondary amine (e.g., piperidine, or cyclohexylamine) to obtain the compound of Formula (I).

[0062] In some embodiments of Formula (V), P is an Alloc group, and step (ii) proceeds via a palladium-catalyzed reaction (e.g., with Pd(PPhs)4) to obtain the compound of Formula (I).

[0063] In some embodiments of Formula (V), P is a formyl group, and step (ii) proceeds via a hydrolysis reaction (e.g., acid promoted hydrolysis, or base promoted hydrolysis).

[0064] In some embodiments, the enantiopure compound of Formula (I) is the 2R,4S-enantiomer having the Formula (IA) or a salt thereof:

[0065] In some embodiments, the compound of Formula (IA) is obtained with greater than 99% enantiopurity, such as greater than 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or greater than 99.9%. In some embodiments, the compound of Formula (IA) is obtained in 99.9% enantiomeric excess (e.e.) or more, such as 99.91% e.e., 99.92% e.e., 99.93% e.e., 99.94% e.e., 99.95% e.e., 99.96% e.e., 99.97% e.e., 99.98% e.e., or 99.99% e.e.

[0066] In some embodiments, the compound of Formula (IA) has a purity of 98% or more, such as 98.5% or more, 99% or more, 99.5% or more, or even more. In some embodiments, the compound of Formula (IA) has a purity of 99.9%.

[0067] In some embodiments, the compound of Formula (I), (IA), (V) or (VB), R1is H, (Ci-Cs)alkyl, (Ci-C3)alkylhalide, halide, hydroxy, or (Ci-C3)alkoxy. In some embodiments, R1is (Ci-C3)alkylhalide. In some embodiments, R1is CF3.

[0068] In some embodiments, the compound of Formula (I), (IA), (V) or (VB), R2is methyl, ethyl or propyl. In some embodiments, R2is methyl. In some embodiments, R2is ethyl. In some embodiments, R2is propyl.

[0069] In some embodiments of Formula (I), (IA), (V) or (VB), R1is CF3 and R2is ethyl.

[0070] In some embodiments the compound of Formula (V) obtained from step (i) is of the Formula (VA) or a salt thereof:

[0071] In some embodiments, the compound of Formula (VA) is crystalline.

[0072] In some embodiments, the compound of Formula (VA) is obtained from step (i) in a yield of at least 80%, such as at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, or at least 90%. In some embodiments the compound of Formula (VA) is obtained from step (i) in a yield of 85% or more.

[0073] In some embodiments, the compound of Formula (VA) is obtained with greater than 99% enantiopurity, such as greater than 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or greater than 99.9%. In some embodiments, the compound of Formula (VA) is obtained in 99.9% enantiomeric excess (e.e.) or more, such as 99.91% e.e., 99.92% e.e., 99.93% e.e., 99.94% e.e., 99.95% e.e., 99.96% e.e., 99.97% e.e., 99.98% e.e., or 99.99% e.e.

[0074] In some embodiments, the compound of Formula (VA) has a purity of 98% or more, such as 98.5% or more, 99% or more, 99.5% or more, or even more. In some embodiments, the compound of Formula (VA) has a purity of 99.9%.

[0075] In some embodiments the compound of Formula (I) obtained from step (ii) is of the Formula (IB) or a salt thereof:

[0076] In some embodiments, the compound of Formula (IB) is crystalline.

[0077] In some embodiments, the compound of Formula (IB) is obtained from step (ii) in a yield of at least 80%, such as at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, or at least 90%. In some embodiments the compound of Formula (IB) is obtained from step (ii) in a yield of 85% or more.

[0078] In some embodiments, the compound of Formula (IB) is obtained with greater than 99% enantiopurity, such as greater than 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or greater than 99.9%. In some embodiments, the compound of Formula (IB) is obtained in 99.9% enantiomeric excess (e.e.) or more, such as 99.91% e.e., 99.92% e.e., 99.93% e.e., 99.94% e.e., 99.95% e.e., 99.96% e.e., 99.97% e.e., 99.98% e.e., or 99.99% e.e.

[0079] In some embodiments, the compound of Formula (IB) has a purity of 98% or more, such as 98.5% or more, 99% or more, 99.5% or more, or even more. In some embodiments, the compound of Formula (IB) has a purity of 99.9%.

[0080] In some embodiments, the compound of Formula (I), (IA) or (IB) is isolated as a salt. In some embodiments, the salt is selected from a sulfonate, a sulfate, a halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate; wherein the sulfonate may be a besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate; the sulfate may be a methylsulfate; and the halogen may be a chloride, iodide, or bromide.

[0081] In some embodiments, the compound of Formula (I), (IA) or (IB) is isolated as a salt selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate. In some embodiments, the salt is selected from chloride, bromide, bitartrate, and mesylate.

[0082] In some embodiments, the compound of Formula (I), (IA), or (IB) is isolated as a mesylate salt.Method of Preparing a compound of Formula (VA) – Steps (a)-(b)

[0083] In some embodiments, there is provided a method of preparing a crystalline compound of Formula (VA) or a salt thereof:

[0084] The process for the synthesis of a crystalline compound of Formula (VA) does not involve any chiral resolution steps or column chromatography and is highly enantioselective.

[0085] In step (a) of the process for preparing a compound of Formula (VA) according to the present disclosure, the compound of Formula (IIA), is reacted with an aldehyde of Formula (IIIA) and a compound of Formula (IVA) in the presence of a solvent and a chiral catalyst to form an enantiopure compound of Formula (VA). In some embodiments of step (i), the amount of the aldehyde of Formula (III) present in the reaction mixture is greater that of the amount of the compound of Formula (IV). In some embodiments of step (i), the amount of the aldehyde of Formula (III) present in the reaction mixture is at least twice the amount of the compound of Formula (IV). In some embodiments of step (a), the ratio of reagent (IIA): (IIIA): (IVA) is 1: 3: 1.2. In some embodiments of step (i), the ratio of reagent (II): (III): (IV) is 1: 2.5:1.1. In some embodiments of step (i), the ratio of reagent (II): (III): (IV) is 1: 2.5: 1.2. In some embodiments of step (i), the ratio of reagent (II): (III): (IV) is 1: 1.5: 1.2. In some embodiments of step (i), the ratio of reagent (II): (III): (IV) is 1: 1.5: 1.o(IIIA)

[0086] In step (a) of the process, use is made of a so-called three component Povarov reaction.A key step in the process is the formation of an enantiopure Povarov product according to Formula (VA).

[0087] In step (b), the enantiopure compound of Formula (VA) is subjected to a crystallization step to obtain a crystalline compound of Formula (VA).

[0088] In some embodiments, the crystalline compound of Formula (VA) is obtained in a yield of at least 80%, such as at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, or at least 90%. In some embodiments the compound of Formula (VA) is obtained in a yield of 85% or more.

[0089] In some embodiments, the crystalline compound of Formula (VA) is obtained with greater than 99% enantiopurity, such as greater than 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or greater than 99.9%. In some embodiments, the compound of Formula (VA) is obtained in 99.9% enantiomeric excess (e.e.) or more, such as 99.91% e.e., 99.92% e.e., 99.93% e.e., 99.94% e.e., 99.95% e.e., 99.96% e.e., 99.97% e.e., 99.98% e.e., or 99.99% e.e.

[0090] In some embodiments, the crystalline compound of Formula (VA) has a purity of 98% or more, such as 98.5% or more, 99% or more, 99.5% or more, or even more. In some embodiments, the crystalline compound of Formula (VA) has a purity of 99.9%.

[0091] In some embodiments of step (a), the chiral catalyst is a chiral Bronsted acid catalyst (e.g., as described herein).

[0092] In some embodiments of step (a), the chiral catalyst is a weakly acidic species, such as a diol, or a (thio)urea.

[0093] In some embodiments of step (a), the chiral catalyst is a chiral carboxylic acid (e.g., as described herein).

[0094] In some embodiments, the chiral catalyst is a tartaric acid, or a derivative thereof. In some embodiments, the chiral catalyst is a N-protected amino acid, such as an N-protected proline derivative (e.g., a V-formyl-a'-aryl-L-proline derivative, or an N-acyl-L-proline derivative). In some embodiments, the chiral catalyst is an a-hydroxy carboxylic acid. In some embodiments, the chiral catalyst is an axially chiral dicarboxylic acid. In some embodiments, the chiral catalyst is an axially chiral hydroxyl carboxylic acid. In some embodiments, the chiral catalyst is a chiral borylbenzoic acid. In some embodiments, the chiral catalyst is a conjugate-base-stabilized chiral carboxylic acid.

[0095] In some embodiments, the chiral catalyst is a phosphoric acid. In some embodiments, chiral catalyst is a BINOL derived chiral phosphoric acid (e.g., (R)-TRIP, (S)-TRIP, (R)-TiPSY, (S)-TiPSY etc. (preferably (R)-TRIP). In some embodiments, the chiral catalyst is a chiral BINOL-based phosphoric acid catalyst, as described herein above.

[0096] In some embodiments of step (a), the catalyst is (R)-3,3'-Bis(2,4,6-triisopropylphenyl)-l,l'-binaphthyl-2,2'-diyl hydrogenphosphate ((R)-TRIP).

[0097] In some embodiments of step (a), the chiral catalyst loading is 1 mol% or less, such as 0.9 mol% or less, 0.8 mol% or less, 0.7 mol% or less, 0.6 mol% or less, 0.5 mol% or less, or even less. In some embodiments of step (i), the chiral catalyst loading is 0.5 mol% or less, such as 0.4 mol% or less, 0.3 mol% or less, 0.2 mol% or less, 0.1 mol% or less, 0.09 mol% or less, 0.08 mol% or less, 0.07 mol% or less, 0.06 mol% or less, or even less. In some embodiments of step (i), the catalyst loading is 0.1 mol%. In some embodiments of step (i), the catalyst loading is 0.05 mol%.

[0098] In some embodiments, step (a) is carried out in a suitable solvent. Such solvent may be an organic solvent. In some embodiments, the organic solvent used in step (a) comprises a mixture of a solvents. In some embodiments, the solvent is selected from one or more of methanol, ethanol, isopropanol, 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-diflurobenzene, toluene, and hexafluoroisopropanol. In some embodiments, the solvent is isopropyl acetate (IP AC). In some embodiments, the solvent is tetrahydrofuran (THF).

[0099] In some embodiments, step (a) further includes the addition of a dehydrating agent. Any convenient dehydrating agent may find use in step (a). In some embodiments, the dehydrating agent comprises molecular sieves. In some embodiments, the dehydrating agent is 3 A molecular sieve powder. In some embodiments, the molecular sieves are added to the solvent and the pH is adjusted to between 9.5-10.5 before addition of one or more of the reagents in step (i). In some embodiments, the pH is adjusted to between 9.5-10.4, 9.5-10.3, 9.5 to 10.2, 9.5-10.1 or 9.5-10.0. In some embodiments, the pH is adjusted to between 9.6-10.5, 9.7-10.5, 9.8-10.5, 9.9-10.5, or 10.0-10.5. In some embodiments, the pH is adjusted to between 9.7-10.1.

[0100] In some embodiments, the reaction in step (a) is conducted at a temperature from -25 °C to 20 °C. In some embodiments, the reaction in step (a) is conducted at a temperature from -15 °C to 20 °C. In some embodiments, the reaction in step (a) is conducted at about -5 °C. In some embodiments, the reaction in step (a) is conducted at -5 °C. In some embodiments, the reaction in step (a) is conducted at a temperature of -5 °C or less. In some embodiments, step (a) comprises simultaneously adding a compound of Formula (IIA) and a compound of Formula (IVA) to a compound of Formula (IIIA) at -5 °C or less in the presence of a chiral catalyst (e.g., (R)-TRIP), ensuring that the temperature stays at -5 ° C or less. The reaction mixture held at -5 ° C or less until a compound of Formula (VA) is obtained, or as deemed complete by an in process control (IPC) assay. In some embodiments, the reaction mixture is held at -5 ° C or for at least 1 hour, then warmed up to about 20 ° C.

[0101] In some embodiments, the reaction in step (a) is conducted at a temperature from -10 °C to -20 °C. In some embodiments, step (a) involves forming a solution of a compound of Formula (IIIA), optionally containing a desiccant, and cooling to -15 °C, then simultaneously adding a solution containing a compound of Formula (IIA) and a chiral catalyst (e.g., (R)-TRIP), and a separate solution of a compound of Formula (IVA). The reaction mixture is held at a temperature from -15 °C to -20 °C for two hours until a compound of Formula (VA) is obtained, or as deemed complete by an in process control (IPC) assay. In some embodiments, the solutions of the compounds of Formula (IIIA), (IIA) and (IVA) comprise isopropyl acetate (IP AC) as solvent. In some embodiments, the solution of the compound of Formula (IIIA) is made by first adding molecular sieves to a solvent (e.g., IP AC), adjusting the pH to between 9.5 and 10.5 (such as 9.7 to 10.1), then adding the compound of Formula (IIIA). In some embodiments, the compound of Formula (IVA) is a solution in IP AC, and the solution is filtered and dried azeotropically to remove residual water before addition to the solution of the compound of Formula (IIIA). In some embodiments, the solution containing the compound of Formula (IIA) and the chiral catalyst, and the solution of Formula (IVA) and simultaneously added to the solution of a compound of Formula (IIIA) over a period of 2 hours or more, such as 2.5 hours or more, 3 hours or more, 3.5 hours or more, 4 hours or more, 4.5 hours or more, 5 hours or more, 5.5 hours or more, 6 hours or more, 7 hours or more, 7.5 hours or more, 8 hours or more, 8.5 hours or more, 9 hours or more, 9.5 hours or more, 10 hours or more, 10.5 hours or more, 11 hours or more, 11.5 hours or more, or 12 hours or even more. In some embodiments, the solution containing the compound of Formula (IIA) is added over a time period that is at least twice the addition time for the solution of Formula (IVA) to the solutionof the compound of Formula (IIIA). In some embodiments, the solution of Formula (IIA) and the chiral catalyst is added over 2 hours or more, and the solution of Formula (IVA) is added over 4 hours or more to the solution of the compound of Formula (IIIA). In some embodiments, the solution of Formula (IIA) and the chiral catalyst is added over 3 hours or more, and the solution of Formula (IVA) is added over 6 hours or more to the solution of the compound of Formula (IIIA). In some embodiments, the solution of Formula (IIA) and the chiral catalyst is added over 6 hours or more, and the solution of Formula (IVA) is added over 12 hours or more to the solution of the compound of Formula (IIIA).

[0102] If step (a) is performed in an organic solvent different from the organic solvent used in step (b), the organic solvent used in step (a) is swapped in step (a) with the organic solvent applied in step (b), such that the compound of Formula (VA) remains in solution.

[0103] In some embodiments where the organic solvents used in steps (a) and (b) are different, at least part of the organic solvent used in step (a) is evaporated, such as by distillation at reduced pressure, and the organic solvent of step (b) is added, such that the compound of Formula (VA) remains in solution during the organic solvent swap. This process can be performed by continuously evaporating the organic solvent used in step (a) and by continuously adding the organic solvent of step (b), for example until the amount of the organic solvent used in step (a), based on the total amount of organic solvent, is below a certain threshold value. Alternatively, this process can be performed batch-wise in more than one steps of evaporating part of the organic solvent used in step (a) and subsequently adding part of the organic solvent used in step (b), for example until the amount of the organic solvent used in step (a), based on the total amount of organic solvent, is below a certain threshold value.

[0104] In some embodiments, the compound of Formula (VA) is crystallized in step (b) in mixture of isopropyl acetate and a non-polar solvent. In some embodiments, the non-polar solvent comprises one or more alkanes. In some embodiments, the non-polar solvent comprises heptane. In some embodiments, the non-polar solvent is an alkane. In some embodiments, the non-polar solvent is heptane. In some embodiments, the ratio of non-polar solvent to IP AC is from 1:4 to 1: 10. In some embodiments, the ratio of non-polar solvent to IP AC is 1:4. In some embodiments, the ratio of non-polar solvent to IP AC is 1: 5. In some embodiments, the ratio of non-polar solvent to IP AC is 1:6. In some embodiments, the ratio of non-polar solvent to IP AC is 1:7. In some embodiments, the ratio of non-polar solvent to IP AC is 1:8. In some embodiments, the ratio of non-polar solvent to IP AC is 1:9. In some embodiments, the ratio of non-polar solvent to IP AC is 1:10.Method of Preparing a compound of Formula (IB) – Steps (c)-(d)

[0105] In some embodiments, there is further provided step (c) for converting the crystalline compound of Formula (VA) to an enantiopure compound of Formula (IB) or a salt thereof:

[0106] The process for the synthesis of an enantiopure compound of Formula (IB) does not involve any chiral resolution steps or column chromatography and is highly enantioselective.

[0107] In some embodiments, step (c) proceeds via a hydrogenation reaction (e.g., by catalytic hydrogenation with a palladium catalyst and hydrogen gas) to obtain the compound of Formula (IB). In some embodiments, the hydrogenation reaction is carried out by treatment with palladium on carbon (Pd-C) catalyst and hydrogen gas. In some embodiments, the hydrogenation reaction is carried out by treatment with palladium on alumina (Pd / Al2O3) catalyst and hydrogen gas. In some embodiments, the catalyst loading is 5% or less, such as 4% or less, 3% or less, or even less. In some embodiments, the catalyst loading is 3%.

[0108] In some embodiments, step (c) is carried out in at least one organic solvent. In some embodiments, step (c) is carried out in a mixture of organic solvents. In some embodiments, the solvent is selected from one or more of methanol, ethanol, isopropanol, isopropyl acetate (IPAC), acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran (THF), methyl t-butyl ether, cyclopentyl methyl ether, N-methyl-2-pyrrolidone, dimethyl sulfoxide, dimethylformamide, 2-methyl-tetrahydrofuran, di chloromethane, 1,4-di oxane, 1,2-diflurobenzene, toluene, and hexafluoroisopropanol. In some embodiments, the solvent is a 1: 1 mixture of THF and IPAC. In some embodiments, the solvent is a 1: 1 mixture of THF and isopropanol (IP A). In some embodiments, the solvent is IPA.

[0109] If step (c) is performed in an organic solvent different from the organic solvent used in step (d), the organic solvent used in step (c) is swapped in step (c) with the organic solvent applied in step (d) such that the compound of Formula (IB) remains in solution.

[0110] In some embodiments, wherein the organic solvents used in steps (c) and (d) are different, at least part of the organic solvent used in step (c) is evaporated, preferably using distillation at reduced pressure, and the organic solvent of step (d) is added, such that the compound of Formula (IB) remains in solution during the organic solvent swap. This processcan be performed by continuously evaporating the organic solvent used in step (c) and by continuously adding the organic solvent of step (d), for example until the amount of the organic solvent used in step (c), based on the total amount of organic solvent, is below a certain threshold value. Alternatively, this process can be performed batch-wise in more than one steps of evaporating part of the organic solvent used in step (c) and subsequently adding part of the organic solvent used in step (d), for example until the amount of the organic solvent used in step (c), based on the total amount of organic solvent, is below a certain threshold value.

[0111] In some embodiments, the method further comprises step (d), crystallization of the compound of Formula (IB) as a salt. In some embodiments of step (d), the salt of Formula (IB) is obtained as a compound of Formula (IC) or (ID):

[0112] In some embodiments, the salt with an anion Am' is selected from a sulfonate, a sulfate, a halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate; wherein the sulfonate may be a besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate; the sulfate may be a methylsulfate; and the halogen may be a chloride, iodide, or bromide.

[0113] In some embodiments, the salt with an anion Am' selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate. In some embodiments, the salt is selected from chloride, bromide, bitartrate, and mesylate.

[0114] In some embodiments, the salt with an anion Am' is mesylate, and has the structure of compound 1A:

[0115] In some embodiments, step (d) is carried out in one organic solvent. In some embodiments, step (d) is carried out in a mixture of organic solvents. In some embodiments, the solvent is selected from one or more of methanol, ethanol, isopropanol, isopropyl acetate (IPAC), acetonitrile, acetone, methyl isobutyl ketone, isopropyl acetate, tetrahydrofuran (THF), di chloromethane, toluene, hexane and heptane. In some embodiments, the solvent is IPAC.

[0116] In some embodiments, the compound of Formula (IB) or compound 1A, is obtained with greater than 99% enantiopurity, such as greater than 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or greater than 99.9%. In some embodiments, the compound of Formula (IB) or compound 1 A, is obtained in 99.9% enantiomeric excess (e.e.) or more, such as 99.91% e.e., 99.92% e.e., 99.93% e.e., 99.94% e.e., 99.95% e.e., 99.96% e.e., 99.97% e.e., 99.98% e.e., or 99.99% e.e.

[0117] In some embodiments, the compound of Formula (IB) or compound 1 A, has a purity of 98% or more, such as 98.5% or more, 99% or more, 99.5% or more, or even more. In some embodiments, the compound of Formula (IB) or compound 1 A, has a purity of 99.9%.

[0118] In some embodiments, the enantiopure compound of Formula (IB) or compound 1 A, is obtained in an overall yield of at least 70%, such as at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, or at least 70%. In some embodiments enantiopure compound of Formula (IB) or compound 1A is obtained in a yield of 71% or more.Method of Preparing Obicetrapib - Step (e)

[0119] In step (e) of the process for preparing obicetrapib according to the present disclosure, the compound of Formula (IB), or a salt thereof, is coupled with a compound of Formula (VI) to provide a compound of Formula (VII) (where X1is a leaving group and Y1is protecting group, e.g., as described herein).(IB) (VI) (VII)

[0120] Step (e) of the subject method, starts with a compound of Formula (IB) (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline), or a salt thereof.

[0121] The compound of Formula (IB) is obtained using a process as described herein above. In some embodiments the compound of Formula (IB) can be obtained from a corresponding salt that is stable and can be obtained in pure and solid form (e.g., a mesylate salt, of structure 1 A). The solid form can be amorphous or crystalline. In some embodiments, the compound of Formula (IB) is obtained from a corresponding crystalline salt.

[0122] In some embodiments, the compound of Formula (IB) provided in step (e) is a salt of the Formula (IC) or (ID).

[0123] In some embodiments, the compound of Formula (IB) provided in step (e) is a salt of Formula (IC). In some embodiments, the compound of Formula (IC) is used directly in the coupling reaction with the compound of Formula (VI) without performing a desalting step.

[0124] In some embodiments, the compound of Formula (IB) provided in step (e) is a salt of Formula (ID). In some embodiments, the compound of Formula (ID) is used directly in the coupling reaction with the compound of Formula (VI) without performing a desalting step.

[0125] In some embodiments, the compound of Formula (IB) in step (e) is obtained from a salt of Formula (IC) or (ID). In some embodiments, the following steps are carried out before the coupling reaction of step (e):(pre-el) providing a compound of Formula (IC) or (ID):(IC) (ID); and(pre-e2) desalting the compound of Formula (IC) or (ID) to obtain the compound of Formula (IB),wherein the reaction in step (pre-e2) is performed in an organic solvent, the compound of Formula (IB) is not isolated from the organic solvent, and the process does not comprise chromatography.

[0126] In some embodiments, the compound of Formula (IB) in step (e) is obtained from a salt of Formula (IC). In some embodiments, the compound of Formula (IB) in step (e) is obtained from a salt of Formula (ID).

[0127] In some embodiments the salts of Formula (IC) or (ID), are chosen from salts with an anion Am' selected from a sulfonate (e.g., besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate), a sulfate (e.g., methyl sulfate), a halogen (e.g., chloride, iodide, or bromide), acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate.

[0128] In some embodiments the salts of Formula (IC) or (ID), are chosen from salts with an anion Am' selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.

[0129] In some embodiments the salts of Formula (IC) or (ID), are chosen from salts with an anion Am' selected from chloride, bromide, bitartrate, and mesylate.

[0130] In some embodiments of the salts of Formula (IC) or (ID), m is 1.

[0131] In some embodiments the salt is of Formula (IC), and the anion Am' is mesylate, where m is 1 (also referred to herein as compound 1 A).

[0132] In some embodiments, the desalting of a compound of Formula (IC) or (ID) in step (pre-e2) is performed in a mixture of an aqueous sodium hydroxide solution and an organic solvent chosen from toluene, di chloromethane, cyclopentyl methyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, chlorobenzene and combinations thereof, followed by heating the mixture then cooling the mixture, and allowing the system to phase separate, and separating off the aqueous phase. In some embodiments, the solvent is toluene. In some embodiments the reaction mixture isheated to a temperature between 45°C and 60°C, then cooled to a temperature between 15°C and 40°C.

[0133] In some embodiments, the organic phase obtained after separating off the aqueous phase is subjected to one or more aqueous washing steps wherein each aqueous washing step is followed by separating off the aqueous phase, such as one or more washing steps with an aqueous sodium chloride solution, followed by separating off the aqueous phase, and subsequently one or more washing steps with deionized water, again followed by separating off the aqueous phase. The resulting washed organic phase is then optionally subjected to distillation to reduce the water content to below 1000 ppm, based on the weight of the solution. Alternatively, in some embodiments, a small amount of water remains in the organic phase with the compound of Formula (IB) and the subsequent coupling with a compound of Formula (VI) proceeds in the presence of this small amount of water.

[0134] In some embodiments the desalting reaction in step (pre-e2) is performed on the mesylate salt (Compound 1A) in a mixture of an aqueous sodium hydroxide solution and toluene, at a temperature between 45 °C and 60°C, followed by cooling the mixture to a temperature between 15°C and 25°C, allowing the system to phase separate, and separating off the aqueous phase. The toluene phase obtained after separating off the aqueous phase is then optionally subjected to one or more washing steps with an aqueous sodium chloride solution, followed by separating off the aqueous phase, and subsequently one or more washing steps with deionized water, again followed by separating off the aqueous phase, after which the resulting washed toluene phase is subjected to distillation at a temperature between 50°C and 65°C under reduced pressure to reduce the water content to below 1000 ppm, based on the weight of the total amount of the solution. Alternatively, a small amount of water remains in the toluene with the compound of Formula (IB) and the subsequent coupling reaction with a compound of Formula (VI) proceeds in the presence of this small amount of water.

[0135] As outlined above, in step (e) the compound of Formula (IB), or a salt thereof (e.g., compound of Formula (IC) or (ID), such as the mesylate salt 1 A), is coupled with a compound of Formula (VI) to provide a compound of Formula (VII). In some embodiments, this process is carried out in an organic solvent.

[0136] The coupling partner of Formula (VI) in step (e) includes a leaving group (X1). It will be understood that any convenient leaving group may find use in the present disclosure for X1. In some embodiments, the leaving group (X1) in the compound of Formula (VI) is selectedfrom a halogen, a carbamate, and a substituted sulfonyloxy group. In some embodiments, the leaving group (X1) in the compound of Formula (VI) is a sulfonyloxy group selected from a methanesulfonyloxy, / ?-toluenesulfonyloxy or a trifluoromethanesulfonyloxy group. In some embodiments, the leaving group (X1) is a carbamate. In some embodiments, the leaving group (X1) is a halogen. In certain embodiments, the halogen is chloride. The coupling partner of Formula (VI) in step (e) also includes a protecting group (Y1). The term “protecting group” refers to any group which when bound to a functional group such as a carboxylic acid moiety of the compounds (including intermediates thereof) prevents reactions from occurring at the functional group and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the functional group e.g., the carboxylic acid moiety. The particular removable protecting group employed is not critical 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 -di ethylallyl esters, 2,2,2-trifluro ethyl esters, phenyl esters, 4-methoxybenzyl esters, silyl esters, ortho esters, esters of 2, 6-di substituted phenols (e.g., 2,6-dimethylphenol) and any other groups that can be introduced chemically onto a carboxylic acid group or like functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product. It will be understood that any convenient protecting group (e.g., ester group) for a carboxylic acid moiety may find use in the present disclosure for Y1, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis, 4thEd., by T. W. Greene and P. G. M. Wuts (John Wiley & Sons, New York, 1999), in Protecting Group Chemistry, 1st Ed., by Jeremy Robertson (Oxford University Press, 2000); and in March's Advanced Organic chemistry: Reactions Mechanisms, and Structure, 8th Ed., by Michael B. Smith (Wiley-Interscience Publication, 2001). In some embodiments, the protecting group (Y1) 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. In some embodiments, the protecting group (Y1) is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluro ethyl, phenyl, 4-methoxybenzyl ester, a 2,6-disubstituted phenol, and a silyl group. In some embodiments, the protecting group (Y1) is a t-butyl group. In some embodiments, the compound of Formula (VI) is of the structure IB below:o

[0137] In some embodiments of the coupling reaction of step (e), the solvent is selected from toluene, / -butanol, 1,4- dioxane, xylene, N-m ethyl -2 -pyrrolidone, dimethylformamide, water, tetrahydrofuran, and combinations thereof. In some embodiments, the solvent is a mixture of organic solvent toluene and organic co-solvent t- butanol.

[0138] If steps (pre-el) and (pre-e2) are performed before step (e), the compound of Formula (IB) is already present in the required solvent, because the same organic solvents are used in steps (pre-e2) and (e) or because of a solvent swap in step (pre-e2). If need be, more organic solvent and for example an organic co-solvent can be added in step (e). As will be appreciated by the skilled person, an organic co-solvent can also be added during a solvent swap in step (pre-e2). In some embodiments, steps (pre-el) and (pre-e2) are performed before step (e) and the compound of Formula (IB) is present in toluene.

[0139] The coupling reaction in step (e) typically is a catalyzed reaction. In some embodiments, the reaction is a palladium-catalyzed coupling reaction in the presence of a base. Suitable examples of palladium catalysts are for example tris(dibenzylideneacetone)dipalladium and Pd(II)acetate. Suitable bases include organic bases (e.g., sodium z-butoxide, and potassium Z-butoxide) and inorganic bases (e.g., K3PO4, K3PO4·H2O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH, and NaOH).

[0140] In many embodiments, anhydrous K3PO4is used as a base. In many such embodiments, the particle size distribution is such that 90% of the particles are smaller than between about 140 and about 307 microns including between about 140 and about 170 microns, including about 160 and about 290 microns, and about 180 and about 220 microns, and about 200 and about 210 microns. In some embodiments, 90% of the particles are less than 205 microns.

[0141] In these and other embodiments, 50% of the particles are between about 35 and about 173 microns or smaller, including between about 35 and about 40 microns.

[0142] In these and other embodiments, 10% of the particles between about 7 and about 74 microns including between about 7 and about 10 microns.

[0143] In some embodiments, the compound of Formula (IB) is reacted in step (e) with a compound of Formula (VI) in a solvent (e.g., an organic solvent), using a palladium catalyst, a base. In some embodiments, the reaction mixture further includes a ligand.

[0144] In some embodiments, the compound of Formula (IC) or (ID) is reacted in step (e) with a compound of Formula (VI) in a solvent (e.g., an organic solvent), using a palladium catalyst, a base. In some embodiments, the reaction mixture further includes a ligand.

[0145] In some embodiments, the desalted compound of Formula (IB) is reacted in step (e) with a compound of Formula (VI) in the solvent (e.g., an organic solvent), using Pd(II)acetate, either fS')-BINAP [(5)-2,2'-bis(diphenylphosphino)-l, 1 '-binaphthyl] or rac-BINAP as a ligand. In some embodiments, (A’)-BINAP is used as the ligand, and a base selected from sodium t-butoxide, potassium Lbutoxide, anhydrous K3PO4, K3PO4 H2O, sodium carbonate, potassium carbonate, cesium carbonate, LiHMDS, NaHMDS, KOH and NaOH.

[0146] In some embodiments, a salt of Formula (IC) or (ID) is reacted in step (e) with a compound of Formula (VI) in the solvent (e.g., an organic solvent), using Pd(II)acetate, either (5)-BINAP [(5)-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl], (R)- BINAP [(S)-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl], or rac-BINAP as a ligand. In some embodiments, CS’)-BINAP is used as the ligand, and a base selected from sodium Lbutoxide, 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 (IC) is the mesylate salt, Compound 1 A.

[0147] In some embodiments, the reaction in step (e) is performed at a temperature from 70°C and 80°C, optionally under a nitrogen atmosphere, for 2 or more hours.

[0148] In some embodiments, the compound of Formula (IB) or salt of Formula (IC) is reacted in step (e) with a compound of Formula (VI) wherein X1is Cl and Y1is t-butyl, in a mixture of organic solvent toluene and organic co-solvent Lbutanol, using Pd(II)acetate as catalyst, CS’)-BINAP as a ligand, and anhydrous K3PO4or K3PO4·H2O as a base, at a temperature between 70°C and 80°C, under a nitrogen atmosphere, for 2 or more hours.

[0149] In some embodiments, the one or more aqueous washing steps comprise one or more washing steps with water, preferably deionized water, followed by separating off the aqueous phase, subsequently one or more washing steps with an aqueous HC1 solution, followed by separating off the aqueous phase, subsequently one or more washing steps with an aqueous sodium chloride solution, followed by separating off the aqueous phase, and finally one ormore washing steps with again deionized water, followed by separating off the aqueous phase. In some embodiments, the one or more aqueous washing steps comprise one or more washing steps with water, preferably deionized water, followed by separating off the aqueous phase, subsequently one or more washing steps with an aqueous HC1 solution, and an aqueous sodium hydroxide solution.

[0150] If / -butanol is used as an organic co-solvent in step (e), this organic co-solvent is removed from the organic phase during the washing steps.

[0151] If step (e) is performed in an organic solvent different from the solvent used in step (f), the organic solvent used in step (e) is swapped in step (e) with the organic solvent applied in step (f), such that the compound of Formula (VII) remains in solution.

[0152] In some embodiments wherein the (organic) solvents used in steps (e) and (f) are different, at least part of the (organic) solvent used in step (e) is evaporated, such as by using distillation at reduced pressure, and the organic solvent of step (f) is added, such that the compound of Formula (VII) remains in solution during the solvent swap. This process can be performed by continuously evaporating the (organic) solvent used in step (e) and by continuously adding the organic solvent of step (f), for example until the amount of the (organic) solvent used in step (e), based on the total amount of solvent, is below a certain threshold value. Alternatively, this process can be performed batch-wise in more than one steps of evaporating part of the (organic) solvent used in step (e) and subsequently adding part of the organic solvent used in step (f), for example until the amount of the (organic) solvent used in step (e), based on the total amount of solvent, is below a certain threshold value.

[0153] In some embodiments, the solvent used in step (e) is a mixture of organic solvent toluene and organic co-solvent / -butanol. The / -butanol is removed from the organic phase comprising the compound of Formula (VII) during the washing steps.

[0154] In some embodiments of step (e), the remaining organic solvent toluene is swapped with acetonitrile by distilling off in two or more steps, at a temperature between 50°C and 65°C under reduced pressure, part of the toluene with intermediate addition of acetonitrile, in an amount to obtain a solvent mixture with less than about 20 weight percent toluene, based on the combined weight of the solvents, such that the compound of Formula (VII) remains in solution. In some embodiments of the compound of Formula (VII), Y1is t-butyl.Method of Preparing Obicetrapib - Step (f)

[0155] In step (f) of the process for preparing obicetrapib according to the present disclosure, the compound of Formula (VII) is converted to the carbamate of Formula (VIII) in an organic solvent, and subsequently isolated as a solid salt of Formula (IX) (where Y1is a protecting group, e.g., as described herein).(VIII) (IX)

[0156] In some embodiments, the organic solvent used in step (e) is selected from acetonitrile, chlorobenzene, toluene, V-methyl-2-pyrrolidone, xylene, 1,4-di oxane, 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.

[0157] As explained hereinbefore, the compound of Formula (VII) is already provided in step (e) in the organic solvent used in step (f), either because the same organic solvents are used in steps (e) and (f) or because of a solvent swap in step (e). In some embodiments of the compounds of Formulae (VII), (VIII) and (IX), Y1is t-butyl.

[0158] In some embodiments, the organic solvent used in step (e) is a mixture of acetonitrile toluene, with less than about 20 weight percent toluene, based on the combined weight of the organic solvents.

[0159] In some embodiments, the conversion of the compound of Formula (VII) to the corresponding carbamate with Formula (VIII) in step (f) is performed in acetonitrile with less than about 20 weight percent toluene, based on the combined weight of the organic solvents, with an excess ethyl chloroformate in the presence of pyridine, at a temperature between 10°C and 20°C.

[0160] If step (f) is performed in an organic solvent different from the organic solvent used in step (g), the organic solvent used in step (f) is swapped in step (f) with the organic solvent applied in step (g), such that the compound of Formula (VIII) remains in solution.

[0161] In some embodiments where the organic solvents used in steps (f) and (g) are different, at least part of the organic solvent used in step (f) is evaporated, such as by distillation at reduced pressure, and the organic solvent of step (g) is added, such that the compound of Formula (VIII) remains in solution during the organic solvent swap. This process can be performed by continuously evaporating the organic solvent used in step (f) and by continuously adding the organic solvent of step (g), for example until the amount of the organic solvent used in step (f), based on the total amount of organic solvent, is below a certain threshold value. Alternatively, this process can be performed batch-wise in more than one steps of evaporating part of the organic solvent used in step (f) and subsequently adding part of the organic solvent used in step (g), for example until the amount of the organic solvent used in step (f), based on the total amount of organic solvent, is below a certain threshold value.

[0162] The resulting mixture is preferably subjected to one or more treatments with an aqueous sodium chloride and / or HC1 solution, followed by separating off the aqueous phase, and subsequently to one or more treatments with an aqueous bicarbonate solution or an aqueous sodium hydroxide solution, followed by separating off the aqueous phase.

[0163] In some embodiments, the conversion of the compound of Formula (VII) to the corresponding carbamate with Formula (VIII) in step (f) is performed in acetonitrile with an excess of ethyl chloroformate in the presence of pyridine, at a temperature between 10°C and 20°C, and this solvent is swapped in step (f) with isopropyl acetate by distilling off in two or more steps, at a temperature of 60°C or less under reduced pressure, part of the acetonitrile with intermediate addition of isopropyl acetate, in an amount to obtain a solution of the compound of Formula (VIII) in isopropyl acetate, wherein the solution may be subjected to one or more treatments with an aqueous NaCl / HCl solution, followed by separating off the aqueous phase, and subsequently to one or more treatments with an aqueous bicarbonate solution or an aqueous sodium hydroxide solution, followed by separating off the aqueous phase.

[0164] Next, the compound of Formula (VIII) dissolved in an organic solvent is converted to a corresponding salt according to Formula (IX), wherein An' is an anion and n is an integer from 1-3. The solid form of the salt according to Formula (IX) is then isolated as a solid form.

[0165] In some embodiments, the salt of Formula (IX) is chosen from salts with an anion An' selected from a sulfonate (e.g., besylate, tosylate, napsylate, camsylate, esylate, edisylate and mesylate), a sulfate (e.g., methyl sulfate), a halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate,hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate.

[0166] In some embodiments, the salt of Formula (IX) is chosen from salts with an anion An' selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.

[0167] In some embodiments, the salt of Formula (IX) is chosen from salt with an anion An' selected from chloride, bromide, bitartrate, and mesylate.

[0168] In some embodiments, the salt from of Formula (IX) is the mesylate salt including the crystalline mesylate salt thereof, Compound ID:9 © ©s II-o NH2o CF3N1D

[0169] In some embodiments, of the salt of Formula (IX), n is 1.

[0170] The organic solvent used in the conversion of Formula (VIII) to (IX) is not particularly limited, but in some embodiments is selected from cyclopentyl methyl ether, isopropyl ether, / -butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof. In some embodiments, isopropyl acetate or a mixture comprising dichloromethane, / / -heptane and isopropyl alcohol, such as a mixture of chlorobenzene, dichloromethane, / / -heptane and isopropyl alcohol is used. It is noted that, the compound of Formula (VIII) is already provided in organic solvent owing to the solvent swap described herein before.

[0171] Accordingly, in some embodiments, the organic solvent used in the conversion of compound of Formula (VIII) to its corresponding salt of Formula (IX) selected from cyclopentyl methyl ether, isopropyl ether, / -butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof, with less than about 20 weight percent toluene and less than about 7 weight percent acetonitrile, based on the combined weight of the solvents. In some embodiments, the solvent is a mixture of isopropyl acetate, toluene and acetonitrile, with less than about 20 weight percent toluene and less than about 7 weight percent acetonitrile, based on the combined weight of the solvents.

[0172] In some embodiments, it is preferred to add an organic co-solvent different from the organic solvent already used in step (f). Exemplary organic co-solvents are selected from cyclopentyl methyl ether, isopropyl ether, / -butyl methyl ether, ethyl acetate, isopropyl acetate, and combinations thereof, such as methyl / -butyl ether. As will be appreciated by the skilled person, the need and advantages of using an organic co-solvent depend on the particular organic solvent already used in step (f). In certain cases, the use of a co-solvent can be dispensed with.

[0173] In some embodiments, the organic solvent for the conversion of a compound of Formula (VIII) to its corresponding salt of Formula (IX) comprises isopropyl acetate and methyl / -butyl ether as an organic co-solvent.

[0174] Subsequently, an acid is added to form the salts of Formula (IX) defined supra. In some embodiments the acid is selected from ditartartic acid, sulfuric acids, sulfonic acids, hydrogen bromide and hydrogen chloride. In some embodiments, the acid is methanesulfonic acid. In embodiments wherein the salt of Formula (IX) can be obtained in crystalline form, part of the acid needed to form the salt of Formula (IX) can be added before the crystallization and part during the crystallization.

[0175] The solid form of the salt of Formula (IX) is isolated by crystallization if the salt of Formula (IX) can be obtained in crystalline form, filtration, one or more optional washing steps of the filtration residue, and drying.

[0176] In some embodiments, the compound of Formula (VIII) is converted to the corresponding mesylate salt according to Formula (IX) with methanesulfonic acid in an organic solvent mixture of isopropyl acetate and methyl / -butyl ether with less than about 20 weight percent toluene and less than 7 weight percent acetonitrile, based on the combined weight of the organic solvents, followed by crystallizing the mesylate salt according to Compound ID from the organic solvent, with subsequent filtration, one or more optional washing steps of the filtration residue, and drying.

[0177] In some embodiments wherein the salt according to Formula (IX) can be obtained in crystalline form, crystallization is induced by adding seed crystals of the salt according to Formula (IX).

[0178] In some embodiments, wherein the salt according to Formula (IX) can be obtained in crystalline form, crystallizing the salt according to Formula (IX) and obtaining the crystalline form of the salt according to Formula (IX) is performed by adding the acid needed to form the salts, by agitating the resulting mixture for more than 60 minutes at a temperature from 20°Cto 25°C, by allowing crystallization under agitation at a temperature between 15°C and 25°C for more than 120 minutes, followed by subjecting the resulting slurry to vacuum filtration, wherein the filtration residue is washed one or more times with the same organic solvent that is used to crystallize the salt according to Formula (IX) from, and by vacuum drying the crystalline form of the salt according to Formula (IX).

[0179] In an embodiment, the disclosure concerns the salt according to Formula (IX), wherein A"' is an anion, wherein n is an integer from 1-3. In some embodiments, the compound is the crystalline mesylate (MSA) salt of Formula (IX) (e.g., Compound ID as described herein).

[0180] In some embodiments, crystallizing the mesylate salt of Formula (IX) from an organic solvent mixture of isopropyl acetate and methyl / -butyl ether and obtaining the crystalline form of the mesylate salt according to Compound ID is performed by adding methanesulfonic acid needed to form the salt, agitating the resulting mixture for more than 60 minutes at a temperature between 15°C and 25°C (e.g., 20°C), then allowing crystallization under agitation at a temperature between 15°C and 25°C for more than 120 minutes. The resulting slurry is subjected to vacuum filtration, wherein the filtration residue is washed one or more times with a mixture of isopropyl acetate and methyl / -butyl ether, and dried under vacuum to provide a crystalline form of the mesylate salt according to Compound ID.

[0181] In some embodiments, the compound of Formula (IX) is obtained in a yield of at least 70%, based on the number of moles of the compound of Formula (IB). In some embodiments, the compound of Formula (IX) is obtained with a purity of 99% or more, such as a purity of 99.1% or more, 99.2% or more, 99.3% or more, 99.5% or more, or even more.Method of Preparing Obicetrapib - Step (g)

[0182] In step (g) of the process according to the present disclosure, the isolated salt of Formula (IX), or the desalted derivative thereof (e.g., the compound according to Formula (VIII)), is alkylated with a compound of Formula (X) to provide a compound of Formula (XI):(X) (XI)where, X2is a leaving group and Y1is a protecting group (e.g., as described herein).

[0183] In some embodiments of step (g), the isolated solid form of the salt according to Formula (IX), such as a crystalline form of the salt according to Formula (IX) (such as the crystalline mesylate salt, Compound ID), is reacted directly with a compound of Formula (X) in an organic solvent, to form a compound of Formula (XI) (i.e., without a desalting step).

[0184] In some embodiments of step (c), the isolated solid form of the salt according to Formula (IX), such as a crystalline form of the salt according to Formula (IX) (such as the crystalline mesylate salt, Compound ID), is desalted and reacted with a compound of Formula (X) in an organic solvent, to form a compound of Formula (XI). Desalting the compound of Formula (IX) results in a compound according to Formula (VIII).

[0185] When the compound of Formula (IX) is subjected to a desalting step, the desalting process and the subsequent reaction with a compound of Formula (VIII) are performed in the same organic solvent. In some embodiments, the organic solvent is selected from xylene, n-hexane, toluene, heptanes (mix of isomers), / / -heptane, di chloromethane, chlorobenzene, and combinations thereof. In some embodiments, the organic solvent is toluene or / / -heptane.

[0186] In some embodiments, step (g) is carried out in the presence of a base. In some embodiments, step (g) is carried out in the presence of a solid-liquid phase-transfer catalyst.

[0187] In some embodiments, the base is selected from alkali metal hydrides, alkali metal hydroxides, alkali earth metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and amines. In some embodiments, the base is chosen from alkali metal alkoxides. In some embodiments, the base is sodium / -pentoxide or a mixture of sodium t-butoxide, and potassium / -butoxide.

[0188] In some embodiments, the solid-liquid phase-transfer catalyst is selected from / -butylammonium hydrogensulfate, tetra-zz-butylammonium bromide, tetra-zz-butylammonium iodide, a crown ether, and combinations thereof. In some embodiments, the catalyst is / -butylammonium hydrogensulfate.

[0189] In some embodiments, the reaction of the compound of Formula (VIII) or (IX) with the compound of Formula (X) is performed at a temperature between 0°C and 25°C (such as from 5°C to 20°C).

[0190] The coupling partner of Formula (X) in step (g) includes a leaving group X2. It will be understood that any convenient leaving group may find use in the present disclosure for X2. Insome embodiments, the leaving group X2in the compound of Formula (X) is selected from a halogen, and a substituted sulfonyloxy group. In some embodiments, the leaving group X2in the compound of Formula (X) is a substituted sulfonyloxy group selected from a methanesulfonyloxy, / ?-toluenesulfonyloxy or a trifluoromethanesulfonyloxy group. In some embodiments, the leaving group X2is a halogen. In certain embodiments, the halogen is bromide. In some embodiments, the compound of Formula (X) is of the structure IE below.CF31E

[0191] In some embodiments, the desalting of the compound of Formula (IX) and the subsequent reaction with a compound of Formula (X) in step (g) is performed in toluene as an organic solvent in the presence of a base and a catalyst at a temperature from 5°C to 25°C. In some embodiments, the desalting of the compound of Formula (IX) and the subsequent reaction with a compound of Formula (X) in step (g) is performed in toluene as an organic solvent in the presence of sodium / -pentoxide as a base and / -butylammonium hydrogensulfate as a catalyst at a temperature between 5°C and 25°C under agitation for about 1 to 8 hours. In some embodiments of the compound of Formula (IX), Y1is t-butyl.

[0192] In some embodiments, the alkylation of a compound of Formula (IX) (i.e., without an additional desalting step) with a compound of Formula (X) in step (g) is performed in toluene as an organic solvent in the presence of a base and a catalyst at a temperature from 5°C to 25°C. In some embodiments, the alkylation of a compound of Formula (IX) with a compound of Formula (X) in step (g) is performed in toluene as an organic solvent in the presence of sodium / -pentoxide as a base and / -butylammonium hydrogensulfate as a catalyst at a temperature between 5°C and 25°C under agitation for about 1 to 8 hours.

[0193] In some embodiments, step (g) includes providing crystalline ID, desalting this compound and reacting the desalted compound with a compound of Formula (X) wherein X2is Br in toluene as an organic solvent in the presence of sodium / -pentoxide as a base and / -butylammonium hydrogensulfate as a catalyst, at a temperature between 5°C and 25°C under agitation for about 1 to 8 hours.

[0194] In some embodiments, step (g) includes reacting crystalline ID with a compound of Formula (X) wherein X2is Br in toluene as an organic solvent in the presence of sodium t-pentoxide as a base and / -butylammonium hydrogensulfate as a catalyst, at a temperature between 5°C and 25°C under agitation for about 1 to 8 hours.

[0195] In some embodiments of step (g), the base is the last reagent added to the reaction mixture. Without being bound to any particular theory, the inventors have discovered that by adding the base as the last reagent, the number of equivalents of both the base and the compound of Formula (X) used in the reaction mixture can be reduced. A reduction in the number of equivalents of the compound of Formula (X) can in turn reduce the risk of carryover of Formula (X) related impurities to the final product.

[0196] Accordingly, step (g) results in the production of a compound of Formula (XI) in an organic solvent. In some embodiments of the compound of Formula (XI), Y1is t-butyl. In some embodiments, this reaction mixture is subjected in step (g) to one or more aqueous washing steps to remove impurities, followed by separating off the aqueous phase, and optionally one or more filtration steps, to obtain a washed reaction mixture comprising the compound of Formula (XI) in the organic solvent. In some embodiments, the reaction mixture comprising the compound of Formula (XI) in the organic solvent is concentrated by distilling off part of the organic phase to obtain a concentrated reaction mixture comprising the compound of Formula (XI) in the organic solvent. In some embodiments, the organic solvent comprises from 30 to 40 weight percent of the compound of Formula (XI) based on the weight of the reaction mixture. In some embodiments, the organic solvent comprises 34 to 37 weight percent of the compound of Formula (XI) based on the weight of the reaction mixture.

[0197] The one or more aqueous washing steps, the optionally one or more filtration steps, and the concentration step are preferably combined such that a washed and concentrated reaction mixture comprising the compound of Formula (XI) in the organic solvent is obtained. In some cases, the organic solvent includes from 30 to 40 weight percent of the compound of Formula (XI). In some embodiments, the organic solvent includes from 34 to 37 weight percent of the compound of Formula (XI) based on the weight of the reaction mixture.

[0198] In some embodiments, the one or more aqueous washing steps comprise one or more washing steps with an aqueous acetic acid solution.

[0199] In some embodiments, the reaction mixture comprising the compound of Formula (XI) in toluene as an organic solvent is subjected in step (g) to one or more aqueous washing steps with an aqueous acetic acid solution followed by separating off the aqueous phase, and subsequently by distilling off part of the toluene, typically at a temperature from 75°C to 90°Cunder reduced pressure, to obtain a washed and concentrated reaction mixture comprising the compound of Formula (XI) in toluene with from 30 to 40 weight percent of the compound of Formula (XI) based on the weight of the reaction mixture. In some embodiments, the concentrated mixture includes from 34 to 37 weight percent of the compound of Formula (XI) based on the weight of the reaction mixture.

[0200] If step (g) is performed in an organic solvent different from the organic solvent used in step (h), the organic solvent used in step (g) is swapped in step (g) with the organic solvent applied in step (h) such that the compound of Formula (XI) remains in solution.

[0201] In some embodiments, wherein the organic solvents used in steps (g) and (h) are different, at least part of the organic solvent used in step (g) is evaporated, preferably using distillation at reduced pressure, and the organic solvent of step (h) is added, such that the compound of Formula (XI) remains in solution during the organic solvent swap. This process can be performed by continuously evaporating the organic solvent used in step (g) and by continuously adding the organic solvent of step (h), for example until the amount of the organic solvent used in step (g), based on the total amount of organic solvent, is below a certain threshold value. Alternatively, this process can be performed batch-wise in more than one steps of evaporating part of the organic solvent used in step (g) and subsequently adding part of the organic solvent used in step (h), for example until the amount of the organic solvent used in step (g), based on the total amount of organic solvent, is below a certain threshold value.Method of Preparing Obicetrapib - Step (h)

[0202] In step (h) of the process according to the present disclosure, the compound of Formula (XI) is converted to obicetrapib (Compound 1) in a first organic solvent (where Y1is a protecting group, e.g., as described herein).(XI) 1

[0203] The selection of the first organic solvent used in step (h) is not particularly limited. In some embodiments, the first organic solvent is not an ether or an ester. In some embodiments,the first organic solvent is toluene or a mixture of / / -heptane and acetic acid. As explained hereinbefore, the compound of Formula (XI) is already provided in step (g) in the first solvent used in step (h), either because the same organic solvents are used in steps (g) and (h) or because of a solvent swap in step (g).

[0204] Accordingly, in some embodiments, the first organic solvent as defined hereinbefore with from 30 to 40 weight percent of the compound of Formula (XI), such as from 34 to 37 weight percent, based on the weight of the reaction mixture, is provided in step (h).

[0205] In some embodiments, toluene as a first organic solvent with from 30 to 40 weight percent of the compound of Formula (XI), such as from 34 to 37 weight percent, based on the weight of the reaction mixture, is provided in step (h).

[0206] Any convenient protecting group for a carboxylic acid, such as an ester moiety, may find use as Y1in the compound of Formula (XI). As disclosed herein, the selection of an appropriate protecting group for a carboxylic acid can be readily determined by one skilled in the art. In some embodiments of Formula (XI), the protecting group (Y1) 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. In some embodiments of Formula (XI), the protecting group (Y1) is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluro ethyl, phenyl, 4-methoxybenzyl ester, a 2,6-disubstituted phenol, and a silyl group. In some embodiments of the compound of Formula (XI), the protecting group Y1is t-butyl. In some embodiments, the conversion of the compound of Formula (XI) to obicetrapib is performed by contacting the compound of Formula (XI) in the first organic solvent, such as toluene or a mixture of / / -heptane and acetic acid, with acetic acid (AcOH) and dry HC1 or concentrated HC1 under agitation. 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 under agitation for at least 3 hours.

[0207] Obicetrapib (Compound 1) can be isolated from the resulting mixture using techniques known to the skilled person.

[0208] In some embodiments, the resulting mixture comprising obicetrapib, is subjected in step (h) to one or more aqueous washing steps. In some embodiments, the one or more aqueous washing steps in step (h) are performed as follows:(AA) the reaction mixture comprising obicetrapib is cooled to a temperature between 15°C and 25°C, and subsequently a mixture of / / -heptane, acetonitrile and water is addedfollowed by agitating the resulting mixture for more than 15 minutes at this temperature;(BB) the system obtained in step (AA) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated;(CC) a mixture of / / -heptane, acetonitrile, toluene and water is added to the aqueous phase obtained in step (BB), followed by agitating the resulting system for more than 15 minutes at a temperature between 15°C and 25°C;(DD) the system obtained in step (CC) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated;(EE) the organic phase obtained in step (BB) and the organic phase obtained in step (DD) are combined, water is added, and the resulting system is agitated for more than 15 minutes at a temperature between 15°C and 25°C;(FF) the system obtained in step (EE) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated;(GG) water is added to the organic phase obtained in step (FF) and the resulting system is agitated for more than 15 minutes at a temperature between 15°C and 25°C;(HH) the system obtained in step (GG) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated;(II) an aqueous solution of sodium citrate tribasic dihydrate is added to the organic phase obtained in step (HH) followed by agitating the resulting mixture for more than 15 minutes at a temperature between 15°C and 25°C;(JJ) the system obtained in step (II) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated;(KK) water is added to the organic phase obtained in step (JJ) and the resulting system is agitated for more than 15 minutes at a temperature between 15°C and 25°C; and (LL) the system obtained in step (KK) is allowed to phase separate into an organic phase and an aqueous phase and both phases are separated.

[0209] Steps (AA) to (LL) in this embodiment result in a washed compound 1 in an organic solvent mixture comprising / / -heptane, acetonitrile and the first organic solvent. In some embodiments the first solvent is toluene.

[0210] In some embodiments, wherein the first organic solvent does not already mainly consist of cyclopentyl methyl ether, the organic solvent mixture is swapped in a subsequent step (MM) with CPME such that obicetrapib remains in solution.

[0211] Hence, in some embodiments, step (LL) is followed by step (MM) wherein at least part of the solvents in the organic solvent mixture obtained in step (LL) is evaporated, such as by distillation at reduced pressure, and wherein cyclopentyl methyl ether is added, such that obicetrapib remains in solution during the solvent swap. In some embodiments, the process results in a solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent based on the weight of the solution. In some embodiments, the concentration of obicetrapib in cyclopentyl methyl ether is from 33 and 37 weight percent, based on the weight of the solution, less than 1 weight percent of the first organic solvent, and less than 1 weight percent of / / -heptane based on the weight of the solution.

[0212] This process can be performed by continuously evaporating the solvents in the organic solvent mixture obtained in step (LL) and by continuously adding cyclopentyl methyl ether, for example until the amount of specific solvents in the organic solvent mixture, based on the total amount of organic solvents, is below a certain threshold value. Alternatively, this process can be performed batch-wise in more than one steps of evaporating part of the solvents in the organic solvent mixture obtained in step (LL) and by subsequently adding cyclopentyl methyl ether, for example until the amount of specific solvents in the organic solvent mixture, based on the total amount of solvent, is below a certain threshold value.

[0213] In some embodiments, the first organic solvent is toluene, step (LL) is followed by step (MM) wherein at least part of the / / -heptane, acetonitrile and toluene in the organic solvent mixture obtained in step (LL) is evaporated, such as by distillation at a temperature of 45 °C or lower and at reduced pressure (in-vacuo), with intermediate additions of cyclopentyl methyl ether, such that obicetrapib remains in solution during the solvent swap, resulting in a solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent. In some embodiments, the concentration of obicetrapib in cyclopentyl methyl is from 33 to 37 weight percent based on the weight of the solution, with less than 0.5 weight percent of toluene, less than 0.5 weight percent of acetonitrile and less than 2.7 weight percent of n-heptane.Method of Preparing a Crystalline obicetrapib HC1 - Step (i)-(i)

[0214] In some embodiments of the subject method, step (h) is followed by step (i)-(j), wherein obicetrapib is treated with HC1 such as in a suitable solvent. Such solvent may be an aqueous solvent or an organic solvent. In some embodiments, the use of an organic solvent provides crystalline obicetrapib HC1 (Compound 2).

[0215] In some embodiments, the organic solvent used in step (i) comprises a mixture of a solvent and an anti-solvent. 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, di chloromethane, 1,4-di oxane, 1,2-diflurobenzene, toluene, hexafluoroisopropanol, and water. In some embodiments, the anti-solvent is selected from n-heptane, n-hexane, n-pentane, and cyclohexane. In some embodiments, the HC1 has sufficient solubility in the anti-solvent such that it 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 / / -heptane. In some embodiments, the organic solvent used in step (i) further comprises toluene.

[0216] In some embodiments, step (i) comprises providing obicetrapib in a mixture of cyclopentyl methyl ether and / / -heptane, raising the temperature to between 35°C and 40°C under agitation, adding dry HC1 in cyclopentyl methyl ether and raising the temperature again to between 50°C and 55°C, then adding further / / -heptane as an anti-solvent. At this point, a small portion of the reaction mixture can be extracted, cooled to a temperature of between 10°C and 15°C, to obtain a slurry of crystals of crystalline obicetrapib HC1 in a mixture cyclopentyl methyl ether and / / -heptane (referred to herein as a “seed crystal slurry”). Optionally, all or a portion of the seed crystal slurry of crystalline obicetrapib HC1 can then be added as seed crystals back to the reaction mixture. The seeds assist with nucleation but are not required and thus the process described herein can be done without seeding. The resulting reaction mixture is then cooled to a temperature between 5°C and 15°C (such as from 10°C to 15°C), followed by crystallizing the crystalline obicetrapib HC1 from the system under agitation. In some embodiments, the resulting reaction mixture is cooled to a temperature between 5°C and 15°C, raised to 40°C, cooled once more to a temperature between 5°C and 15°C, followed by crystallizing the crystalline obicetrapib HC1 from the system under agitation. In some embodiments, the crystalline obicetrapib HC1 is crystallized over a period of 12 hours or more, with subsequent filtration (e.g., through a filter dryer), one or more optional washing steps,such as with a mixture of cyclopentyl methyl ether and / / -heptane, and drying. In some cases, a wet filter cake of crystalline obicetrapib HC1 is dried in vacuo in steps using temperatures of 25°C-30°C, 30°C-40°C, 40°C-50°C then 50°C-55°C, such as 25°C, 35°C, 46°C, and 54°C.

[0217] Accordingly, in some embodiments, the method of preparing crystalline obicetrapib HC1 comprises the addition of seed crystals (e.g., as a seed crystal slurry). The seed crystals of crystalline obicetrapib HC1 can be formed as a slurry and after addition of dry HC1 in cyclopentyl methyl ether and anti-solvent / / -heptane, extracting a small portion of the reaction mixture, cooling to a temperature between 10°C and 15°C, to provide a slurry of crystals of crystalline obicetrapib HC1 in cyclopentyl methyl ether and / / -heptane.

[0218] In some embodiments, the organic solvent used in step (i) comprises a mixture of cyclopentyl methyl ether and / / -heptane. Accordingly, in one embodiment, step (i) comprises providing obicetrapib in a mixture of cyclopentyl methyl ether and / / -heptane, raising the temperature to 35°C-45°C under agitation, adding dry HC1 in cyclopentyl methyl ether and raising the temperature again to 50°C-55°C, addition of further / / -heptane as anti-solvent, the optional addition of seed crystals of crystalline obicetrapib HC1 (e.g., as a seed crystal slurry prepared as described herein), cooling to a temperature between 5°C and 15°C (such as from 10°C to 15°C), followed by crystallizing the crystalline obicetrapib HC1 from the system under agitation. In some embodiments, the crystalline obicetrapib HC1 is crystallized over a period of at least 12 hours, with subsequent filtration, one or more optional washing steps, such as with a mixture of cyclopentyl methyl ether and / / -heptane, and drying. In some embodiments, the crystalline obicetrapib HC1 is dried in vacuo. In some embodiments, the crystalline obicetrapib HC1 is subjected to drying in a vacuum drying cabinet at 25 mbar pressure and at a temperature of 55 °C for 10 hours or more. In some embodiments, after the drying procedure, the crystalline obicetrapib HC1 includes less than 0.1 weight percent residual cyclopentyl methyl ether.

[0219] In some embodiments described hereinbefore, step (MM) of step (h) results in a solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent, such as from 33 to 37 weight percent, based on the weight of the solution, less than 1 weight percent of the first organic solvent used in step (h), and less than 1 weight percent of / / -heptane. In some embodiments described hereinbefore, step (MM) of step (h) results in a solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent, such as from 33 to 37 weight percent, based on the weight of the solution, less than 1 weight percent of toluene, and less than 1 weight percent of / / -heptane. These solutionscan, after addition of / / -heptane, advantageously be used in step (i). As will be appreciated by the skilled person, the / / -heptane can also be added in step (h).

[0220] Accordingly, in some embodiments, step (i) comprises providing the solution of obicetrapib in cyclopentyl methyl ether with a concentration between 30 and 40 weight percent, such as from 33 to 37 weight percent, based on the weight of the solution, less than 1 weight percent of the first organic solvent used in step (h) (such as toluene), and less than 1 weight percent of / / -heptane, addition of / / -heptane, raising the temperature to 35°C to 45°C under agitation, adding dry HC1 in cyclopentyl methyl ether and raising the temperature again to 50°C to 55°C, addition of further / / -heptane as anti-solvent, the optional addition of seed crystals of crystalline obicetrapib HC1 (e.g., as a seed crystal slurry prepared as described herein), cooling to a temperature between 5°C and 15°C (such as from 10°C to 15°C), followed by crystallizing the crystalline obicetrapib HC1 from the system under agitation, such as during a period of at least 12 hours, with subsequent filtration, one or more washing steps with a mixture of cyclopentyl methyl ether and / / -heptane, and drying. In some cases, a wet filter cake of crystalline obicetrapib HC1 is dried in vacuo in steps using temperatures of 25°C-30°C, 30°C-40°C, 40°C-50°C then 50°C-55°C, such as 25°C, 35°C, 46°C, and 54°C.

[0221] In some embodiments of the subject method, crystalline obicetrapib HC1 is isolated in step (j) with a purity of 98% or more, such as 98.5% or more, 99% or more 99.5% or more, or even more.

[0222] In some embodiments, crystalline obicetrapib HC1 is stored at controlled room temperature and under a nitrogen atmosphere and is protected from moisture to prevent the formation of an amorphous solid, because crystalline obicetrapib HC1 including crystalline obicetrapib HC1 is hygroscopic.Method of Preparing Amorphous Obicetrapib Hemicalcium - Step (k)-(l)

[0223] In some embodiments of the subject method, step (j) is followed by steps (k)-(l), wherein the crystalline obicetrapib HC1 (Compound 2) is converted to amorphous obicetrapib hemicalcium (Compound 3) (see, Scheme 2 “Improved Synthesis of amorphous obicetrapib hemicalcium”).

[0224] In some embodiments step (k), the preparation of amorphous obicetrapib hemicalcium includes steps (k-l)-(k-3) as set out below:(k-1) converting crystalline obicetrapib HC1 of step (j) to obicetrapib in an organic solvent;(k-2) treating obicetrapib in the organic solvent with aqueous sodium hydroxide to form a sodium salt of obicetrapib; and(k-3) treating the sodium salt of obicetrapib with aqueous calcium chloride to form amorphous obicetrapib hemicalcium;wherein the compounds in steps (k-1) and (k-2) are not isolated.

[0225] Accordingly, in some embodiments step, (k-1) comprises the following steps:(aa) providing crystalline obicetrapib HC1 as defined or obtained in step (j);(bb) dissolving crystalline obicetrapib HC1 in a mixture of water and isopropyl acetate under agitation. In some embodiments, step (bb) is conducted at a temperature between 15°C and 25°C;(cc) allowing phase separation and subjecting the resulting organic phase to one or more subsequent washing steps with water, wherein each washing step is followed by separating off the aqueous phase, resulting in a washed organic phase; and (dd) performing two or more distillations on the washed organic phase resulting from step (cc) at a temperature of 50°C or lower (such as 30°C or lower), with intermediate additions of ethanol, to obtain a solution of the compound of obicetrapib in ethanol.

[0226] In some embodiments step, (k-2) comprises the following steps:(ee) adding an aqueous NaOH solution to the solution obtained in step (dd) and agitating the resulting mixture, such as at a temperature between 20°C and 25 °C for at least 4 hours, to obtain a solution of the sodium salt of obicetrapib; and(ff) optionally filtering the solution obtained in step (ee).

[0227] In some embodiments step, (k-3) comprises the following steps:(gg) preparing a CaCl₂ solution by adding deionized water to CaCl₂ under agitation, followed by adding ethyl acetate as a co-solvent, and stirring the resulting mixture for 10 to 30 minutes;(hh) cooling the CaCl₂ solution obtained in step (gg) to a temperature from 8°C to 12°C and adding via a filter to the solution obtained in step (ff) or (ee) under agitation at said temperature;(ii) stirring the slurry resulting from step (hh) for about 1 to 10 hours. In some embodiments of step (ii), the stirring is conducted at a temperature between 8°C and 12°C;(jj) isolating the solids from the slurry obtained in step (ii) by filtration. In some embodiments of step (jj), the isolating is conducted at a temperature between 8°C and 12°C;(kk) washing the filtration residue obtained in step (jj ) with water in one or more washing steps. In some embodiments of step (kk), the washing is conducted at a temperature between 8°C and 12°C; and(11) drying the washed residue obtained in step (kk), such as in vacuo at a temperature from 40°C to 50°C for more than 16 hours (such as 50 hours, 100 hours, 150 hours, or 200 hours, or even more), to obtain the amorphous obicetrapib hemicalcium (also sometimes referred to herein as compound 3).

[0228] In some embodiments, step (k) comprises the following steps:(aa) providing crystalline obicetrapib HC1, as defined or obtained in step (j);(bb) dissolving crystalline obicetrapib HC1 in ethanol under agitation. In some embodiments at a temperature between 15°C and 25°C;(cc) adding an aqueous NaOH solution to the solution obtained in step (bb) and agitating the resulting mixture, such as at a temperature from 20°C to 25 °C for at least 4 hours, to obtain a solution of the sodium salt of obicetrapib;(dd) optionally filtering the solution obtained in step (cc);(ee) preparing a CaCl₂ solution by adding deionized water to CaCl₂ under agitation, followed by adding ethyl acetate as a co-solvent, and stirring the resulting mixture for 10 to 30 minutes;(ff) cooling the CaCh solution obtained in step (ee) to a temperature between 8°C and 12°C and adding via a filter to the solution obtained in step (dd) or (cc) under agitation at said temperature;(gg) stirring the slurry resulting 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) isolating the solids from the slurry obtained in step (gg) by filtration. In some embodiments the isolating is conducted at a temperature between 8°C and 12°C; (ii) washing the filtration residue obtained in step (hh) with water in one or more washing steps. In some embodiments the washing is conducted at a temperature between 8°C and 12°C; and(jj) drying the washed residue obtained in step (ii), such as in vacuo 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 even more), to obtain the amorphous hemicalcium-salt of obicetrapib.

[0229] In some embodiments, amorphous obicetrapib hemicalcium is stored sealed at a temperature of less than 30°C and protected from light.

[0230] In some embodiments, amorphous obicetrapib hemicalcium is submitted to a subsequent reworking procedure, as described in U. S. Patent No. 12,006,305, the disclosure of which is incorporated herein by reference in its entirety.

[0231] Amorphous obicetrapib hemicalcium of the disclosure can be made with high chemical purity according to the processes of the disclosure. Such levels of purity include greater than 98.0 % pure such as greater than 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 more. The highest level of purities such as greater than 99.8% or 99.9% pure are more readily achieved with processes where crystalline obicetrapib HC1 is used as an intermediate.

[0232] The term “pharmaceutically acceptable” indicates that the material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectables.

[0233] The term “carrier” refers to a glidant, diluent, adjuvant, excipient, or vehicle etc. with which the compound is administered, without limitation. Examples of carriers are described herein and also in Remington: The Science and Practice of Pharmacy (Remington: The Science and Practice of Pharmacy, 23rd Edition, ISBN-13: 978-0128200070).

[0234] The term “effective amount” or “therapeutically effective amount” refers to an amount that is sufficient to effect treatment, as defined herein, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the patient being treated, the weight and age of the patient, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

[0235] The term “solvate” means a complex, such as an adduct, formed between an organic compound and a solvent molecule in the solid state. Solvates may be held together by hydrogen bonding, van der Waals forces, or other non-covalent bonding interactions. Solvates may be channel solvates in that variable amounts of solvent may be present in a channel of the structure of the solid.

[0236] The term “treatment” or “treating,” to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and / or relieving one or more symptoms of the disease or condition.

[0237] Unless specifically stated otherwise, where a compound may assume alternative tautomeric, regioisomeric and / or stereoisomeric forms, all alternative isomers, are intended to be encompassed within the scope of the claimed subject matter. For example, when a compound is described as a particular optical isomer D- or L-, it is intended that both optical isomers be encompassed herein. For example, where a compound is described as having one of two tautomeric forms, it is intended that both tautomers be encompassed herein. Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. The compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (5) configurations, or may be a mixture thereof. The chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (A) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (5) form.

[0238] The present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether radioactive or not. An isotopic variant of a compound according to the present disclosure is understood to mean a compound in which at least one atom within the compound according to the present disclosure has been exchangedfor another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound according to the present disclosure are those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as2H (deuterium),3H (tritium),13C,14C,15N,17O,18O,18F,36C1,82Br,123I,124I,125I,129I and131I. Particular isotopic variants of a compound according to the present disclosure, especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body. Compounds labelled with3H,14C and / or18F isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required. In some embodiments, hydrogen atoms of the compounds described herein may be replaced with deuterium atoms. In certain embodiments, “deuterated” as applied to a chemical group and unless otherwise indicated, refers to a chemical group that is isotopically enriched with deuterium in an amount substantially greater than its natural abundance. Isotopic variants of the compounds according to the present disclosure can be prepared by various, including, for example, the methods described below and in the working examples, by using corresponding isotopic modifications of the particular reagents and / or starting compounds therein.

[0239] Thus, any of the embodiments described herein are meant to include, a single stereoisomer, a mixture of stereoisomers and / or an isotopic form of the compounds.

[0240] Unless otherwise indicated, the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means 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 a the explicitly recited value, rounded either up or down to the nearest integer.

[0241] Thus, the subject method has been described by reference to certain embodiments discussed above. It will be recognized that these embodiments are susceptible to various modifications and alternative forms well known to those of skill in the art.

[0242] The present disclosure may be further described by one or more of the non-limiting clauses that follow:

[0243] Clause 1. A method for preparing an enantiopure compound of Formula I or a salt thereof:wherein:R1is H, optionally substituted (C1-6)alkyl, optionally substituted (C1-6)alkylhalide, halide, hydroxy, or optionally substituted (C1-6)alkoxy; andR2is H or optionally substituted(C1-6)alkyl;comprising the steps of:i. reacting the amine of Formula (II)R1,v NH2(II)with an aldehyde according to Formula (III)oH^R2(ill); anda compound of formula (IV)H (IV),wherein P is an amine protecting group (e.g., Cbz, Boc, Fmoc etc.),in the presence of a solvent and a chiral catalyst to form an enantiopure compound of formula (V) or a salt thereofn. removing the protecting group in the compound of Formula (V) to form an enantiopure compound of formula (I).

[0244] Clause 2. The method according to clause 1, wherein the method does not include a chiral resolution step.

[0245] Clause 3. The method according to clause 1 or 2, wherein the enantiopure compound of formula (I) is the 2R,4S-enantiomer having the formula (IA) or a salt thereof:

[0246] Clause 4. The method according to clause 3, wherein the compound of formula (IA) is obtained with greater than 99% enantiopurity (e.g., 99.9, greater than 99.95%).

[0247] Clause 5. The method according to clause 4, wherein the compound according to Formula (IA) is obtained with an enantiopurity of 99.9% enantiomeric excess (e.e.) or more.

[0248] Clause 6. The method according to any one of clauses 1 to 5, wherein the chiral catalyst is a chiral Bronsted acid catalyst.

[0249] Clause 7. The method according to clause 6, wherein the chiral catalyst is a BINOL-derived chiral acid.

[0250] Clause 8. The method according to clause 7, wherein the chiral catalyst is a BINOL derived chiral phosphoric acid (e.g., (R)-TRIP, (S)-TRIP, (R)-TiPSY, (S)-TiPSY etc. (preferably (R)-TRIP).

[0251] Clause 9. The method according to clause 8, wherein the chiral catalyst is (R)-TRIP.

[0252] Clause 10. The method according to any one of clauses 1 to 9, wherein the catalyst loading is 1 mol% or less.

[0253] Clause 11. The method according to clause 10, wherein the catalyst loading is 0.5 mol% or less.

[0254] Clause 12. The method according to clause 11, wherein the catalyst loading is 0.1 mol%.

[0255] Clause 13. The method according to clause 11, wherein the catalyst loading is 0.05 mol%.

[0256] Clause 14. The method according to any one of clauses 1 to 13, wherein the ratio of reagent (II): (III): (IV) is 1: 3: 1.2.

[0257] Clause 15. The method according to any one of clauses 1 to 14, wherein the solvent in step i) comprises isopropyl acetate (IP AC).

[0258] Clause 16. The method according to any one of clauses 1 to 15, wherein step i) further comprises a dehydrating agent.

[0259] Clause 17. The method according to clause 16, wherein the dehydrating agent comprises molecular sieves.

[0260] Clause 18. The method according to any one of clauses 1 to 17, wherein the reaction in step i) is conducted at a temperature of from -25 °C to 20 °C.

[0261] Clause 19. The method of clause 18, wherein the reaction in step i) is conducted at about -5 °C.

[0262] Clause 20. The method according to any one of clauses 1 to 17, wherein the reaction in step i) is conducted at a temperature of -5 °C or less.

[0263] Clause 21. The method according to any one of clauses 1 to 20, wherein step i) further comprises a crystallization step.

[0264] Clause 22. The method of clause 21, wherein the crystallization step is conducted in a mixture of isopropyl acetate and a non-polar solvent.

[0265] Clause 23. The method of clause 22, wherein the non-polar solvent comprises one or more alkanes.

[0266] Clause 24. The method of clause 23, wherein the non-polar solvent comprises n-heptane.

[0267] Clause 25. The method of any one of clauses 22 to 24, wherein the ratio of non-polar solvent to IP AC is from 1: 4 to 1: 10.

[0268] Clause 26. The method of any one of the preceding clauses, wherein R1is H, (Ci-Cs)alkyl, (Ci-C3)alkylhalide, halide, hydroxy, or (Ci-C3)alkoxy.

[0269] Clause 27. The method of clause 26, wherein R1is (Ci-C3)alkylhalide.

[0270] Clause 28. The method of clause 27, wherein R1is CF3.

[0271] Clause 29. The method of any one of the preceding clauses wherein R2is methyl, ethyl or propyl.

[0272] Clause 30. The method of clause 29, wherein R2is ethyl.

[0273] Clause 31. The method of any one of the preceding clauses wherein P is selected from benzyloxycarbonyl (Cbz), tertiary butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), and formyl (CHO).

[0274] Clause 32. The method of clause 31, wherein P is Cbz.

[0275] Clause 33. The method of any one of clauses 1 to 32, wherein the compound of Formula (V) obtained in step a) is of the Formula (VA) or a salt thereof:

[0276] Clause 34. The method of clause 33, wherein the compound of Formula (VA) is crystalline.

[0277] Clause 35. The method according to clause 34, wherein the compound of Formula (VA) is obtained from step i) in a yield of at least 80% (e.g., 85.3%).

[0278] Clause 36. The method according to any one of clauses 33 to 35, wherein the compound of formula (VA) is obtained with greater than 99% enantiopurity (e.g., 99.9, greater than 99.95%).

[0279] Clause 37. The method according to clause 36, wherein the compound according to Formula (VA) is obtained with an enantiopurity of 99.9% enantiomeric excess (e.e.) or more.

[0280] Clause 38. The method according to any one of clauses 32 to 37, wherein step ii) comprises a hydrogenation reaction.

[0281] Clause 39. The method of any one of clauses 1 to 38, wherein the compound of Formula (I) is of the Formula (IB):

[0282] Clause 40. The method according to any one of the preceding clauses, wherein the method further comprises:iii. isolation of the compound of Formula (I) as a salt.

[0283] Clause 41. The method according to clause 40, wherein the salt is selected from a sulfonate, a sulfate, a halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate; wherein the sulfonate may be a besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate; the sulfate may be a methylsulfate; and the halogen may be a chloride, iodide, or bromide.

[0284] Clause 42. The method of clause 41, wherein the salt is selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.

[0285] Clause 43. The method of clause 42, wherein the salt is selected from chloride, bromide, bitartrate, and mesylate.

[0286] Clause 44. The method according to clause 43, wherein the salt is mesylate.

[0287] Clause 45. The method according to any one of clauses 1 to 44, wherein the compound of Formula (I) is obtained with greater than 99% enantiopurity (e.g., 99.9, greater than 99.95%).

[0288] Clause 46. A method for preparing a crystalline compound of Formula (VA) or a salt thereof:comprising the steps of:a) reacting the amine of Formula (IIA)(IIA)with an aldehyde according to Formula (IIIA)(IIIA); anda compound of formula (IVA)o(IVA),in the presence of a solvent and a chiral catalyst to form an enantiopure compound of formula (VA); andb) crystallization of the compound of the enantiopure compound of formula (VA) to form a crystalline compound of formula (VA).

[0289] Clause 47. The method according to clause 46, wherein the crystalline compound of Formula (VA) is obtained in a yield of at least 80% (e.g., 85.3%).

[0290] Clause 48. The method according to clause 46 or 47, wherein the compound of formula (VA) is obtained with greater than 99% enantiopurity (e.g., 99.9, greater than 99.95%).

[0291] Clause 49. The method according to clause 48, wherein the compound according to Formula (VA) is obtained with an enantiopurity of 99.9% enantiomeric excess (e.e.) or more.

[0292] Clause 50. The method according to any one of clauses 46 to 49, further comprising:c) converting the compound Formula (VA) to an enantiopure compound of Formula (IB) or a salt thereof:NH2H(IB)

[0293] Clause 51. The method according to clause 50, wherein step c) comprises a hydrogenation reaction.

[0294] Clause 52. The method according to clause 50 or 51, wherein the method further comprises:d) crystallization of the compound of Formula (IB) as a salt.

[0295] Clause 53. The method according to clause 52, wherein the salt of Formula (IB) in step d) is obtained as a compound of Formula (IC) or (ID):(IC) (ID).

[0296] Clause 54. The method according to clause 53, wherein the salt of Formula (IC) or (ID) is chosen from salts with an anion Am' selected from a sulfonate, a sulfate, a halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate; wherein the sulfonate may be a besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate; the sulfate may be a methylsulfate; and the halogen may be a chloride, iodide, or bromide.

[0297] Clause 55. The method of clause 54, wherein the salt with an anion Am' is selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.

[0298] Clause 56. The method of clause 55, wherein the salt with an anion Am' is selected from chloride, bromide, bitartrate, and mesylate.

[0299] Clause 57. The method according to clause 56, wherein the salt with an anion Am' is mesylate.

[0300] Clause 58. The method according to any one of clauses 46 to 57, wherein the method does not include a chiral resolution step.

[0301] Clause 59. The method according to any one of clauses 46 to 58, wherein the chiral catalyst is a chiral Bronsted acid catalyst.

[0302] Clause 60. The method according to clause 59, wherein the chiral catalyst is a BINOL-derived chiral acid.

[0303] Clause 61. The method according to clause 60, wherein the chiral catalyst is a BINOL derived chiral phosphoric acid (e.g., (R)-TRIP, (S)-TRIP, (R)-TiPSY, (S)-TiPSY etc. (preferably (R)-TRIP).

[0304] Clause 62. The method according to clause 61, wherein the catalyst is (R)-TRIP.

[0305] Clause 63. The method according to any one of clauses 46 to 62, wherein the catalyst loading is 1 mol% or less.

[0306] Clause 64. The method according to clause 63, wherein the catalyst loading is 0.5 mol% or less.

[0307] Clause 65. The method according to clause 64, wherein the catalyst loading is 0.1 mol%.

[0308] Clause 66. The method according to clause 64, wherein the catalyst loading is 0.05 mol%.

[0309] Clause 67. The method according to any one of clauses 46 to 66, wherein the ratio of reagent (IIA): (IIIA): (IVA) in step a) is 1: 3: 1.2.

[0310] Clause 68. The method according to any one of clauses 46 to 67, wherein the solvent in step a) comprises isopropyl acetate (IP AC).

[0311] Clause 69. The method according to any one of clauses 46 to 68, wherein step a) further comprises a dehydrating agent.

[0312] Clause 70. The method according to clause 69, wherein the dehydrating agent comprises molecular sieves.

[0313] Clause 71. The method according to any one of clauses 46 to 70, wherein the reaction in step a) is conducted at a temperature of from -25 °C to 20 °C.

[0314] Clause 72. The method of clause 71, wherein the reaction in step a) is conducted at about -5 °C.

[0315] Clause 73. The method according to any one of clauses 46 to 70, wherein the reaction in step a) is conducted at a temperature of -5 °C or less.

[0316] Clause 74. The method according to any one of clauses 46 to 73, wherein the step b) crystallization is conducted in a mixture of isopropyl acetate and a non-polar solvent.

[0317] Clause 75. The method according to clause 74, wherein the non-polar solvent comprises one or more alkanes.

[0318] Clause 76. The method of clause 75, wherein the non-polar solvent comprises heptane.

[0319] Clause 77. The method of any one of clauses 74 to 76, wherein the ratio of non-polar solvent to IP AC is from 1: 4 to 1: 10.

[0320] Clause 78. The method according to any one of clauses 50 to 77, wherein the compound of Formula (IB) is obtained in an overall yield of at least 70% and with greater than 99% enantiopurity (e.g., 99.9, greater than 99.95%).

[0321] Clause 79. The method according to any one of clauses 50 to 78, wherein the method further comprises:(e) preparing a compound of Formula (VII), by coupling a compound of Formula (IB) or a salt thereof, with a compound of Formula (VI):where X1is a leaving group and Y1is a protecting group;(f) preparing a carbamate of Formula (VIII) from the compound of Formula (VII) and isolating as a solid salt form of Formula (IX):VIIwhere Y1is a protecting group, An' is an anion and n is an integer from 1-3;(g) optionally desalting the compound of Formula (IX) and alkylating with a compound of Formula (X) to provide a compound of Formula (XI):(X) (XI)where X2is a leaving group and Y1is a protecting group; and(h) deprotection of the compound of Formula (XI) to provide obicetrapib (1),1wherein the reaction steps (e)-(h) are performed in an organic solvent, compounds (VII), (IX), and (XI) are optionally not isolated from the organic solvent, and wherein the method does not require chromatography.

[0322] Clause 80. The method according to clause 79, wherein the compound of Formula (IB) in step (e) is obtained by applying the following steps before step (e):(pre-el) providing a compound of Formula (IC) or (ID):(ID); and(pre-e2) desalting the compound of Formula (IC) or (ID) to obtain the compound of Formula (IB);wherein the reaction in step (pre-e2) is performed in an organic solvent and the compound of Formula (IB) is optionally not isolated from the organic solvent, and the method does not require chromatography.

[0323] Clause 81. The method according to clause 80, wherein the salt of Formula (IC) or (ID) is chosen from salts with an anion Am' selected from a sulfonate, a sulfate, a halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate; wherein the sulfonate may be a besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate; the sulfate may be a methylsulfate; and the halogen may be a chloride, iodide, or bromide.

[0324] Clause 82. The method of clause 81, wherein the salt with an anion Am' is selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.

[0325] Clause 83. The method of clause 82, wherein the salt with an anion Am' is selected from chloride, bromide, bitartrate, and mesylate.

[0326] Clause 84. The method of any one of clauses 79 to 83, wherein Y1in the compounds of Formulae (VI)-(IX) and (XI) 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.

[0327] Clause 85. The method of clause 84, wherein Y1in the compounds of Formulae (VI)-(IX) and (XI) is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluroethyl, phenyl, 4-methoxybenzyl ester, a 2, 6-di substituted phenol, and a silyl group.

[0328] Clause 86. The method of clause 85, wherein Y1in the compounds of Formulae (VI)-(IX) and (XI) is t-butyl.

[0329] Clause 87. The method of any one of clauses 79 to 86, wherein the salt of Formula (IX) is chosen from salts with an anion An' selected from a sulfonate, a sulfate, a halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate; wherein the sulfonate may be a besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate; the sulfate may be a methylsulfate; and the halogen may be a chloride, iodide, or bromide.

[0330] Clause 88. The method of clause 87, wherein the salt with an anion An' is selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.

[0331] Clause 89. The method of clause 88, wherein the salt with an anion An' is selected from chloride, bromide, bitartrate, and mesylate.

[0332] Clause 90. The method of clause 89, wherein the salt form of Formula (IX) is the mesylate salt, Compound 1D:

[0333] Clause 91. The method of clause 90, wherein the mesylate salt is crystalline.

[0334] Clause 92. The method of any one of clauses 79 to 91, wherein X1in the compound of Formula (VI) is selected from a halogen, a carbamate, and a substituted sulfonyloxy group.

[0335] Clause 93. The method of clause 92, wherein X1in the compound of Formula (VI) is a halogen.

[0336] Clause 94. The method of clause 93, wherein the halogen is chloride.

[0337] Clause 95. The method of any one of clauses 79 to 94, wherein X2in the compound of Formula (X) is selected from a halogen and a substituted sulfonyloxy group.

[0338] Clause 96. The method of clause 95, wherein X2in the compound of Formula (X) is a halogen.

[0339] Clause 97. The method of clause 96, wherein the halogen is bromide.

[0340] Clause 98. A method for preparing an amorphous hemicalcium salt of obicetrapib wherein the method comprises:a) reacting an amine of Formula (IIA) with an aldehyde according to Formula (IIA) and a compound of Formula (IVA) in the presence of a solvent and a chiral catalyst to form an enantiopure compound of Formula (VA):o(IIIA) b) crystallization of the compound of the enantiopure compound of formula (VA) to form a crystalline compound of formula (VA);c) deprotection of the compound Formula (VA) to an enantiopure compound of Formula (IB) or a salt thereof:d) optionally crystallizing the compound of Formula (IB) to form a crystalline compound of Formula (IB);e) preparing a compound of Formula (VII), by coupling a compound of Formula (IB) or a salt thereof, with a compound of Formula (VI):where X1is a leaving group and Y1is a protecting group;(f) preparing a carbamate of Formula (VIII) from the compound of Formula (VII) and isolating as a solid salt form of Formula (IX):(VIII) (IX)where Y1is a protecting group, An' is an anion and n is an integer from 1-3;g) optionally desalting the compound of Formula (IX) and alkylating with a compound of Formula (X) to provide a compound of Formula (XI):IX CF3(X) (XI) where X2is a leaving group and Y1is a protecting group;h) deprotection of the compound of Formula (XI) to provide obicetrapib (1),1(i) treating obicetrapib (1) with HC1 to obtain a crystalline obicetrapib HC1 compound;(j) isolating the crystalline obicetrapib HC1 compound;(k) preparing an amorphous hemicalcium salt of obicetrapib from the crystalline obicetrapib HC1 compound isolated in step (j); and(l) isolating an amorphous hemicalcium salt of obicetrapib.

[0341] Clause 99. The method of clause 98, wherein the isolated crystalline obicetrapib HC1 compound in step (j) comprises a compound of Formula (IH):wherein y varies from 0.002 to 1.5.

[0342] Clause 100. The method according to clause 98 or 99, wherein the preparation of the amorphous hemicalcium salt of obicetrapib in step (k) comprises the following steps:(k-1) converting the crystalline obicetrapib HC1 compound of step (j) to provide obicetrapib in one or more suitable solvents selected from organic solvents and aqueous solvents;(k-2) treating obicetrapib in the organic solvent with aqueous sodium hydroxide to form a sodium salt of obicetrapib; and(k-3) treating the sodium salt of obicetrapib with aqueous calcium chloride to form the amorphous hemicalcium salt of obicetrapib;wherein the compounds in steps (k-1) and (k-2) are optionally not isolated.

[0343] Clause 101. The method according to any one of clauses 98 to 100, wherein the amorphous hemicalcium salt of obicetrapib is amorphous obicetrapib hemicalcium.

[0344] Clause 102. The method of any one of clauses 98 to 101, wherein the amorphous calcium salt of obicetrapib is isolated with a chemical purity of at least 99%.

[0345] Clause 103. Crystalline CbzDIAM.

[0346] Clause 104. Crystalline CbzDIAM having an x-ray powder diffraction pattern comprising a peak at about 7.3°2θ.

[0347] Clause 105. Crystalline CbzDIAM having an x-ray powder diffraction pattern comprising a peak at about 9.4°2θ.

[0348] Clause 106. Crystalline CbzDIAM having an x-ray powder diffraction pattern comprising one or peaks selected from about 7.3°2θ, 9.4°2θ, 12.3°2θ 15.8°2θ, and 18.3°2θ.

[0349] Clause 107. The crystalline CbzDIAM of clause 106, having a differential calorimetry thermogram having an endotherm onset at about 156 °C.

[0350] Clause 108. Crystalline CbzDIAM having an x-ray powder diffraction pattern substantially the same as that of Figure 1.EXAMPLES

[0351] The Examples in this section are offered by way of illustration, and not by way of limitation. The examples can represent only some embodiments, and it should be understood that the following examples are illustrative and not limiting. All substituents, unless otherwise specified, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare the compounds described herein.Improved Synthesis of the mesylate salt of (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1A)MsOH, I PA; H basic resin tr Crystallize from heptane 1A eatment >99.95% enantiopurity >99.95% enantiopurity85% 84%Scheme 1

[0352] With reference to Scheme 1, the mesylate salt of (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1A), was prepared in two steps from 4- (trifluoromethyl)aniline (TFMA). Compound TFMA and benzyl vinyl carbamate (BVC) were simultaneously added to propionaldehyde at low temperature (-5 °C or lower) in the presence of chiral catalyst (R)-3,3'-Bis(2,4,6-triisopropylphenyl)-l,l'-binaphthyl-2,2'-diyl hydrogenphosphate (R)-TRIP to form benzyl ((2R,4S)-2-ethyl-6-(trifluoromethyl)-l,2,3,4-tetrahydroquinolin-4-yl)carbamate (Compound VA) as a crystalline compound in high enantiopurity. Compound VA was then subjected to a hydrogenation reaction, followed by solvent swap and crystallization to obtain the mesylate salt of (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1A) in high enantiopurity.

[0353] Each of the steps in the manufacturing process for the mesylate salt of (2R,4S)-4- amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1A), and the intermediate benzyl carbamate crystalline compound of Formula (VA) will be described in more detail in Examples 1-2 below. The methods in these examples sometimes represent more than one batch prepared of the indicated compounds made.Example 1 Preparation of benzyl ((2R,4S)-2-ethyl-6-(trifluoromethyl)-l, 2,3,4- tetrahydroquinolin-4-yl)carbamate (Compound VA)(R)-TRIP 0.001 eq.-5 °C, IPAC,0.5 g / g 3A MS powder>99.95% enantiopurityMethod A:

[0354] TFMA solution was prepared by mixing 4-(Trifluoromethyl)analine (TFMA) in isopropyl acetate (IP AC) (6.15 kg, 0.49 w / w) and (R)-3,3'-Bis(2,4,6-triisopropylphenyl)-l,l'-binaphthyl-2,2'-diyl hydrogenphosphate (R)-TRIP (14.44 g, 0.001 eq.) in IP AC (2.15 kg); and BVC solution was prepared by dissolving benzyl vinyl carbamate (B VC, 4.40 kg, 1.2 eq) IP AC (5.4 kg) and polish filtering (2L, 20 micron).

[0355] Propionaldehyde (3.30 kg, 3 eq.) was dissolved in isopropyl acetate (IP AC, 5.20 kg) in a reaction vessel along with molecular sieves (3 A, 1.6 kg) and the contents were cooled to -6 °C. The TFMA solution and BVC solution were simultaneously added to the reaction vessel at an initial flow rate of 68 g / min and 213 g / min respectively until a total of 8.35 kg of TFMA solution and 9.20 kg of BVC solution was added (2 hours, 5 minutes for the TFMA solution; and 1 hour 10 minutes for the BVC solution). During addition of the TMFA solution and BVC solution the initial flowrates were reduced by approximately 10%, and the temperature was lowered to -15 °C. The resulting reaction mixture was stirred for 1 hour 15 minutes, at which point the reaction was deemed to be complete by an in-process control (IPC) assay.

[0356] The reaction mixture was then warmed to 20 °C and filtered to remove the molecular sieves. The reaction vessel and collected molecular sieves were rinsed with IP AC (1 volume). Amberlite IRA67 resin (0.1 kg / kg TFMA, 0.3 kg total resin) was added to the combined organic phases and the mixture was stirred for 2 hours. The mixture was then filtered to remove the resin, and rinsed with IP AC.

[0357] The combined reaction mixture organic phases were reduced to approximately 10 L by vacuum distillation at approximately 40 °C, then heptane (13.5 kg) was added, and the solution was distilled back to approximately 10 L (83 / 17 heptane: IP AC w / w).

[0358] The reaction mixture was then adjusted to 37 °C and IP AC (0.89 kg) was added. Heptane (8.75 kg) was then added over approximately 15 minutes. The reaction mixture was held for one hour, then cooled to 20 °C over 200 minutes and held for an additional 14.5 hours. The resulting solids were collected by filtration, washed with IP AC in heptane (approximately 8% v / v), then dried using heated nitrogen and vacuum at 40 °C to provide the title compound as a white crystalline solid (Compound VA, 6.01 kg, 85.3%, >99.95% enantiopurity).Method B:

[0359] TFMA solution was prepared by mixing 4-(Trifluoromethyl)analine (TFMA) (100 g, 1 eq.) and (R)-3,3'-Bis(2,4,6-triisopropylphenyl)-l,l'-binaphthyl-2,2'-diyl hydrogenphosphate (R)-TRIP (044 g, 0.001 eq.) in isopropyl acetate (IP AC) (200 mL); and BVC solution wasprepared by dissolving benzyl vinyl carbamate (BVC, 132 g, 1.2 eq) in IP AC (200 mL), filtering and washing the filtrate with IP AC (50 mL). The combined filtrates were then azeotropically dried by concentrating under vacuum to 200-300 mL below 35 °C, the azeotropic process was repeated as needed by addition of additional IP AC and concentration of the solution to 200-300 mL.

[0360] 3 A molecular sieves (50g) were added to IP AC (600ml). If required, the pH was adjusted to between 9.70 and 10.1 by addition of a solution of 6% HC1 in IP AC.Propionaldehyde (108 g, 3 eq.) is added, then the slurry is cooled to -15°C. Simultaneously the BVC solution was added over 3 hours or more, and the TFMA solution was added over 6 hours or more, maintaining the temperature between -20°C to -12°C. The reaction mixture was then stirred for 2 hours at between -20°C to -12°C. The mixture was then filtered to remove molecular sieves, washing with IP AC (50ml). The combined filtrates were then treated with 3 A molecular sieves (50 g, pH about 11.3) then stirred for 2 hours or more at -20°C to -12°C. The mixture was then filtered and washed with IP AC (2 x 50ml).

[0361] The combined filtrates were concentrated under vacuum at below 35°C to a volume of 300ml, then the mixture was warmed to 37°C. n-Heptane (660ml) was added and then the mixture concentrated under vacuum at below 35°C to a volume of 330ml, then the mixture warmed to 37°C. IP AC (35ml) was added followed by n-heptane (425ml) over 1 hour. The mixture was stirred for 30-60 minutes, cooled to 20°C over 3-4 hours, then stirred for 12 hours.

[0362] The mixture was filtered, washed with a mixture of IP AC and n-heptane (1:9, 200ml, 800ml then 200ml), then dried under vacuum at 40°C to provide the title compound (compound VA, 200 g, 85%).Example 2 Preparation of (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline as the mesylate salt (Compound 1A)4 eq. H2, 200 PSIpacked bed: 200 g, 3%Pd / AI2O38 volumes 1:1 IPA / THF120 °C>99.95% enantiopurity Hydrogenation ReactionMethod A:

[0363] Compound VA Feedstock solution was prepared by dissolving Compound VA (6.1 kg) in tetrahydrofuran (THF, 21.3 kg, 4 volumes) in an inert vessel. The solution was then diluted with isopropyl alcohol (IP A, 18.9 kg, 4 volumes).

[0364] Separately, a 1:1 v / v solution of THF (7.10 kg) and IPA (8.20 kg) was prepared in a second vessel (“Flush solution”).

[0365] A hydrogenation flow reactor was prepared by loading two columns with 100 g of 3 weight % palladium on alumina (Pd / Al2O3) catalyst (200 g, total) using glass wool to secure them. The reactor was flushed with nitrogen for at least 5 minutes then sealed to prevent air intrusion.

[0366] The hydrogenation flow reactor temperature control unit (TCU), temperature heat exchanger, reactor TCU and condenser TCU were set to 50 °C, 20 °C, 20 °C and 5 °C, respectively. The 1:1 THF: IPA flush solution was pumped through the reactor at approximately 100 g / min until the reactor system was fully liquid full, then the pump was adjusted to lOg / min, at 195 psig back pressure, and the hydrogenation flow reactor TCU setpoint was increased to 120 °C.

[0367] Once the desired hydrogenation flow reactor temperature was achieved, the hydrogen flow was set to 2000 SCCM for 30 minutes. After this time, the Compound VA feedstock solution was introduced at a pump flow rate of 50 g / minute. The reaction progress was monitored via high performance liquid chromatography, and temperature, pressure and flowrates were adjusted as necessary to achieve over 95% conversion from compound VA to compound IB. Any fractions that did not achieve over 95% conversion of compound VA to IB were processed through the hydrogenation reactor again.

[0368] The hydrogenation process was repeated over multiple batches to obtain the intermediate compound IB with an average conversion from compound VA of 97.2%. Compound IB was used directly in the next step without further purification.Compound 1A crystallization

[0369] Following the hydrogenation reaction, crude compound IB solution (36.88 kg) was concentrated to approximately 8 L by vacuum distillation at 40 °C. IPA (13.1 kg) was then added, and the vacuum distillation process was continued until the solvent volume was approxiamtely 15 L with a composition of <1 w / w% THF. Additional IPA (1.15 kg) was added to adjust the final volume to about 16.6 L.

[0370] The reaction mixture was then warmed to 23 °C and methane sulfonic acid (MSA) (57% MSA in IPA, 2.0 kg total solution) was added over 2.5 hours. The resulting reaction mixture was held for 20 minutes at approximately 25 °C, then heptane (4.6 kg) was added over 1 hour, and the resulting slurry was cooled to 4.5 °C at a rate of 0.1 °C / min. The slurry was held over night at 5 °C, at which point IPC analysis indicated the crystallization was complete.

[0371] The solids were collected by filtration and washed with 2.5 kg IPA:heptane (44:56 w / w). The solids were dried under light vacuum using heated nitrogen (40.2 °C) until heptane and IP AC targets of <8000 ppm and <4000 ppm respectively were achieved. The title compound 1A was obtained as a white solid (4.04 kg, 99.7% yield, >99.95% enantiopurity). Method B:

[0372] 5% Pd / C (5.6g) was added to a solution of compound VA (1 eq.) in IPA (500ml) at 25 °C. The mixture was hydrogenated (H2 pressure 4-5kg / cm2) until no further uptake of H2 was observed. The mixture was filtered, and washed the IPA (100ml). The combined filtrates contained compound IB, and was used directly in the next step without further purification.

[0373] The combined filtrates containing compound IB were concentrated under vacuum below 40°C to a final volume of 400ml then cooled to 25°C. A solution of methane sulfonic acid (28g, 1.1 eq.) in IPA (65ml) was added over 1 hour or more, then n-heptane (230ml) was added over 1-2 hours. The mixture was cooled to 0°C then stirred for 8-10 hours. The mixture was filtered, the solids washed with IPA / n-heptane (2:5, 50ml, 450ml, then 100ml), then the solids were dried at below 40°C to provide the title compound (compound IA (80g, 89%). Improved Synthesis of amorphous obicetrapib hemicalcium (compound 3)A1 2 eq. benzyl vinylcarbamate (BVC) 3 eq. EtCHOCF3H2, Pd / AI2O3, IPA / THF;MsOH, IPA; 3A MS, IPAC, -5 °C; basic resin treatment Crystallize from heptane >99.95% enantiopurity 84% >99.95% enantiopurity 85%Scheme 2

[0374] With reference to Scheme 2, amorphous obicetrapib hemicalcium (compound 3) was prepared in eight chemical steps and five isolations starting from a highly enantioselective one pot Povarov reaction of 4-(Trifluoromethyl)analine (TFMA), benzyl vinyl carbamate (BVC)and propionaldehyde (EtCHO). Compound TFMA and benzyl vinyl carbamate (BVC) were simultaneously added to propionaldehyde (EtCHO) at low temperature in the presence of a chiral catalyst ((R)-3,3'-Bis(2,4,6-triisopropylphenyl)-l,l'-binaphthyl-2,2'-diyl hydrogenphosphate (R)-TRIP) to form benzyl ((2R,4S)-2-ethyl-6-(trifluoromethyl)-l,2,3,4-tetrahydroquinolin-4-yl)carbamate (Compound VA) as a crystalline compound with high enantiopurity. Compound VA was then subjected to a hydrogenation reaction, followed by crystallization to obtain the mesylate salt of (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1A) with equally high enantiopurity. Compound 1A was then coupled with compound IB through a palladium-catalyzed reaction to produce a solution of (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (compound 1C), which was not isolated but directly reacted with excess ethyl chloroformate in the presence of pyridine to produce (2R,4S)-4-[5-(3-t-butoxycarbonylpropoxy)pyrimidin-2-yl)]amino-2-ethyl-6-trifluoromethyl-3, 4-dihy dro-2H-quinoline-l -carboxylic acid ethyl ester, which was isolated as a crystalline mesylate salt (Compound ID). The crystalline mesylate salt, Compound ID was alkylated with 3,5 bis(trifluoromethyl)benzyl bromide (compound IE) under strongly basic conditions to produce a solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-t-butoxycarbonylpropoxy) pyrimi din-2 -yl]amino}-2-ethyl-6-trifluoromethyl-3, 4-dihy dro-2H-quinoline-l -carboxylic acid ethyl ester (compound IF) in toluene. Compound IF was then subjected to an acidic cleavage of the tert-butyl ester to produce a solution of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (compound 1). Compound 1 was then converted to compound 2, which is a solvate of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimi din-2 -yl]amino}-2-ethyl-6-tri fluoromethyl-3, 4-dihy dro-2H-quinoline-1 -carboxylic acid ethyl ester (compound 2). Finally, compound 2 was converted to the amorphous hemicalcium salt (compound 3) and milled to the target particle size. Compound 2 is crystalline obicetrapib HC1 and compound 3 is amorphous obicetrapib hemicalcium.

[0375] Each of the steps in the manufacturing process for the mesylate salt of (2R,4S)-4-amino-2-ethyl-6-trifluoromethyl-3, 4-dihy dro-2H-quinoline (compound 1A) starting from the highly enantioselective one pot Povarov reaction of 4-(Trifluoromethyl)analine (TFMA), benzyl vinyl carbamate (BVC) and propionaldehyde (EtCHO), is described above in Examples 1 and 2.

[0376] Each of the steps in the manufacturing process for (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-carboxypropoxy)pyrimidin-2-yl]amino}-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (compound 1) from compound 1A, the intermediate HC1 intermediate (compounds 2), and the corresponding amorphous calcium salt (compound 3) is described in Examples 1-16 of U. S. Patent No.12,006,305, the disclosure of which is incorporated herein by reference in its entirety.

[0377] With reference to US 12,006,305, examples 1-3, 5, 7, 9, 11-12 describe a method for manufacturing steps in the process for preparing amorphous obicetrapib hemicalcium (compound 3); and Examples 4, 6, 8, 10 and 13 provide additional methods of preparing the compounds indicated. The methods in these examples sometimes represent more than one batch prepared of the indicated compounds made. US 12,006,305, examples 14-15 describe methods for milling amorphous obicetrapib hemicalcium (compound 3); and example 16 describes a method for preparing crystalline obicetrapib hemicalcium. An FT-IR spectrum of milled amorphous obicetrapib hemicalcium can be found in Figure 4 of US 12,006,305. A solution-state 'H-NMR spectrum consistent with chemical structure of obicetrapib hemicalcium can be found at Figure 5 of US 12,006,305.Example 3 - X-ray Powder Diffraction (XRPD)

[0378] XRPD was performed with a Bruker D2 Phaser in transmission mode. The sample was prepared as a thin layer and measured in accordance with the parameters set forth in Table 1.Table 1Parameter ValueDetector Lynxeye (ID mode)CoupledScan Type TwoTheta / ThetaScan Mode Continuous PSD Fast2Theta-Start 6.5°2Theta-Stop 40°Time / Step 0.325°PSD opening 5°

[0379] Figure 1 illustrates an x-ray powder diffraction pattern of crystalline CbzDIAM.

[0380] Figure 2 illustrates a peak-picked x-ray powder diffraction pattern of crystalline CbzDIAM.

[0381] A peak table associated with the calculated pattern of crystalline CbzDIAM is set forth in Table 2.Table 2°20 Intensity7.3 2105.09.4 12164.012.3 9284.015.8 11441.018.3 16666.018.9 3704.020.5 5488.021.2 12914.022.0 3853.022.5 5797.024.3 2545.025.4 1942.027.2 2455.030.0 1958.0Example 4 - Differential Scanning Calorimetry (DSC)

[0382] A Mettler toledo DSC with a closed pan configuration was used for differential scanning calorimetry measurements. The ramp rate was 30 °C to 200 °C at 5 ° / min and the closed pan was a 40 pL single-use gold-plated pan.

[0383] Figure 3 illustrates a differential scanning calorimetry thermogram of crystalline CbzDIAM.Example 5 - Optimization Studies for synthesis of benzyl ((2R,4S)-2-ethyl-6-(trifluoromethyl)-l,2,3,4-tetrahydroquinolin-4-yl)carbamate (Compound VA)Catalyst studies

[0384] Experiments were carried out to assess the suitability of various chiral catalysts for the Povarov reaction. The results are set out in Table 3 below.RTable 3Structure of R Solvent Yield (% HPLC) e.r.R=.i-Pr THF 82% <1:99i-Pr^^'Ki-PrTHF 76% 11:89THF 80% 8:92CF3THF 70% 13:87’Xi' \^CF3R=.i-Pr IPAC 80% 2:98i-Pr~^^'")\i-PrIPAC 71% 14:86CF3IPAC 69% 14:86R£1' ^^CF3Carbamate Studies

[0385] Experiments were carried out to assess the suitability of various carbamates for the Povarov reaction. The results are set out in Table 4 below.Table 4Structure of R Catalyst, Solvent Yield (% HPLC) e.r.o (R)-TRIP, IPAC Not determined 86:14tBuO^N^55^HStructure of R Catalyst, Solvent Yield (% HPLC) e.r.0 (R)-TRIP, IP AC 32% 89:11HO (R)-TRIP, IP AC 80% 2:98H (BVC)Catalyst Loading and Addition Order

[0386] Experiments were carried out to assess the TRIP catalyst loading and the addition order of reagents in the Povarov reaction.1.2 eq. BVC1.0 eq TFMA

[0387] Reactions were carried out as indicated in Table 5 below using various addition orders:• A: A solution of TFMA + TRIP catalyst (TFMA solution) was added to a solution of aldehyde (CH3CH2CHO) + BVC.• B: A solution of aldehyde was added to a solution of TFMA + TRIP catalyst + BVC.• C: A solution of TFMA and a solution of aldehyde were added separately to a solution of BVC + TRIP catalyst.• D: A solution of TMFA + TRIP catalyst (TFMA solution) and a solution of BVC (BVC solution) were added separately to a solution of aldehyde.

[0388] The results are set out in Table 5 below.Table 5Catalyst Catalyst Temp. Yield e.r. Addition Addition loading Enantiomer (°C) time order (mol%) (mins)1 S -25 84% 3:97 20 A0.1 R -25 79% >2:98 20 A0.01 S -25 31% ND. 10 A0.05 S -25 64% 0.1:99.9 20 A0.05 s -15 67% 0.9:99.1 20 A0.05 s -5 74% 0.1:99.9 40 ACatalyst Catalyst Temp. Yield e.r. Addition Addition loading Enantiomer (°C) time order (mol%) (mins)0.05 S -5 35% ND. 25 B0.05 S -5 73% 0.1:99.9 60 C0.05 s -5 68% (1.05 0.3:99.7 60 Ceq. BVC)0.05 s 5 61% 0.1:99.9 60 C *N. D. = not determined

[0389] The following impurities were sometimes observed under various reaction conditions carried out in Table 5:HO NHCbzHImpurity 2

[0390] Without being bound to any particular theory, it is believed that impurity 1 may arise due to low amounts of aldehyde present at the start of the reaction relative to the amount of BVC present, and impurity 2 may arise due to residual water present in the reaction mixture. Adjusting Amounts of aldehyde and carbamate

[0391] Experiments were carried out to assess if adjusting the amount and order of carbamate (BVC) and aldehyde (CH3CH2CHO) added in the Povarov reaction would eliminate the occurrence of Impurity 1. The results are set out in Table 6 below.Table 6TFMA BVC (eq.) CH3CH2CHO Addition Time point Impurity 1 (eq.) (eq.) Order (hours) vs compound VA (%) 1.0 1.2 1.5 C 2 0.111.0 1.0 1.5 C 2 0.061.0 1.2 1.5 A 2 0.051.0 1.2 3 A 2 0.021.0 1.2 3 A 26** 1.301.0 1.0 0 N / A* 4 2***1.0 1.2 3 D 2 0.04 Note: all reactions were carried out with 0.1 mol% (R)-TRIP catalyst loading at -5 °C in 6 volumes of IP AC. *N / A = not applicable; ** 24 h at 40 °C after complete addition; *** Compound VA not detected.

[0392] As seen in Table 6, increasing the amount of aldehyde present at the start of reaction relative to the amount of BVC decreases the occurrence of impurity 1. The amount of aldehyde present at the start of the reaction can be increased by a) increasing the number of equivalents of the aldehyde; and b) using dosing method D over two hours (addition of a solution of TFMA + TRIP (TFMA solution) and a separate solution of BVC (BVC solution) to a solution of the aldehyde).Desiccant Addition

[0393] Experiments were carried out to assess if the addition of a desiccant to the Povarov reaction would eliminate the occurrence of Impurity 2. The results are set out in Table 7 below.Table 7Desiccant Loading Scale Temp. Compound Impurity Isolated (g / g (g TFMA) (°C) VA (%)* 2 (%)* yield TFMA)None N / A 1.0 -5 90.7 5.2 56%3 Å 1.0 1.0 -5 95.6 2.4% 72% molecularsieve(MS)powder3 Å MS 0.5 10.0 -5 94.3 2.5 82%** powderMgSO41.0 1.0 -5 89.6 5.2 58%*** 3 Å MS 1.0 0.2 20 89.0 5.5 58%*** powder(postreaction)3 Å MS 0.5 10.0 -5 90.0 6.0 64% (crushedspheres)Note: all reactions were carried out with 1.0 eq. TFMA, 1.2 eq. BVC, 1.5 eq. CH3CH2CHO and 0.1 mol% (R)-TRIP catalyst loading in 6 volumes of IP AC. *percentage as liquid chromatography area percent (LCAP); ** 99.95% enantiopurity: *** as measured by quantitative NMR (qNMR).

[0394] As seen in Table 7, addition of 3 Å molecular sieve (MS) powder reduced the amount of impurity 2 formed relative to the same reaction performed in the absence of a desiccant.6. EQUIVALENTS AND INCORPORATION BY REFERENCE

[0395] While the disclosure has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the disclosure.

[0396] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.

Claims

1. WHAT IS CLAIMED IS:

1. A method for preparing an enantiopure compound of Formula I or a salt thereof:

4. 6.wherein:7.R1is H, optionally substituted (C1-6)alkyl, optionally substituted (C1-6)alkylhalide, halide, hydroxy, or optionally substituted (C1-6)alkoxy; and8.R2is H or optionally substituted(C1-6)alkyl;9.comprising the steps of:10.i. reacting the amine of Formula (II)11.R1,13.

14. NH2(II)15.with an aldehyde according to Formula (III)16.o17.H18.

19. R2(III); and20.a compound of formula (IV)22.

23. H (IV),24.wherein P is an amine protecting group (e.g., Cbz, Boc, Fmoc etc.),25.in the presence of a solvent and a chiral catalyst to form an enantiopure compound of formula (V) or a salt thereof27. 29.n. removing the protecting group in the compound of Formula (V) to form an enantiopure compound of formula (I).

2. The method according to claim 1, wherein the method does not include a chiral resolution step.

3. The method according to claim 1 or 2, wherein the enantiopure compound of formula(I) is the 2R,4S-enantiomer having the formula (IA) or a salt thereof:32.NH234. 35.H(IA).

4. The method according to claim 3, wherein the compound of formula (IA) is obtained with greater than 99% enantiopurity.

5. The method according to claim 4, wherein the compound according to Formula (IA) is obtained with an enantiopurity of 99.9% enantiomeric excess (e.e.) or more.

6. The method according to any one of claims 1 to 5, wherein the chiral catalyst is a chiral Bronsted acid catalyst.

7. The method according to claim 6, wherein the chiral catalyst is a BINOL-derived chiral acid.

8. The method according to claim 7, wherein the chiral catalyst is a BINOL derived chiral phosphoric acid.

9. The method according to claim 8, wherein the chiral catalyst is (R)-TRIP.

10. The method according to any one of claims 1 to 9, wherein the catalyst loading is 1 mol% or less.

11. The method according to claim 10, wherein the catalyst loading is 0.5 mol% or less.

12. The method according to claim 11, wherein the catalyst loading is 0.1 mol%.

13. The method according to claim 11, wherein the catalyst loading is 0.05 mol%.

14. The method according to any one of claims 1 to 13, wherein the ratio of reagent (II): (III): (IV) is 1: 3: 1.2.

15. The method according to any one of claims 1 to 14, wherein the solvent in step i) comprises isopropyl acetate (IP AC).

16. The method according to any one of claims 1 to 15, wherein step i) further comprises a dehydrating agent.

17. The method according to claim 16, wherein the dehydrating agent comprises molecular sieves.

18. The method according to any one of claims 1 to 17, wherein the reaction in step i) is conducted at a temperature of from -25 °C to 20 °C.

19. The method of claim 18, wherein the reaction in step i) is conducted at about -5 °C.

20. The method according to any one of claims 1 to 17, wherein the reaction in step i) is conducted at a temperature of -5 °C or less.

21. The method according to any one of claims 1 to 20, wherein step i) further comprises a crystallization step.

22. The method of claim 21, wherein the crystallization step is conducted in a mixture of isopropyl acetate and a non-polar solvent.

23. The method of claim 22, wherein the non-polar solvent comprises one or more alkanes.

24. The method of claim 23, wherein the non-polar solvent comprises heptane.

25. The method of any one of claims 22 to 24, wherein the ratio of non-polar solvent to IP AC is from 1: 4 to 1: 10.

26. The method of any one of the preceding claims, wherein R1is H, (C1-C3)alkyl, (C1-C3)alkylhalide, halide, hydroxy, or (C1-C3)alkoxy.

27. The method of claim 26, wherein R1is (Ci-C3)alkylhalide.

28. The method of claim 27, wherein R1is CF3.

29. The method of any one of the preceding claims wherein R2is methyl, ethyl or propyl.

30. The method of claim 29, wherein R2is ethyl.

31. The method of any one of the preceding claims wherein P is selected from benzyloxycarbonyl (Cbz), tertiary butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), and formyl (CHO).

32. The method of claim 31, wherein P is Cbz.

33. The method of any one of claims 1 to 32, wherein the compound of Formula (V) obtained in step a) is of the Formula (VA) or a salt thereof:

65.

34. The method of claim 33, wherein the compound of Formula (VA) is crystalline.

35. The method according to claim 34, wherein the compound of Formula (VA) is obtained from step i) in a yield of at least 80%.

36. The method according to any one of claims 33 to 35, wherein the compound of formula (VA) is obtained with greater than 99% enantiopurity.

37. The method according to claim 36, wherein the compound according to Formula (VA) is obtained with an enantiopurity of 99.9% enantiomeric excess (e.e.) or more.

38. The method according to any one of claims 32 to 37, wherein step ii) comprises a hydrogenation reaction.

39. The method of any one of claims 1 to 38, wherein the compound of Formula (I) is of the Formula (IB):73.N75.

76. (IB).

40. The method according to any one of the preceding claims, wherein the method furthercomprises:78.iii. isolation of the compound of Formula (I) as a salt.

41. The method according to claim 40, wherein the salt is selected from a sulfonate, a sulfate, a halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate; wherein the sulfonate may be a besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate; the sulfate may be a methylsulfate; and the halogen may be a chloride, iodide, or bromide.

42. The method of claim 41, wherein the salt is selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.

43. The method of claim 42, wherein the salt is selected from chloride, bromide, bitartrate, and mesylate.

44. The method according to claim 43, wherein the salt is mesylate.

45. The method according to any one of claims 1 to 44, wherein the compound of Formula (I) is obtained with greater than 99% enantiopurity.

46. A method for preparing a crystalline compound of Formula (VA) or a salt thereof:

86. 88.comprising the steps of:89.a) reacting the amine of Formula (IIA)91. 93.with an aldehyde according to Formula (IIIA)94.

95. H (HIA); and96.a compound of formula (IVA)97.o98.H JH100.

101. (IVA),102.in the presence of a solvent and a chiral catalyst to form an enantiopure compound of formula (VA); and103.b) crystallization of the compound of the enantiopure compound of formula (VA) to form a crystalline compound of formula (VA).

47. The method according to claim 46, wherein the crystalline compound of Formula (VA) is obtained in a yield of at least 80%.

48. The method according to claim 46 or 47, wherein the compound of formula (VA) is obtained with greater than 99% enantiopurity.

49. The method according to claim 48, wherein the compound according to Formula (VA) is obtained with an enantiopurity of 99.9% enantiomeric excess (e.e.) or more.

50. The method according to any one of claims 46 to 49, further comprising:108.c) converting the compound Formula (VA) to an enantiopure compound of Formula (IB) or a salt thereof:109.NH2111. 112.H(IB)51. The method according to claim 50, wherein step c) comprises a hydrogenation reaction.

52. The method according to claim 50 or 51, wherein the method further114.comprises:115.d) crystallization of the compound of Formula (IB) as a salt.

53. The method according to claim 52, wherein the salt of Formula (IB) in step d) is obtained as a compound of Formula (IC) or (ID):

118.

54. The method according to claim 53, wherein the salt of Formula (IC) or (ID) is chosen from salts with an anion Am' selected from a sulfonate, a sulfate, a halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate; wherein the sulfonate may be a besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate; the sulfate may be a methylsulfate; and the halogen may be a chloride, iodide, or bromide.

55. The method of claim 54, wherein the salt with an anion Am' is selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.

56. The method of claim 55, wherein the salt with an anion Am' is selected from chloride, bromide, bitartrate, and mesylate.

57. The method according to claim 56, wherein the salt with an anion Am' is mesylate.

58. The method according to any one of claims 46 to 57, wherein the method does not include a chiral resolution step.

59. The method according to any one of claims 46 to 58, wherein the chiral catalyst is a chiral Bronsted acid catalyst.

60. The method according to claim 59, wherein the chiral catalyst is a BINOL-derived chiral acid.

61. The method according to claim 60, wherein the chiral catalyst is a BINOL derived chiral phosphoric acid.

62. The method according to claim 61, wherein the catalyst is (R)-TRIP.

63. The method according to any one of claims 46 to 62, wherein the catalyst loading is 1 mol% or less.

64. The method according to claim 63, wherein the catalyst loading is 0.5 mol% or less.

65. The method according to claim 64, wherein the catalyst loading is 0.1 mol%.

66. The method according to claim 64, wherein the catalyst loading is 0.05 mol%.

67. The method according to any one of claims 46 to 66, wherein the ratio of reagent (IIA): (IIIA): (IVA) in step a) is 1: 3: 1.2.

68. The method according to any one of claims 46 to 67, wherein the solvent in step a) comprises isopropyl acetate (IP AC).

69. The method according to any one of claims 46 to 68, wherein step a) further comprises a dehydrating agent.

70. The method according to claim 69, wherein the dehydrating agent comprises molecular sieves.

71. The method according to any one of claims 46 to 70, wherein the reaction in step a) is conducted at a temperature of from -25 °C to 20 °C.

72. The method of claim 71, wherein the reaction in step a) is conducted at about -5 °C.

73. The method according to any one of claims 46 to 70, wherein the reaction in step a) is conducted at a temperature of -5 °C or less.

74. The method according to any one of claims 46 to 73, wherein the step b) crystallization is conducted in a mixture of isopropyl acetate and a non-polar solvent.

75. The method according to claim 74, wherein the non-polar solvent comprises one or more alkanes.

76. The method of claim 75, wherein the non-polar solvent comprises n-heptane.

77. The method of any one of claims 74 to 76, wherein the ratio of non-polar solvent to IP AC is from 1: 4 to 1: 10.

78. The method according to any one of claims 50 to 77, wherein the compound of Formula (IB) is obtained in an overall yield of at least 70% and with greater than 99% enantiopurity.

79. The method according to any one of claims 50 to 78, wherein the method further comprises:144.(e) preparing a compound of Formula (VII), by coupling a compound of Formula (IB) or a salt thereof, with a compound of Formula (VI):

146.

147. (f) preparing a carbamate of Formula (VIII) from the compound of Formula (VII) and isolating as a solid salt form of Formula (IX):148.VII150. 152.(VIII) (IX)153.where Y1is a protecting group, An' is an anion and n is an integer from 1-3;154.(g) optionally desalting the compound of Formula (IX) and alkylating with a compound of Formula (X) to provide a compound of Formula (XI):

156. 158.(X) (XI)159.where X2is a leaving group and Y1is a protecting group; and160.(h) deprotection of the compound of Formula (XI) to provide obicetrapib (1),162. 164.1165.wherein the reaction steps (e)-(h) are performed in an organic solvent, compounds (VII), (IX), and (XI) are optionally not isolated from the organic solvent, and wherein the method does not require chromatography.

80. The method according to claim 79, wherein the compound of Formula (IB) in step (e) is obtained by applying the following steps before step (e):166.(pre-el) providing a compound of Formula (IC) or (ID):

168.

169. (ID); and170.(pre-e2) desalting the compound of Formula (IC) or (ID) to obtain the compound of Formula (IB);171.wherein the reaction in step (pre-e2) is performed in an organic solvent and the compound of Formula (IB) is optionally not isolated from the organic solvent, and the method does not require chromatography.

81. The method according to claim 80, wherein the salt of Formula (IC) or (ID) is chosen from salts with an anion Am' selected from a sulfonate, a sulfate, a halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate; wherein the sulfonate may be a besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate; the sulfate may be a methylsulfate; and the halogen may be a chloride, iodide, or bromide.

82. The method of claim 81, wherein the salt with an anion Am' is selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.

83. The method of claim 82, wherein the salt with an anion Am' is selected from chloride, bromide, bitartrate, and mesylate.

84. The method of any one of claims 79 to 83, wherein Y1in the compounds of Formulae (VI)-(IX) and (XI) 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.

85. The method of claim 84, wherein Y1in the compounds of Formulae (VI)-(IX) and (XI) is selected from t-butyl, methyl, ethyl, benzyl, allyl, substituted allyl, 2,2,2-trifluroethyl, phenyl, 4-methoxybenzyl ester, a 2,6-disubstituted phenol, and a silyl group.

86. The method of claim 85, wherein Y1in the compounds of Formulae (VI)-(IX) and (XI) is t-butyl.

87. The method of any one of claims 79 to 86, wherein the salt of Formula (IX) is chosen from salts with an anion An' selected from a sulfonate, a sulfate, a halogen, acetate, aspartate, benzoate, bicarbonate, bitartrate, carbonate, citrate, decanoate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mucate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, and teoclate; wherein the sulfonate may be a besylate, tosylate, napsylate, camsylate, esylate, edisylate, or mesylate; the sulfate may be a methylsulfate; and the halogen may be a chloride, iodide, or bromide.

88. The method of claim 87, wherein the salt with an anion An' is selected from chloride, bromide, bitartrate, a sulfate, and a sulfonate.

89. The method of claim 88, wherein the salt with an anion An' is selected from chloride, bromide, bitartrate, and mesylate.

90. The method of claim 89, wherein the salt form of Formula (IX) is the mesylate salt, Compound 1D:

182.

91. The method of claim 90, wherein the mesylate salt is crystalline.

92. The method of any one of claims 79 to 91, wherein X1in the compound of Formula (VI) is selected from a halogen, a carbamate, and a substituted sulfonyloxy group.

93. The method of claim 92, wherein X1in the compound of Formula (VI) is a halogen.

94. The method of claim 93, wherein the halogen is chloride.

95. The method of any one of claims 79 to 94, wherein X2in the compound of Formula (X) is selected from a halogen and a substituted sulfonyloxy group.

96. The method of claim 95, wherein X2in the compound of Formula (X) is a halogen.

97. The method of claim 96, wherein the halogen is bromide.

98. A method for preparing an amorphous hemicalcium salt of obicetrapib wherein the method comprises:191.a) reacting an amine of Formula (IIA) with an aldehyde according to Formula (IIA) and a compound of Formula (IVA) in the presence of a solvent and a chiral catalyst to form an enantiopure compound of Formula (VA):192.o H194.

195. (IIIA) b) crystallization of the compound of the enantiopure compound of formula (VA) to form a crystalline compound of formula (VA);196.c) deprotection of the compound Formula (VA) to an enantiopure compound of Formula (IB) or a salt thereof:197.NH2198.CF3199.VA200.N202.

203. H (IB);204.d) optionally crystallizing the compound of Formula (IB) to form a crystalline compound of Formula (IB); e) preparing a compound of Formula (VII), by coupling a compound of Formula (IB) or a salt thereof, with a compound of Formula (VI):

206.

207. where X1is a leaving group and Y1is a protecting group;208.(f) preparing a carbamate of Formula (VIII) from the compound of Formula (VII) and isolating as a solid salt form of Formula (IX):209.VII211. 213.(VIII) (IX)214.where Y1is a protecting group, An' is an anion and n is an integer from 1-3;215.g) optionally desalting the compound of Formula (IX) and alkylating with a compound of Formula (X) to provide a compound of Formula (XI):216.IX218.

219. (X) where X2is a leaving group and Y1is a protecting group; h) deprotection of the compound of Formula (XI) to provide obicetrapib (1),221. 223.(i) treating obicetrapib (1) with HC1 to obtain a crystalline obicetrapib HC1 compound;224.(j) isolating the crystalline obicetrapib HC1 compound;225.(k) preparing an amorphous hemicalcium salt of obicetrapib from the crystalline obicetrapib HC1 compound isolated in step (j); and226.(l) isolating an amorphous hemicalcium salt of obicetrapib.

99. The method of claim 98, wherein the isolated crystalline obicetrapib HC1 compound in step (j) comprises a compound of Formula (IH):228.HO2C^^OX^N229.r if230.CF N N CF3231.%'S CF3233. 235.wherein y varies from 0.002 to 1.5.

100. The method according to claim 98 or 99, wherein the preparation of the amorphous hemicalcium salt of obicetrapib in step (k) comprises the following steps:237.(k-1) converting the crystalline obicetrapib HC1 compound of step (j) to provide obicetrapib in one or more suitable solvents selected from organic solvents and aqueous solvents;238.(k-2) treating obicetrapib in the organic solvent with aqueous sodium hydroxide to form a sodium salt of obicetrapib; and239.(k-3) treating the sodium salt of obicetrapib with aqueous calcium chloride to form the amorphous hemicalcium salt of obicetrapib;240.wherein the compounds in steps (k-1) and (k-2) are optionally not isolated.

101. The method according to any one of claims 98 to 100, wherein the amorphous hemicalcium salt of obicetrapib is amorphous obicetrapib hemicalcium.

102. The method of any one of claims 98 to 101, wherein the amorphous calcium salt of obicetrapib is isolated with a chemical purity of at least 99%.

103. Crystalline CbzDIAM.

104. Crystalline CbzDIAM having an x-ray powder diffraction pattern comprising a peak at about 7.3°2θ.

105. Crystalline CbzDIAM having an x-ray powder diffraction pattern comprising a peak at about 9.4°2θ.

106. Crystalline CbzDIAM having an x-ray powder diffraction pattern comprising one or peaks selected from about 7.3°2θ, 9.4°2θ, 12.3°2θ 15.8°2θ, and 18.3°2θ.

107. The crystalline CbzDIAM of claim 106, having a differential calorimetry thermogram having an endotherm onset at about 156 °C.

108. Crystalline CbzDIAM having an x-ray powder diffraction pattern substantially the same as that of Figure 1.

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