Methods for the preparation of LP(a) inhibitor compounds

Abstract

Methods for the preparation of Lp(a) inhibitor compounds, such as muvalaplin. Convergent synthetic process to prepare Lp(a) inhibitor compounds, such as muvalaplin, with a fewer number of synthetic steps than a linear synthetic process. Disclosed herein are also crystalline intermediates that can be separately isolated during the preparation of Lp(a) inhibitor compounds, such as muvalaplin, that allow for the easier purification of the final product.

Description

METHODS FOR THE PREPARATION OF LP(A) INHIBITOR COMPOUNDSFIELD OF THE INVENTION

[0001] The present invention relates to the fields of pharmaceutical chemistry and synthetic organic chemistry, and provides processes and a novel crystalline intermediate for the preparation of Lp(a) inhibitor compounds, such as (2S,2'S,2"S)-3,3',3"-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid), or muvalaplin.BACKGROUND OF THE INVENTION

[0002] It has been previously reported, such as in U.S. Patent No. 11,286,249, that certain Lp(a) inhibitor compounds, such as (2S,2'S,2"S)-3,3',3"-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid), or muvalaplin, can be used to reduce Lp(a) levels.

[0003] While methods for the preparation of Lp(a) inhibitor compounds, such as muvalaplin have been previously reported in U.S. Patent No. 11,286,249, these methods are more suitable for the preparation of Lp(a) inhibitor compounds, such as muvalaplin, at laboratory scale. Thus, there is a need for alternative methods for the commercial scale preparation of Lp(a) inhibitor compounds, such as muvalaplin.SUMMARY OF THE INVENTION

[0004] Accordingly, the present invention is directed to methods for the preparation of Lp(a) inhibitor compounds, such as muvalaplin. It has been unexpectedly found that the convergent synthesis of Lp(a) inhibitor compounds can lead to a route to these compounds with a fewer number of steps and lead to the efficient isolation of a crystalline intermediate compound, tritert-butyl 3,3',3"-((2S,2'S,2"S)-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(3-(((lS')-l-hydroxy-3-phenylpropan-2-yl)amino)-3-oxopropane-l,2-diyl))(3R,3'R,3"R)-tris(pyrrolidine-l-carboxylate). The existence of a crystalline intermediate can lead to impurity rejection, which can improve the purity of the muvalaplin final product without the need for extensive purification at the final step of the preparation.

[0005] In an aspect, provided herein is a method to prepare Lp(a) inhibitor compounds using a convergent synthetic process through a novel crystalline intermediate.

[0006] Disclosed herein is a method for the preparation of an Lp(a) inhibitor compound of the formula:, wherein the method comprises the steps of:(a) combining a pyrrolidine compound of the formula:comprises Ci to Cio alkyl, C3 to C7 cycloalkyl, a four member to seven-member heterocycloalkyl, a Cr, to Cio aryl, a four member to seven-member heteroaryl, or combinations thereof;, wherein X is Cl, Br, I, OTs, OTf, or OMs,to form a trialkylated compound of the formula:(b) combining the trialkylated compound with a hydroxide or an alkoxide to form an intermediate compound of the formula:(c) combining the intermediate compound with an acid to form the Lp(a) inhibitor compound.

[0007] Also disclosed herein is a method of preparing an Lp(a) inhibitor compound of the formula:n the method comprises the steps of: (a) combining a pyrrolidine compound of the formula:, I, OTs, OTf, or OMs;to form a trialkylated compound of the formula:(b) combining the trialkylated compound with a hydroxide or an alkoxide to form an intermediate compound of the formula:(c) combining the intermediate compound with an acid to form the Lp(a) inhibitor compound.

[0008] Also disclosed herein a method of preparing an Lp(a) inhibitor compound of the formula:n the method comprises the steps of: (a) combining a pyrrolidine compound of the formula:(b) combining the trialkylated compound with a hydroxide or an alkoxide to form an intermediate compound of the formula:(c) combining the intermediate compound with an acid to form the Lp(a) inhibitor compound.

[0009] Also disclosed herein is a method for the preparation of an Lp(a) inhibitor compound of the formula:, wherein the method comprises the steps of:(a) combining a pyrrolidine compound of the formula:, wherein R is ;Pr, Bn, or Ph;, , , I, OTs, OTf, or OMs, to form a trialkylated compound of the formula:(b) combining the trialkylated compound with a peroxide to form a triacid compound of the formula:(c) combining the triacid compound with an acid to form Lp(a) inhibitor compound.

[0010] Also disclosed herein is a method for the preparation of Lp(a) inhibitor compound of the formula:, wherein the method comprises the steps of:(a) combining a pyrrolidine compound of the formula:Ci to Cio alkyl, C3 to C7 cycloalkyl, a four member to seven-member heterocycloalkyl, a Ce to C10 aryl, a four member to seven-member heteroaryl, or combinations thereof;form a trialkylated compound of the formula:(b) adding an acid to form the Lp(a) inhibitor compound.

[0011] Also disclosed herein is a method for the preparation of an Lp(a) inhibitor compound of the formula:, wherein the method comprises the steps of:(a) combining a pyrrolidine compound of the formula:, wherein R comprises Ci to Cio alkyl, C3 to C7 cycloalkyl, a four member to seven-member heterocycloalkyl, a C6 to Cio aryl, a four member to seven-member heteroaryl, or combinations thereof;(b) adding an acid to form the Lp(a) inhibitor compound.

[0012] Also disclosed herein is an intermediate compound for the preparation of an Lp(a) inhibitor compound, the intermediate compound of the formula:

[0013] Also disclosed herein is an intermediate compound for the preparation of an Lp(a) inhibitor compound, the intermediate compound of the formula:wherein R is z'Pr, Bn, or Ph.

[0014] Also disclosed herein is a method for the preparation of an Lp(a) inhibitor compound of the formula:wherein the method comprises the steps of:(a) combining a pyrrolidine compound of the formula:Boccomprises Ci to Cio alkyl, C3 to C7 cycloalkyl, a four member to seven-member heterocycloalkyl, a C> to Cio aryl, a four member to seven-member heteroaryl, or combinations thereof;wherein X is Cl, Br, I, OTs, OTf, or OMs,to form a trialkylated compound of the formula:(b) combining the trialkylated compound with a hydroxide or an alkoxide to form an intermediate compound of the formula:(c) combining the intermediate compound with an acid to form the Lp(a) inhibitor compound.

[0015] Also disclosed herein is a method for the preparation of an Lp(a) inhibitor compound ofthe formula:wherein the method comprises the steps of:(a) combining a pyrrolidine compound of the formula:, wherein R is z'Pr. Bn, or Ph;withX , wherein X is Cl, Br, 1, OTs, OTf, or OMs,to form a trialkylated compound of the formula:(b) combining the trialkylated compound with a peroxide to form a triacid compound of the formula:(c) combining the triacid compound with an acid to form the Lp(a) inhibitor compound.

[0016] Also disclosed herein is a method for the preparation of an Lp(a) inhibitor compound of the formula:wherein the method comprises the steps of:(a) combining a pyrrolidine compound of the formula:Ci to Cio alkyl, C3 to C7 cycloalkyl, a four member to seven-member heterocycloalkyl, a Ce to C10 aryl, a four member to seven-member hctcroaryl, or combinations thereof;form a trialkylated compound of the formula:(b) adding an acid to form the Lp(a) inhibitor compound.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 shows the X-Ray Powder Diffraction (XRPD) pattern of lri- / c / 7-bulyl 3,3’,3"-((2S 2A,2"S)-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(3-(((S')-l -hydroxy-3-phenylpropan-2-yl)amino)-3-oxopropane-l,2-diyl))(3R,3'R,3"R)-tris(pyrrolidine-l -carboxylate).

[0018] FIG. 2 shows multiple pathways to prepare pyrrolidine compounds, such as muv alaplin, from the trialkylated compound.

[0019] FIG. 3 shows the X-Ray Powder Diffraction (XRPD) pattern of (2S,2'S,2"S)-3,3',3"-((mtrilotris(methylene))tris(benzene-3,l-diyl))tris(2-((R)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid).

[0020] FIG. 4 shows the X-Ray Powder Diffraction (XRPD) pattern of Trimethyl 3, 3', 3"-(nitrilotris(methylene))tribenzoate (Preparation 2)

[0021] FIG. 5 shows the X-Ray Powder Diffraction (XRPD) pattern of ((Nitrilotris(methylene))tris(benzene-3, 1 -diyl))trimethanol (Preparation 3)

[0022] FIG. 6 shows the X-Ray Powder Diffraction (XRPD) pattern of Tris(3-(bromomethyl)benzyl) amine (Preparation 4)

[0023] FIG. 7 shows the X-Ray Powder Diffraction (XRPD) pattern of Tri -tert-butyl 3,3',3"-((2S,2'S,2"S)-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(3-(((S)-l -hydroxy-3-phenylpropan-2-yl)amino)-3-oxopropane-l,2-diyl))(3R,3'R,3"R)-tris(pyrrolidine-l -carboxylate) (Preparation 6)DETAILED DESCRIPTION OF THE INVENTION

[0024] Linear Synthesis of Lp(a) Inhibitor Compounds

[0025] The method for the preparation of Lp(a) inhibitor compounds, such as muvalaplin, (2S,2'S,2"S)-3,3',3"-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid), Formula I, disclosed in U.S. Patent No. 11,286,249, requires 16-linear steps (or 14-synthetic steps) commencing from commercially available (L)-4-hydroxyproline. A high number of synthetic steps can lead to a highly variable or higher cost synthetic approach as each step requires additional reactants to be added to the process. Additionally, the penultimate intermediate in the preparation of U.S. Patent No. 11,286,249 is amorphous, which can lead to the accumulation of impurities in the final synthetic step that can be difficult to separate from the final Lp(a) inhibitor compound, such as muvalaplin. Formula I-A shows an additional Lp(a) inhibitor compound that can be prepared from the methods disclosed herein.Formula I. (2S,2'S,2"S)-3,3',3"-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(2-((R)- pyrrolidin-3-yl)propanoic acid), muvalaplinFormula I-A. Lp(a) Inhibitor Compound

[0026] Convergent Synthesis of Lp(a) Inhibitor Compounds

[0027] Disclosed herein is a new method for the preparation of Lp(a) inhibitor compounds, such as muvalaplin. It has been unexpectedly found that convergent synthesis can lead to a route to Lp(a) inhibitor compounds, such as muvalaplin, with a smaller number of steps and lead to the isolation of a crystalline intermediate compound, tri-tert-butyl 3,3',3"-((2S,2'S,2"S)-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(3-(((S)-l-hydroxy-3-phenylpropan-2-yl)amino)-3-oxopropane- l,2-diyl))(3 / ?, 3'R, 3" / ?)-tris(pyrrolidine-l -carboxylate), which can improve the purity of the Lp(a) inhibitor final product without the need for extensive purification at the final step of the preparation.

[0028] The disclosed method for the preparation of an Lp(a) inhibitor compounds can also comprise the steps of:(a) combining a pyrrolidone compound and a tertiary amine compound to form a trialkylated compound;(b) combining the trialkylated compound with a suitable base, such as a hydroxide or alkoxide, to form an intermediate compound; and(c) combining the intermediate compound with a suitable acid to form the Lp(a) inhibitor compound.

[0029] The disclosed method for the preparation of an Lp(a) inhibitor compound can also comprise the steps of:(a) combining a pyrrolidone compound and a tertiary amine compound to form a trialkylated compound;(b) combining the trialkylated compound with a peroxide to form a triacid compound; and (c) combining the tri acid with a suitable acid to form the Lp(a) inhibitor compound.

[0030] The disclosed method for the preparation of an Lp(a) inhibitor compound can comprise the steps of:(a) combining a pyrrolidone compound and a tertiary amine compound to form a trialkylated compound; and(b) adding an acid to form the Lp(a) inhibitor compound.

[0031] Pyrrolidone Compound

[0002] The disclosed method for the preparation of the Lp(a) inhibitor compound of Formula I or I-A comprises the use of a pyrrolidone compound. The pyrrolidine compound can be combined with the tertiary amine compound to form the trialkylated compound.

[0033] The pyrrolidine compound can comprise a compound of Formula II, wherein Y iscomprises Ci to Cio alkyl, C3 to C7 cycloalkyl, a four member to seven-member heterocycloalkyl, a C<> to Cio aryl, a four member to seven-member heteroaryl, or combinations thereof.BocFormula II. Pyrrolidine Compound

[0034] The pyrrolidine compound can also comprise a compound of Formula III, wherein R comprises iPr, Bn, or Ph.Formula III. Pyrrolidone Compound

[0035] The pyrrolidine compound can also comprise a compound of Formula IV.Formula IV. Pyrrolidone Compound[0036| Tertiary Amine Compound

[0037] The disclosed method for the preparation of the Lp(a) inhibitor compound of Formula I or I-A comprises the use of a tertiary amine compound. The tertiary amine compound can be combined with the pyrrolidine compound to form the trialkyated compound.

[0038] The tertiary amine compound can comprise a compound of Formula V or V-A, wherein X is Cl, Br, I, OTs, OTf, or OMs.Formula V. Tertiary Amine CompoundFormula V-A. Tertiary Amine Compound

[0039] The tertiary amine compound can also be a compound of Formula VI or VI-A.Formula VI. Tertiary Amine CompoundFormula V-A. Tertiary Amine Compound

[0040] An initial step of the preparation of muvalaplin can be the preparation of the tertiary amine compound. The tertiary amine compound can be prepared by a person of ordinary skill in the art using known methods in the literature, such as in R. Cao et al., Chem. Eur. J. 2016, 22, 17576, which is shown in Formula VII.Formula VII. Preparation of Tertiary Amine Compound

[0041] The tertiary amine compound of Formula VI can also be prepared by a method comprising the steps of:( 1 ) combiningwith ammonium hydroxide and sodium carbonate in acetonitrile to form a tribenzoate compound;(2) combining the tribenzoate compound with lithium aluminum hydride to form a tribenzyl alcohol compound; and(3) combining the tribenzyl alcohol compound with HBr and a bromide salt to form the tertiary amine compound of Formula VI.

[0042] The tertiary amine compound of Formula VI can also be prepared by a method comprising the steps of:g um hydroxide and sodium carbonate in acetonitrile to form a tribenzoate compound of Formula VIII;(2) combining the tribenzoate compound with lithium aluminum hydride to form a tribenzyl alcohol compound of Formula IX; and(3) combining the tribenzyl alcohol compound with HBr and a bromide salt to form the tertiary amine compound of Formula VI.Fomiula VIII. Tribenzoate CompoundFormula IX. Tribenzyl alcohol Compound

[0043] Trialkylated Compound

[0044] The disclosed method for the preparation of the Lp(a) inhibitor compound of Formula I or I-A comprises the use of a trialkylated compound. The trialkylated compound can be prepared through the combination of the pyrrolidine compound and the tertiary amine compound.

[0045] The preparation of the trialkylated compound can also comprise the addition of a suitable strong non-nucleophilic base. Suitable strong non-nucleophilic bases can include sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), lithiumhexamethyldisilazide (LiHMDS), lithium diisopropylamide (LDA), lithium dicyclohexylamide, or combinations thereof.

[0046] The preparation of the trialkylated compound can be done at a temperature of from about -78°C to about 20 °C, from about -40 °C to about 15 °C, or from about -20 °C to about 10 °C

[0047] The trialkylated compound can comprise a compound of Formula X or X-A, wherein Y iscomprises Ci to Cio alkyl, C3 to C7 cycloalkyl, a four member to seven-member heterocycloalkyl, a Co to Cio aryl, a four member to seven-member heteroaryl, or combinations thereof.Formula X-A. Trialkylated Compound.

[0048] The trialkylated compound can also comprise a compound of Formula XI or XI- A, wherein R is z'Pr, Bn, or Ph, Formula XII, or Formula XII-A.Formula XI-A. Trialkylated CompoundFormula XII-A. Trialkylated Compound

[0049] As disclosed herein, and illustrated in FIG. 2, there are multiple processes to prepare the Lp(a) inhibitor compound of Formula I or I-A from the trialkylated compound.

[0050] In an embodiment, the trialkylated compound can be combined with a hydroxide or an alkoxide to form an intermediate compound followed by the preparation of muvalaplin under acidic conditions.

[0051] In an embodiment, the trialkylated compound can be combined with an acid to form muvalaplin without the isolation of an intermediate compound. Y can be removed from the trialkylated compound followed by the preparation of muvalaplin under acidic conditions.

[0052] In an embodiment, the trialkylated compound can be combined with peroxide, such as hydrogen peroxide, and optionally a base, such as tetrabutylammonium hydroxide, followed by subsequent treatment with an acid to form crude tech grade muvalaplin, followed by di- / e / -bulyl dicarbonate to prepare a triacid compound of Formula XII-B or XII-C. The Lp(a) inhibitor compound of Formula I or I-A can be prepared from the triacid compound under acidic conditions to remove the remaining Boc protecting groups.Formula XII-C. Triacid Compound

[0053] The triacid compound, such as the compound of Formula XILA can be a crystalline compound. The intermediate compound of Formula XII-A can be characterized by a powder x-ray diffraction pattern of FIG. 3. The intermediate compound of Formula XII-A can becharacterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of Table 1.

[0054] The intermediate compound of Formula XII-A can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 5.6° and 17.6° ± 0.2° 20. The intermediate compound of Formula XII-A can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 5.6°, 16.8°, 17.6°, 18.4°, 20.7°, and 22.5° ± 0.2° 20. The intermediate compound of Formula XII-A can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 5.6°, 11.2°, 16.8°, 17.6°, 18.4°, 19.9°, 20.7°, and 22.5° ± 0.2° 20. The intermediate compound of Formula XII-A can also be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 5.6°, 8.8°, 10.2°, 11.2°, 15.9°, 16.8°, 17.6°, 18.4°, 19.9°, 20.7°, 22.5°, 25.0°, 26.9°, 27.8°, and 29.8° ± 0.2° 20 .Table 1. X-ray powder diffraction peaks of Formula XII-A

[0055] Intermediate Compound

[0056] The disclosed method for the preparation of the Lp(a) inhibitor compound of Formula I or I-A can comprise the preparation of an intermediate compound. The intermediate compound can be prepared by combining the trialkylated compound with a hydroxide or an alkoxide.

[0057] The intermediate compound can comprise a compound of Formula XIII, wherein R comprises Ci to Cio alkyl, C3 to C7 cycloalkyl, a four member to seven-member heterocycloalkyl, a Cr, to Cio aryl, a four member to seven-member heteroaryl, or combinations thereof. The intermediate compound can also comprise a compound of Formula XIII or XIII- A, wherein R is z'Pr, Bn, or Ph. The intermediate compound can also comprise a compound of Formula XIV or XIV-A.Formula XIII-A. Intermediate CompoundFormula XIV. Intermediate CompoundFormula XIV- A. Intermediate Compound

[0058] The intermediate compound, such as the compound of Formula XIV can be a crystalline compound. The intermediate compound of Formula XIV can be characterized by a powder x-ray diffraction pattern of FIG. 1. The intermediate compound of Formula XIV can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of Table 2. The intermediate compound of Formula XIV can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 14.9°, 18.7°, and 19.0° ± 0.2° 20. The intermediate compound of Formula XIV can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 6.4°, 9.8°, 13.4°, 13.9°, 14.9°, 15.4°, 16.7°, 18.7°, and 19.0° ± 0.2° 20. The intermediate compound of Formula XIV can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 6.4°, 9.8°,13.4°, 13.9°, 14.9°, 15.4°, 16.3°, 16.7°, 17.5°, 18.7°, and 19.0° ± 0.2° 20. The intermediate compound of Formula XIV can also be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 6.4°, 9.8°, 13.4°, 13.9°, 14.9°, 15.4°, 16.3°, 16.7°, 17.5°, 18.7°, 19.0°, 20.2°, 21.1°, 21.9°, 22.9°, 24.9°, 27.2°, and 29.9°± 0.2° 20 .Table 2. X-ray powder diffraction peaks of Formula XIV

[0059] The hydroxide that can be used to combine with the trialkylated compound to form the intermediate compound can comprise NaOH, LiOH, KOH, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, or combinations thereof.

[0060] The tetramethylammonium hydroxide can be generated in situ from the combination of tetramethylammonium chloride and NaOH, LiOH, or KOH.

[0061] The tetrabutylammonium hydroxide can be generated in situ from the combination of tetrabutylammonium chloride and NaOH, LiOH, or KOH

[0062] The alkoxide that can be used to combine with the trialkylated compound to form the intermediate compound can be directly added to the trialkylated compound or the alkoxide can be generated in situ. Suitable alkoxides include, but are not limited to, sodium methoxide (NaOMe), potassium methoxide (KOMe), sodium ethoxide (NaOEt), potassium ethoxide (KOEt), sodium isopropoxide (NaOzPr), potassium isopropoxide (KOzPr), sodium zerz-butoxide (NaOzBu), potassium zerZ-butoxide (KOzBu), or combinations thereof.

[0063] The alkoxide can be generated in situ from the combination of (1) an alcoholic solvent and (2) a carbonate base. The carbonate base can comprise K2CO3, Li2CO3, Na2CC>3, CS2CO3, or combinations thereof. The alkoxide can also be generated in situ from the combination of (1) an alcoholic solvent and (2) a hydroxide base. Suitable hydroxide bases include NaOH, LiOH, KOH, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, or combinations thereof.

[0064] The alcohol solvent can comprise methanol, ethanol, isopropanol, propanol, or combinations thereof.

[0065] In some embodiments, such as when the pyrrolidone compound is a compound ofFormula IT, whereinintermediate compound may not be isolated in the preparation of muvalaplin.

[0066] Preparation of Lp(a) Inhibitor Compound

[0067] The Lp(a) inhibitor compound can be Muvalaplin, Formula I, which can be prepared from the intermediate compound of Formula XIII or XIV by combining the intermediate compound with an acid.

[0068] The acid can comprise HC1, H2SO4, H3PO4, or HBr.

[0069] The preparation of muvalaplin from the intermediate compound can be performed in water.

[0070] In some embodiments, the preparation of muvalaplin from the intermediate compound can be performed in water and a co-solvent.

[0071] In some embodiments, the preparation of muvalaplin from the intermediate compound can be performed in water and a nonpolar co-solvent. The nonpolar co-solvent can comprise xylenes, o-xylene, m-xylene, / z-xylene, toluene, n-butyl ether, cyclopentyl methyl ether, or combinations thereof.

[0072] The preparation of muvalaplin from the intermediate compound can be performed at a temperature of from about 90 °C to about 150 °C, from about 120 °C to about 150 °C, or about 115 °C to about 125 °C.

[0073] The final compound, Muvalaplin, Formula I, can be prepared from the intermediate compound of Formula XIII or XIV by ( 1 ) combining the intermediate compound with an acid.

[0074] Additional Crystalline Intermediates

[0075] Also disclosed herein are additional crystalline intermediates, such as the crystalline compound of Trimethyl 3,3',3"-(nitrilotris(methylene))tribenzoate (Preparation 2, FIG. 4), ((Nitrilotris(methylene))tris(benzene-3,l-diyl))trimethanol (Preparation 3, FIG. 5), Tris(3-(bromomethyl)benzyl)amine (Preparation 4, FIG. 6), and / or Tri -tert-butyl 3,3',3"-((2S,2'S,2"S)-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(3-(((S)-l-hydroxy-3-phenylpropan-2-yl)amino)-3-oxopropane-l,2-diyl))(3R,3'R,3"R)-tris(pyrrolidine-l -carboxylate) (Preparation 6, FIG. 7)

[0076] The crystalline compound of Preparation 2 can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of Table A.

[0077] The intermediate compound of Preparation 2 can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 6.6°, 13.2 °, and 20.7° ± 0.2° 29. The intermediate compound of Preparation 2 can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 6.6°, 13.2°, 16.5°, 19.9°, 20.7°, 21.8 °, and 22.7° ± 0.2° 20. The intermediate compound of Preparation 2 can also be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 6.6°, 13.2°, 13.9°, 16.5°. 18.3°, 19.9°, 20.7°, 21.8°, 22.7°, and 23.9° ± 0.2° 29.Table A. X-ray powder diffraction peaks of Preparation 2

[0078] The crystalline compound of Preparation 3 can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of Table B.

[0079] The intermediate compound of Preparation 3 can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 15.7°, 17.4°, and 21.2° ± 0.2° 29. The intermediate compound of Preparation 3 can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 15.7°, 17.4°, 18.4°, 21.2°, 22.1°, and 22.5° ± 0.2° 20. The intermediate compound of Preparation 3 can also be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 15.7°, 17.4°, 17.8°, 18.4°, 21.2°, 21.6°, 22.1°, 22.5°, 23.7°, and 25.4° ± 0.2° 20.Table B. X-ray powder diffraction peaks of Preparation 3

[0080] The crystalline compound of Preparation 4 can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of Table C.

[0081] The intermediate compound of Preparation 4 can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 14.0°, 21.0°, and 28.3° ± 0.2° 29. The intermediate compound of Preparation 4 can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 14.0°, 20.3°, 21.0°, 21.4°, 21.8°, 22.8°, and 28.3° ± 0.2° 20. The intermediate compound of Preparation 4 can also be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 14.0°, 16.5°. 20.3°, 21.0°, 21.4°, 21.8°, 22.8°, 23.5°, 26.2°, and 28.3° ± 0.2° 20.Table C. X-ray powder diffraction peaks of Preparation 4

[0082] The crystalline compound of Preparation 6 can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of Table D.

[0083] The intermediate compound of Preparation 6 can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 3.7°, 13.5°, and 18.8° ± 0.2° 20. The intermediate compound of Preparation 6 can be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 3.7°, 9,9°, 13.5°, 14.9°, 18.8°, and 19.1° ± 0.2° 20. The intermediate compound of Preparation 6 can also be characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising the peaks of 3.7°, 6.5°, 9.9°, 13.5°, 14.9°, 16.4°, 16.7°, 18.8°, 19.1°, and 23.0 ° ± 0.2° 20.Table D. X-ray powder diffraction peaks of Preparation 6

[0084] Definitions

[0085] As used herein, the term “alkyl” means saturated linear or branched-chain monovalent hydrocarbon radical, containing the indicated number of carbon atoms. For example, “C1-C20 alkyl” means a radical having 1-20 carbon atoms in a linear or branched arrangement.

[0086] As used herein, the term “cycloalkyl” means a radical derived from a non-aromatic monocyclic or polycyclic ring comprising carbon and hydrogen atoms. The cycloalkyl can have one or more carbon-carbon double bonds in the ring as long as the ring is not rendered aromatic by their presence. The cycloalkyl group can be unsubstituted or substituted with from one to three suitable substituents, which are well known to a person of ordinary skill in the art. The cycloalkyl group can be referred to by the number of total carbon atoms in the monocyclic or polycyclic ring. For example, a C3 to C7 cycloalkyl includes cycloalkyl radical group with 3, 4, 5, 6, or 7 carbon atoms.

[0087] As used herein, the term "heterocycloalkyl" means a radical derived from a non-aromatic monocyclic or polycyclic ring comprising one or more carbon atoms and one or more heteroatoms, such as nitrogen, oxygen, and sulfur. A heterocycloalkyl group can have one or more carbon-carbon double bonds or carbon-heteroatoms double bonds in the ring as long as the ring is not rendered aromatic by their presence. Examples of heterocycloalkyl groups include aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl. A heterocycloalkyl group can be unsubstituted or substituted with one or two suitable substituents. The heterocycloakyl group can be referred to by the number of total atoms in the monocyclic or polycyclic ring. For example, a four member to seven-member heterocycloalkyl includes four, five, six, or seven members (including carbon atoms and hctcroatoms).

[0088] As used, herein, the term “aryl” means a radical derived from an aromatic monocyclic or polycyclic ring including only carbon atoms in the monocyclic or polycyclic ring. The aryl group can be unsubstituted or the aryl group can be substituted with from 1 to 5 suitable substituents, which are well known to a person of ordinary skill in the art. The aryl group can be referred to by the number of total carbon atoms in the monocyclic or polycyclic ring. For example, a C / > to C10 aryl includes an aryl radical group with 6, 7, 8, 9, or 10 carbon atoms.

[0089] As used herein, the term “heteroaryl” means a radical derived from an aromatic monocyclic or polycyclic ring including one or more carbon atoms and one or more heteroatomsin the monocyclic or polycyclic ring. The heteroaryl group can be unsubstituted or the heteroaryl group can be substituted with from 1 to 5 suitable substituents, which are well known to person of ordinary skill in the art. The heteroaryl group can be referred to by the number of total atoms in the monocyclic or polycyclic ring. For example, a four member to seven-member heteroaryl includes four, five, six, or seven members (including carbon atoms and heteroatoms).

[0090] As used herein, the term, “Boc” means the tert-Butyloxycarbonyl protecting group and / or the functional group of the formula (CH3)JCO(C=O)-

[0091] As used herein, the term “OTs” means the tosylate protecting group and / or the functional group of the formula CH3C6H4SO3-

[0092] As used herein, the term “OTf” means the triflate protecting group and / or the functional group of the formula CF3SO3-.

[0093] As used herein, the term “OMs” means the mesylate protecting group and / or the functional group of the formula CH3SO3-.

[0094] As used herein, the term “zPr” means the Ao-propyl functional group.

[0095] As used herein, the term “Bn” means the benzyl functional group and / or the functional group C6H5-CH2-.

[0096] As used herein, the term “Ph” means the phenyl functional group and / or the functional group CeHs-.EXAMPLES

[0097] General: All chemicals were purchased from commercial sources and used without further purification. NMR spectra were taken on either a Bruker Avance Neo (400 MHz) or a Bruker Avance III™ (400 MHz) NMR spectrometer. Mass spectra were obtained using a Thermo Ultimate 3000 mass spectrometer. Analytical methods for IPC and product purity analysis are provided in Supporting Information.Preparation 1z -butyl (R)-3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine-l-carboxylate

[0098] To a mixture of (R)-2-(l-(tert-butoxycarbonyl)pyrrolidin-3-yl)acctic acid (1.2 kg, 5.2 mol, 1.0 eq) in THF (9.6 L, 8 vol) was added triethylamine (1.3 kg, 13 mol, 2.4 eq.). The reaction was cooled to -10 °C and pivaloyl chloride (0.76 kg, 6.3 mol, 1.2 eq.) was added. The reaction was stirred for 2 h. In a separate flask, (S)-4-benzyloxazolidin-2-one (0.97 kg, 5.5 mol, 1.05 eq.) and LiBr (0.50 kg, 5.8 mol, 1.1 eq.) were dissolved in THF (3.6 L, 3 vol). This solution was charged dropwise to the reactor. After stirring for 12 h, the reaction was quenched by addition of 5% citric acid (6 L, 5 vol) and the mixture was concentrated to 5 vol. To this mixture was added EtOAc (9.6 L, 8 vol) and the aqueous layer was removed. The organic layer was washed twice with aqueous NaOH (8.4 g in 5 volumes of water). The organic layer was washed with 10% aqueous NaCl (6 L, 5 vol) and concentrated to 2 vol. n-Heptane (7.2 L, 6 vol) was added and the mixture was concentrated to 2 vol. This operation was completed three times. Methyl terr-butyl ether (2.4 L, 2 vol) was added and n-heptane was added dropwise (3.6 L, 3 vol) at 50 °C. The mixture was cooled to 0 °C, filtered, and washed with n-heptane (1.2 L, 1 vol). The wet cake was dried at 40 °C to afford the title compound as a white solid (1.79 kg, 93.4% assay, 83% yield). ’ll NMR (400 MHz, Chloroform-rZ) 57.37-7.32 (m, 2H), 7.31-7.27 (m, 1H), 7.22-7.18 (m, 2H), 4.67 (d, J= 9.1 Hz, 1H), 4.27-4.15 (m, 2H), 3.75-3.62 (m, 1H), 3.56-3.39 (m, 1H), 3.37-3.26 (m, 2H), 3.01 (tt, 7= 19.2, 8.6 Hz, 3H), 2.78 (dt, J= 16.8, 8.5 Hz, 1H), 2.67 (dt, 7 = 14.9, 7.5 Hz, 1H), 2.11 (d, J= 11.9 Hz, 1H), 1.63-1.55 (m, 1H), 1.47 (s, 9H).Preparation 2Trimethyl 3,3',3"-(nitrilotris(methylene))tribenzoate

[0099] A mixture of methyl 3 -(bromomethyl) benzoate (1910 g, 7.4 mol, 1.0 eq.), 35% aqueous NH4OH (230.0 g, 2.3 mol, 0.31 eq.), and Na2CO3(887.0 g, 1.1 eq.) in acetonitrile (9500 mL, 5 vol) was stirred under N2 at 40 °C for 42 h or until <0.2% of starting material methyl 3-(bromomethyl)benzoate remained. The reaction was filtered, and the solid was washed with acetonitrile (2000 mL, 1 vol). The filtrate was concentrated to 1-2 vol below 45 °C, tetrahydrofuran was added (6000 mL, 3 vol), and the mixture was further concentrated to 1-2 vol below 45 °C. The residue was diluted with tetrahydrofuran (3000 mL, 1.8 vol), and the mixture was filtered. Tetrahydrofuran (2000 mL, 1.2 vol) was used to rinse the wet cake. n-Heptane (8000 mL, 4.7 vol) was charged into the filtrate and stirred at 20 °C. Trimethyl 3,3', 3"-(nitrilotris(methylene))tribenzoate (21.00 g, 1.0 wt%) was charged as seed at 20 °C. The mixture was stirred for over 3 h and then concentrated to 2-4 vol below 20 °C. n-Heptane (8000 mL, 4.7 vol) was charged dropwise at 10-20 °C over 3 h and then concentrated to 4-6 vol below 35 °C. The mixture was cooled to 0 °C and stirred for over 4 h. The mixture was filtered, and the solid was rinsed with n-heptane (1000 mL, 0.5 vol). The wet cake was dried under vacuum at 25-40 °C for 24 h to afford the title compound as an off-white solid (1200 g, 99.8% purity, 99% assay, 90.8% yield). 'l l NMR (400 MHz, DMSO-d6): 53.56 (s, 6 H), 3.85 (s, 9 H), 7.42-7.50 (m, 3 H), 7.58 (d, J = 7.63 Hz, 3 H), 7.80 (d, J = 7.63 Hz. 3 H). 7.93 (s, 3 H).13C NMR (101 MHz, DMSO-ri6): 552.55, 57.19, 128.33, 129.19, 129.66. 130.13, 133.72, 139.91, 166.61. TOF-MS (ESI) m / z calculated for [C LsNOef ([M+H]+): 462.1 11, found: 462.1924.Preparation 3 ((Nitrilotris(methylene))tris(benzene-3, 1 -diyl))trimethanol

[0100] To a stirred solution of trimethyl 3,3',3"-(nitrilotris(methylene))tribenzoate (1055 g, 2.3 mol, 1.0 eq.) in tetrahydrofuran (10000 mL, 10 vol) was added Li Al I [4 (2.5M solution in tetrahydrofuran, 4300 mL, 10.8 mol, 4.7 eq.) at -10-10 °C over 3 h under nitrogen blanket. The mixture was warmed to 25 °C and stirred for 64 h or until <0.05% of starting material trimethyl 3,3',3"-(nitrilotris(methylene))tribenzoate remained. The reaction was cooled to 0 °C, followedby sequential, slow addition of water (440.0 g), 10% aqueous NaOH (440.00 g) and water (1320.00 g) at 0-10 °C. After complete addition, the mixture was warmed to 25 °C and stirred for 3 h. The reaction mixture was filtered, and the solid was washed with tetrahydrofuran (1000 mL, 1 vol). The filter cake was washed with ethyl acetate (8000 mL, 8 vol), and the combined mother liquors were concentrated to 2 vol below 45 °C. Ethyl acetate (1000 mL, 1 vol) was charged into the residual to dissolve it. The mixed solution was washed with water (2000 mL, 2 vol) at 20 °C and concentrated to 2 vol below 45 °C and exchanged with ethyl acetate (3000 mL, 3 vol) and further concentrated to 2 vol below 45 °C. To the residual, ethyl acetate (1000 mL, 1 vol) and n-heptane (200 mL, 0.2 vol) was charged and mixture was stirred.((Nitrilotris(methylene))tris(benzene-3,l-diyl))trimethanol (1.00 g, 0.1 wt%) was charged into the solution as seed and the mixture was stirred at 20 °C for 2 h. zz-Heptane (10000 mL, 10 vol) was charged dropwise at 20 °C over 6 h. The mixture was stirred at 20 °C for 8 h. The mixture was filtered, and the solid was rinsed with n -heptane (5000 mL, 5 vol). The wet cake was dried under vacuum at 40 °C for 18 h to afford the title compound as an off-white solid (806.0 g, 97.9% purity, 96% assay, 90.6% yield). ’ll NMR (400 MHz, DMSO-zfc): 83.48 (s, 6 H) 4.50 (d, 7 = 5.72 Hz, 6 H) 5.18 (t, J= 5.72 Hz, 3 H) 7.19 (d, 7= 7.03 Hz, 3 H) 7.25 - 7.35 (m, 9 H).13C NMR (101 MHz, DMSO-zfc): 857.05, 62.92, 125.12, 126.72, 126.83. 128.04, 138.88, 142.5. TOF-MS (ESI) m / z calculated for [C^HzsNCLr ([M+H]+): 378.20637, found: 378.2077.Preparation 4Tris(3-(bromomethyl)benzyl)amine

[0101] To a slirred mixture of ((nitrilotris(methylene)) tris(benzene-3,l-diyl))trimethanol (700.9 g, 1.8 mol, 1.0 eq.), KBr (232.5 g, 2.0 mol, 1.1 eq.), and toluene (3500 mL, 5 vol) was added 33 wt% hydrobromic acid in acetic acid (3353 g, 13.7 mol, 7.7 eq.) at 45 °C and stirred for 37 h or until <0.05% of starting material ((nitrilotris(methylene))tris(benzene-3,l-diyl))trimethanol remained. The reaction mixture was concentrated to 3 vol below 60 °C. The residue was diluted with toluene (6700 mL, 10 vol) and quenched by the addition of 25% aqueous NH4OH (~1133 g,170 wt%) at 0-10 °C. The mixture was washed with water (1340 mL, 2 vol) at 5 °C two times. The organic layer was dried over MgSCh (335 g, 50 wt%) and concentrated to 2 vol below 60 °C. n-IIeptane (670 mL, 1 vol) was charged drop wise at 45 °C over 1 h. n-I leptane (6030 mL, 9 vol) was charged dropwise at 45 °C over 3 h. The mixture was stirred at 45 °C for 3 h. The mixture was adjusted to 20 °C and stirred for 6 h. The resulting suspension was filtered, the cake was rinsed with n-heptane (670 mL, 1 vol) and dried under vacuum at 45 °C for 20 h to afford the title compound as a solid (927.1 g, 98.3% purity, 98% assay, 90.6% yield). 'll NMR (400 MHz, acetonitrile-*): 53.51 (s, 6 H), 4.61 (s, 6 H), 7.26-7.38 (m, 9 H), 7.45-7.54 (m. 3 H).13C NMR (101 MHz, acetonitrile-*): 534.51, 57.67, 128.28, 129.26, 129.45. 130.12, 138.93, 140.83. TOF-MS (ESI) m / z calculated for [C24H25Br3N]+([M+H]+): 563.95316, found: 563.9542.Preparation 5Tri-tert-butyl 3,3',3"-((2S,2’S,2"S)-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(3-((S)-4- benzyl-2-oxooxazolidin-3-yl)-3-oxopropane-l,2-diyl))(3R,3'R,3"R)-tris(pyrrolidine-l-

[0102] Under a nitrogen blanket, a 25 wt% solution of lithium hexamethyldisilazide in tetrahydrofuran (3580 g, 5.35 mol, 1.05 eq.) was charged dropwise into a solution of tert-butyl (R)-3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine-l -carboxylate (2007 g, 5.09 mol, 1.00 eq.) in tetrahydrofuran (2000 mL, 1 vol) at -10 °C over 1 h. A solution of tris(3-(bromomethyl)benzyl) amine (832.00 g, 1.43 mol, 0.28 eq.) in tetrahydrofuran (2000 mL, 1 vol) was charged dropwise into the reaction solution. Tetrahydrofuran (200 mL, 0.1 vol) was used to rinse the charging funnel and charged into the mixture at -10 °C over 1 h. The reaction solution was stirred at -10 °C for 42 h or until <0.08% of intermediate di-tert-butyl 3,3'-((2S,2'S)-((((3-(bromomethyl)benzyl)azanediyl) bis(methylene))bis(3, 1 -pheny lene))bis(3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-oxopropane-l,2-diyl))(3R,3'R)-bis(pyrrolidine-l -carboxylate) remained.13% Aqueous NH4CI (8000 g) was charged into the reactor dropwise at -10-10 °C. The mixture was extracted with ethyl acetate (4000 mL, 2 vol) at 20 °C. The organic layer was washed with 13% aqueous NaCl (8000 g) at 20 °C and concentrated to 2 vol. To the residual was added methanol (8000 mL, 4 vol) and the mixture was concentrated to 2 vol below 50 °C. The mixture was diluted with methanol (6000 mL, 3 vol) and then charged into water (30 L, 15 vol) dropwise at 25 °C over 3 h. The mixture was stirred at 25 °C for over 15 h. The resulting suspension was filtered, and the filter cake was rinsed with water (8000 mL, 4 vol) and dried under vacuum at 50 °C for 15 h to afford the title compound as an off-white solid (2388 g, 86% purity, 75% assay, 84% yield). ’ll NMR (400 MHz, DMSO-ffc): 5 1.36 (br d, J = 12.55 Hz, 27 H), 1.50-1.73 (m, 3 H), 1.89 (br s, 3 H), 2.21-2.47 (m, 6 H), 2.59 (br s, 3 H), 2.73-3.18 (m, 15 H), 3.34-3.56 (m, 6 H), 3.83-3.97 (m, 3 II), 4.19 (br d, J = 7.03 Hz, 3 II), 4.28-4.40 (m, 3 II), 4.57 (br s, 3 II), 6.70 (br s, 6 H), 6.7-7.27 (m, 27H).13C NMR (101 MHz, DMSO-ife): 828.09, 28.46, 28.95, 36.42, 40.41, 41.26, 44.92, 48.79, 54.28, 56.74, 65.47, 78.07, 126.60, 127.66, 128.32, 128.50, 129.16, 129.43, 135.21, 138.51, 138.85, 138.93, 152.94, 153.32, 173.81. TOF-MS (ESI) m / z calculated for [C87H106N7015]+([M+H]+): 1488.7741, found: 1488.7748.Preparation 6Tri-tert-butyl 3,3',3”-((2S,2'S,2”S)-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(3-(((S)-l- hydroxy-3-phenylpropan-2-yl)amino)-3-oxopropane-l,2-diyl))(3R,3'R,3"R)-tris(pyrrolidine-l-

[0103] To a mixture of lri- / c / 7-bulyl 3,3',3"-((2S,2'S,2"S)-((nitrilotris(methylene))tris(benzene- 3,l-diyl))tris(3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-oxopropane-1.2-diyl))(3R,3,R,3"R)-tris(pyrrolidine-l -carboxylate) (300 g, 0.20 mol, 1.0 eq.) in isopropanol (3000 mL, 10 vol), tetrabutylammonium hydroxide (40 wt% solution in isopropanol, 280 g, 2.0 eq.) was charged into the mixture at 0-10 °C dropwise. The reaction was warmed to 20-30 °C and stirred for 21 h or until <0.5% of iri- / c / 7-bulyl 3,3',3"-((2S,2'S,2"S)-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-oxopropane-l,2-diyl))(3R,3'R,3"R)-tris(pyrrolidine-l -carboxylate) remained. Citric acid (36 g, 1.0 eq.) was charged into the mixture at 20-30 °C, and the mixture was stirred at 20-30 °C for 1-3 h. The reaction mixture was concentrated to 5-6 vol (1.8 L) below 50 °C under vacuum. Water (4500 mL, 15 vol) was charged into the mixture at 20-30 °C dropwise. The mixture was filtered, and the cake was rinsed with water (1500 ml, 5 vol) three times. The wet cake was slurried in methanol (7500 mL, 25 vol) at 50 °C for 4 h, then cooled to 20-30 °C over 2 h, and finally stirred at 20-30 °C for 6 h. The mixture was filtered, and the cake was washed with methanol (1500 mL, 5 vol). The wet cake was dried under vacuum at 55 °C for 24 h to afford the title compound as a solid (208 g, 96.1% purity, 96.9% assay, 94.0% yield). ‘H NMR (400 MHz, DMSO-A): 5 (br d, J = 17.64 Hz, 27H), 1.44-1.74 (m, 6H), 2.00-2.28 (m, 3H), 2.34-2.48 (m, 6H), 2.55 (br t, J = 12.70 Hz, 6H), 2.69-2.91 (m, 6H), 2.92-3.11 (m, 3H), 3.19 (br s, 6H), 3.25-3.33 (m, 6H), 3.35-3.50 (m, 6H), 3.86 (br s, 3H), 4.66 (br d, J = 5.96 Hz, 3H), 6.55-7.26 (m, 27H), 7.49-7.76 (m, 3H).13C NMR (101 MHz, DMSO-rfe): 528.62, 29.13, 29.74, 36.90, 37.44, 45.40, 45.76, 50.09, 52.30, 57.34, 62.60, 78.51, 126.15, 126.52, W.Tl, 128.36, 129.46, 139.23, 140.05, 153.88, 172.86. TOF-MS (ESI) m / z calculated for [Cs4Hn2N70i2]+([M+H]+): 1410.8363, found: 1410.8385.Preparation 7(2S,2'S,2"S)-3,3',3"-((Nitrilotris(methylene))tris(benzene-3,l-diyl))tris(2-((R)-l-(tert- butoxycarbonyl)pyrrolidin-3-yl)propanoic acid)

[0104] To a mixture of tri-tert-butyl 3,3',3"-((2S,2'S,2"S)-((nitrilotris(methylene))tris(benzene- 3,l-diyl))tris(3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-oxopropane-L2-diyl))(3R,3'R,3"R)-tris(pyrrolidine-l -carboxylate) (500.0 g, 0.25 mol, 1.0 eq.) and KI (3.34 g, 0.015 mol, 0.06 eq.) in tetrahydrofuran (2500 mL, 5 vol) was added 30 wt% aqueous H2O2 (348.30 g, 3.07 mol, 9.1 eq.) dropwise at 0 °C over 1 h, followed by a solution of 40 wt% aqueous tetrabutylammonium hydroxide (850.00 g. 1.31 mol, 3.90 eq.) in tetrahydrofuran (500 mL, 1 vol) at 0 °C over 2h. The reaction mixture was stirred at 0 °C for 16 h or until <0.05% of tri-tert-butyl 3,3',3"-((2S,2'S,2"S)-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-oxopropane-l, 2-diyl))(3R,3'R,3"R)-tris(pyrroli dine- 1 -carboxylate) remained. A 30 wt% aqueous solution Na2S2<)3 (885.0 g, 3.06 mol, 9.1 eq.) was charged dropwise to the reaction mixture below 10 °C. The mixture was extracted with isopropyl acetate (500 mL, 1 vol) 3 times. The aqueous layer was adjusted to pH = 5 with 10 wt% aqueous citric acid (75 mL, 0.15 vol). The aqueous layer was extracted with isopropyl acetate (1000 mL, 2 vol). The organic layers were combined and washed with 10 wt% aqueous citric acid (5000 mL, 10 vol), and then tetrahydrofuran was solvent exchanged using 10 vol isopropyl acetate (5 L, 10 vol). The organic layer was washed with 10 wt% aqueous K2CO3 solution (5500 mL, 11 vol), and the organic layer was discarded. The aqueous layer was washed with isopropyl acetate (2500 mL, 5 vol) 2 times. The aqueous layer was adjusted to pH 4-5 with 20 wt% aqueous H2SO4 (1500 mL, 3 vol) at 20-30 °C, and then extracted with methyl tert-butyl ether (2500 mL, 5 vol) 3 times. The combined organic layers were washed with 5 wt% aqueous Na2SC>4 (5000 mL, 10 vol). The organic layer was concentrated and solvent exchanged to 3 V of toluene. 3M Aqueous H2SO4 (1500 mL, 13.40 eq.) was charged dropwise to the organic layer. The reaction was heated to reflux and stirred for 36 h (jacket temp, was 110 °C, reaction temp, was 92 °C). The pH was adjusted to 1-2 with 20 wt% aqueous NaOH (1600 mL, 3.2 vol). The organic layer was separated and discarded. 20 wt% aqueous NaOH (250 mL, 0.6 vol) was charged to adjust the pH to 10.5 (target pH range is 10.5-11.5). The aqueous layer was washed with methyl tert-butyl ether (500 mL, 1 vol) 2 times; the organic layers were discarded. Tetrahydrofuran (750 mL, 1.5 vol) and ditert-butyl dicarbonate (250.0 g, 1.15 mol, 3.4 eq.) were charged to the aqueous layer and the mixture was stirred at 20-30 °C for 16 h. The mixture was adjusted to pH to 11.5 with 20 wt% aqueous sodium hydroxide (50 mL, 0.1 vol) at 20-30 °C and then washed with n-heptane (750 mL, 1.5 vol). The aqueous layer pH was adjusted to 4-5 with 20 wt% aqueous H2SO4 (60 mL, 0.1 vol) at 20-30 °C. The aqueous layer was extracted with methyl tert-butyl ether (1000 mL, 2 vol) 4 times, the organic layer was washed with 5 wt% aqueous NazSC (1000 mL, 2 vol) and concentrated to 2 vol. The concentrated solution was charged into n-heptane (500 mL, 1 vol) dropwise, the mixture was stirred at 15-25 °C for 20 h. The mixture was filtered, and the filtratewas washed with n-heptane (300 mL, 0.6 vol). The filter cake was dried under vacuum at 50 °C for 16 h to afford the title compound as an off-white solid (269.50 g, 0.16 mol, 93.4% assay, 97.0% purity, 99.6% yield).NMR (400 MHz, DMSO-rfc): 5 1.37 (br d, J = 11.04 Hz, 27 II), 1.51-1.68 (m, 3 H) 1.78-1.90 (m, 3 H), 2.20-2.35 (m, 3 H), 2.53-2.64 (m, 3 H), 2.68-2.85 (m, 6 H) 2.86-3.01 (m, 3 H), 3.03-3.20 (m, 3 H), 3.36-3.57 (m, 12 H), 7.02-7.11 (m, 3 H), 7.18-7.26 (m, 9 H), 12.23 (br s, 3 H);13C NMR (101 MHz, DMSO-rf6): 528.17, 28.82, 29.71, 36.82, 40.97, 45.06, 45.44, 49.39, 50.08, 50.40, 56.78, 78.18, 126.48, 127.38, 128.14, 129.14, 138.87, 139.18, 153.37, 175.00. TOF-MS (ESI) ni / z calculated for [C57H79N4O12 ]+([M+H]+): 1011.5689, found: 1011.5623.Preparation 8(4S,4'S,4"S)-3,3',3"-((2S,2'S,2"S)-3,3',3"-((Nitrilotris(methylene))tris(benzene-3,l-diyl))tris(2- ((R)-pyrrolidin-3-yl)propanoyl))tris(4-benzyloxazolidin- 2-one)

[0105] To a mixture of tri-terf-butyl 3,3',3"-((2S,2'S,2"S)-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-oxopropane-l,2-diyl))(3R,3'R,3"R)-tris(pyrrolidine-l-carboxylate) (6.0 g, 4.03 mmol, 1.0 eq.) in tetrahydrofuran (16 mL, 2 vol) was added 98% H2SO4 (1.57 g, 15.7 mmol, 4 eq.) dropwise. The reaction mixture was heated to 40 °C and stirred for 1 h at which time a white solid precipitated from the reaction mixture. The reaction was filtered, and the cake was washed with 2-methyltetrahydrofuran (30 mL, 5 vol.) to afford the title compound as an off-white solid (4.3 g, 3.62 mmol, 90.9% purity). LC-MS m / z =1188.4413.Example 1(2S,2'S,2"S)-3,3',3"-((Nitrilotris(methylene))tris(benzene-3,l-diyl))tris(2-((R)-pyrrolidin-3- yl)propanoic acid), Muvalaplin

[0106] To a mixture of tri-tert-butyl 3,3,,3"-((2S,2'5,2"5)-((nitrilotris(methylene))tris(benzene-3, 1 -diyl))tris (3 -(((£)- 1 -hydroxy-3-phenylpropan-2-yl)amino)-3-oxopropane- 1 ,2-diyl))(3R,37?,3"R)-tris(pyrrolidine-l -carboxylate) (180 g, 0.13 mol, 1.0 eq.) in o-xylene (1.08 L, 6 vol) was added dropwise 3N aqueous H2SO4 (1.28 L, 7.1 vol, 30 eq.) at 85 °C. After complete addition, the mixture was heated to 110 °C and stirred for 40 h or until <0.5% of starting material tri-fert-butyl 3,3',3"-((2S,2'S,2"S)-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(3-(((S)-l-hydroxy-3-phenylpropan-2-yl)amino)-3-oxopropane-l,2-diyl))(3R,3'R,3"R)-tris(pyrrolidine-l-carboxylate) remained. The reaction was cooled to 0-10 °C and the pH was adjusted to 3 with 20% aqueous NaOH (1360 g). The o-xylene layer was separated. The pH of the aqueous layer was adjusted to 6.5-7.5 with 20 wt% aqueous NaOH (81 g) at 20-30 °C. (2S,2'S,2"S)-3,3',3"-((Nitrilotris(methylene))tris(benzene-3, 1 -diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid) hemihydrate (5.4 g, 3 wt%) was charged into the mixture as seed. The mixture was slowly adjusted pH to 8.0-8.5 with 20 wt% aqueous NaOH (31 g) at 20-30 °C. Isopropanol (1.08 L, 6 vol) was charged into the mixture over 2 h at 20-30 °C, followed by stirring at 25 °C for 20 h. The mixture was filtered, and the cake was washed with water (360 g, 2 vol). The wet cake was dried under vacuum at 50 °C for 10 h to afford the title compound as an off-white solid (136 g, 99.0% purity, 54.5% assay, 84.3% yield). Ol NMR (400 MHz, DMSO-A): 5 1.46-1.76 (m, 3H), 2.01 (br dd, J = 11.15. 4.71 Hz, 3H), 2.41 (dq, J = 16.63, 8.44 Hz, 3H), 2.60-2.72 (m, 3H), 2.75-2.90 (m, 6H), 2.92-3.05 (m, 3H), 3.15 (br d, J = 4.53 Hz, 3H), 3.22-3.35 (m, 3H), 3.42 (br d, J = 2.86 Hz, 3H), 4.18 (br s, 6H), 7.11-7.46 (m, 12H), 8.77-9.16 (m, 6H).13C NMR (101 MHz, DMSO-cfo): 528.38, 36.81, 44.76, 48.03, 49.65, 56.74, 111.49, 114.37, 117.25, 120.13, 140.13, 174.83. TOF-MS(ESI) m / z calculated for [CEHSSN^? ([M+H]+): 711.4116, found: 711.4117.Altemative Preparation of Example 1(2S,2'S,2"S)-3,3',3"-((Nitrilotris(methylene))tris(benzene-3,l-diyl))tris(2-((R)-pyrrolidin-3- yl)propanoic acid) , Muvalaplin

[0107] To a slurry of (2S,2'S,2"S)-3,3',3"-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(2-((R)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid) (268.00 g, 0.26 mol, 1.0 eq.) in toluene (1.5 L, 6 vol) was added dropwise 1.8 M aqueous H2SO4 (1500 mL, 20.00 eq.). The mixture was warmed to 60 °C and stirred for 6 h or until <0.05% of (2S,2’S,2"S)-3,3',3"-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(2-((R)-l-(te,rt-butoxycarbonyl)pyrroli din-3-yl)propanoic acid) was present. The mixture was cooled to 20-30 °C and then adjusted to pH 3-4 with 20 wt% aqueous NaOH (1130 mL, 4.2 vol). The organic layer was separated and discarded. The aqueous layer was adjusted pH to 6.8 (target pH range is 6.5-7.0) with 20 wt% aqueous NaOH (30 mL, 0.1 vol). 5.60 g of (2S,2'S,2"S)-3,3',3”-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid) hemihydrate seed (3% wt for theoretical yield)) was charged. The mixture was stirred at 15-25 °C for 1 h, and then adjusted pH to 8.25 with 20 wt% aqueous NaOH (10 mL, 0.1 vol). Isopropanol (1.5 L, 6 vol) was added dropwise to the mixture over 2 h at 15-25 °C, then stirred at 15-25 °C for 18 h. The mixture was filtered, and the wet cake was washed with water (300 mL, 1 vol). The wet cake was dried under vacuum at 50 °C for 66 h to afford the title compound as an off-white solid (406.1 g, 94.7 % purity, 40.0% assay, 92.0% yield). TOF-MS (ESI) m / z calculated for [CazHssNaOef ([M+H]+): 711.4117, found: 711.4121.Alternative Preparation of Example 1(2S,2'S,2"S)-3,3',3"-((Nitrilotris(methylene))tris(benzene-3,l-diyl))tris(2-((R)-pyrrolidin-3- yl)propanoic acid) , Muvalaplin

[0108] (4S,4'S,4"S)-3,3',3"-((2S,2'S,2"S)-3,3',3"-((Nitrilotris(methylene))tris(benzene-3,l-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoyl))tris(4-benzyloxazolidin-2-one) was converted to the title compound using aqueous acid in a manner similar to that described in Table 5.Alternative Preparation of Example 1(2S,2'S,2"S)-3,3',3"-((Nitrilotris(methylene))tris(benzene-3,l-diyl))tris(2-((R)-pyrrolidin-3- yl)propanoic acid) , Muvalaplin

[0109] Tri-tert-butyl 3,3',3"-((2S,2'S,2"S)-((nitrilotris(methylene))tris(benzene-3,l-diyl))tris(3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-oxopropane-l,2-diyl))(3R,3'R,3 "R)-tris(pyrrolidine-l-carboxylate) (1 equiv., 85% purity) in a mixture of o-xylene:3M aq. H2SO4 (10 volumes, 4:6) was heated to 135 °C for 18 h. HPLC indicated 60% of the title compound, along with 10% of amide intermediate (2S,2'S)-3,3'-((((3-((S)-3-(((S)-l-hydroxy-3-phenylpropan-2-yl)amino)-3-oxo-2-((R)-pyrrolidin-3-yl)propyl)benzyl)azanediyl)bis(methylene))bis(3,l-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) and 6% of diastereomer (2S,2'S)-3,3'-((((3-((R)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)azanediyl)bis(methylene))bis(3,l-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid). Muvalaplin, prepared by the above procedure was identical to muvalaplin prepared according to Example 1 based on HPLC retention time and mass (m / z).Example 2(2S,2'S,2"S)-3,3',3"-((Nitrilotris(methylene))tris(benzene-3,l-diyl))tris(2-((R)-pyrrolidin-3- yl)propanoic acid) hemihydrate , Muvalaplin hemihydrate

[0110] To a mixture of (2S,2’S,2"S)-3,3',3"-((nitrilotris(methylene))tris (benzene-3,l-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid) (405.0 g, 0.23 mol, 1.0 eq.), water (440 mL, 2.7 vol), and methanol (280 mL, 1.7 vol) was added at 25 °C a solution of KOH (38.40 g, 0.68 mol, 3.0 eq.) in water (160 mL, 1 vol). The mixture was heated to 60 °C over 0.5 h, stirred at 60 °C for 3 h, then cooled to 20 °C over 0.5 h. The mixture was polish-filtered and rinsed with the mixture of water (40 mL, 0.25 vol) and methanol (40 mL, 0.25 vol). The combined filtrates were heated to 60 °C again, then the pH was slowly adjusted to 10.30 with freshly prepared 20 wt% acetic acid in methanol solution (115 mL, 0.72 vol). After complete addition, mixture was stirred for 2 h at 60 °C at which point the mixture becomes cloudy. Stirring was continued at 60 °C for 16 h. The pH was adjusted to 7.21 with 5 wt% of freshly prepared acetic acid in methanol solution (550 mL, 3.4 vol) over 8 h at 60 °C and stirred at 60 °C for 2 h. The mixture was cooled to 20 °C over 3 h, and stirred for 20 h. The mixture was filtered, and the filtrate was washed sequentially with solution of methanol-water (V / V=l:2, 320 mL, 2.0 vol) and methanol-water mixture (V / V=l:9, 320 mL, 2.0 vol). The wet cake was dried under vacuum at 50 °C for 40 h to afford the title compound as an off-white solid. (135.0 g, 99.4% purity, 100.5% assay, 83.8% yield). ’ll NMR (400 MHz, DMSO- e): 8 1.57-1.72 (m, 3H), 1.91-2.90 (m, 3H), 2.30-2.46 (m, 3H), 2.61-2.72 (m, 3H), 2.73-2.88 (m, 6H), 2.89-3.01 (m, 3H), 3.08-3.18 (m, 3H), 3.32-3.30 (m, 3H), 3.40-3.46 (m, 3H), 4.12 (dr s, 6H), 4.18-4.74 (m, 12H), 9.07 (br d, J = 40 Hz, 6H);13C NMR (101 MHz, DMSO-rfc): 628.13, 36.54, 39.86, 44.37, 47.66, 49.33, 56.41, 128.88, 129.15, 129.91, 131.63, 1 9.73, 139.73, 174.55. TOF-MS (ESI) m / z calculated for [C42H55N4O6 ]+([M+H]+): 711.4117, found: 711.4128.

[0111] Small scale preparations of Preparation 5 using Preparation 4 and tert-butyl (R)-3-(2-((S)-4-benzyL2-oxooxazolidin-3-yl)-2-oxoethyl) pyrrolidine- 1 -carboxylate as described above while varying either the base or the temperature were conducted. The yields of trialkylated product Preparation 5 and dialkylated impurity di-tert-butyl 3,3'-((2S,2'S)-((((3-(bromomethyl)benzyl)azanediyl)bis(methylene))bis(3,l-phenylene))bis(3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-oxopropane-l,2-diyl))(3R,3'R)-bis(pyrrolidine-l -carboxylate) are shown in Table 3.

[0112] Table 3. Variation of Base and Temperature to Prepare Preparation 5Reactions were run with 4-10 volumes THF using 1.0-1.1 eq Base, 1.0 eq oxooxazolidine, and 0.28-0.30 eq Preparation 4 for 12-24 h. % Yield based on HPLC area% of the crude reaction mixture.

[0113] Small scale preparations of Preparation 6 using Preparation 5 as described above while varying either the base or the solvent were conducted. The yields of triamide product Preparation 6 and carboxylic acid impurity (S)-3-(3-((bis(3-((S)-2-((R)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-(((S)-l-hydroxy-3-phenylpropan-2-yl)amino)-3-oxopropyl)benzyl)amino)methyl)phenyl)-2-((R)-l-(te -butoxycarbonyl)pyrrolidin-3-yl)propanoic acid are shown in Table 4.

[0114] Table 4. Base and Solvent Screen for Auxiliary-Opening ReactionReactions were run with 13 volumes of solvent for 16 h. 40% tetrabutylammonium hydroxide (aqueous) was used. % Yield based on HPLC area% of the crude reaction mixture.

[0115] Small scale preparations of Preparation 6 using Preparation 5 as described above while varying the base were conducted. The yields of triamide product Preparation 6 and carboxylic methyl ester impurity di-tert-butyl 3,3'-((2S,2'S)-((((3-((S)-2-((R)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-methoxy-3-oxopropyl)benzyl)azanediyl)bis(methylene))bis(3,l-phenylene))bis(3-(((S)-l -hydroxy-3-phenylpropan-2-yl)amino)-3-oxopropane-l,2-diyl))(3R,3'R)-bis(pyrrolidine-l -carboxylate) are shown in Table 5.

[0116] Table 5. Base Screen for Auxiliary-Opening ReactionReactions were run with 13 volumes of methanol and 9.0 eq Base for 16 h at 20 °C. % Yield based on IIPLC area% of the crude reaction mixture.

[0117] Small scale preparations of Preparation 6 using Preparation 5 as described above while varying the base were conducted. The yields of triamide product Preparation 6 and carboxylic isopropyl ester impurity di-tert-butyl 3,3'-((2S,2'S)-((((3-((S)-2-((R)-l-(terr-butoxycarbonyl)pyrrolidin-3-yl)-3-isopropoxy-3-oxopropyl)benzyl)azanediyl)bis(methylene))bis(3,l-phenylene))bis(3-(((S)-l -hydroxy-3-phenylpropan-2-yl)amino)-3-oxopropane-l,2-diyl))(3R,3'R)-bis(pyrrolidine-l -carboxy late) are shown in Table 6.

[0118] Table 6. Base Screen for Auxiliary-Opening ReactionReactions were run with 10 volumes of isopropanol and 2.0 eq Base for 16 h at 20 °C. % Yield based on HPLC arca% of the crude reaction mixture.

[0119] Small scale preparations of Example 1 (muv alaplin) using Preparation 6 as described above while varying the acid, cosolvent, and temperature were conducted. The yields of Example 1, amide intermediate (2S,2'S)-3,3'-((((3-((S)-3-(((S)-l-hydroxy-3-phenylpropan-2-yl)amino)-3-oxo-2-((R)-pyrrolidin-3-yl)propyl)benzyl)azanediyl)bis(methylene))bis(3,l-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid), and Example 1 isomer impurity (2S,2'S)-3,3'-((((3-((R)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)azanediyl)bis(methylene))bis(3,l-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) are shown in Tables 7 and 8.

[0120] Table 7. Amide Hydrolysis and BOC Deprotection ScreenReactions were run with 20-30 eq aqueous sulfuric acid and 6 volumes of cosolvent for 40-48 h at 100-110 °C. The isomer impurity is reported as the amount of isomer generated in the hydrolysis reaction. Entry 7 was run for 64 h. Entry 8 was run for 22 h. Entry 11 was run with 51 eq of acid. % Yield based on HPLC area% of the crude reaction mixture.

[0121] Table 8. Amide Hydrolysis and BOC Deprotection ScreenReactions were run with 30 eq aqueous sulfuric acid and 7 volumes of o-xylene for 2 h under flow conditions. The isomer impurity is reported as the amount of isomer generated in the hydrolysis reaction. % Yield based on HPLC area% of the crude reaction mixture.

[0122] Small scale preparations of tert-butyl (R)-3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine- 1 -carboxylate using (S)-4-benzyloxazolidin-2-one and (R)-2-(l-(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid as described above while varying conditions were conducted. The yields of tert-butyl (R)-3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl) pyrrolidine- 1 -carboxylate are shown in Table 9.

[0123] Table 9. Solvent and Lewis Acid ScreenReactions were run with 1 eq (R)-2-( l-(7ert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid, 2.4 eq tri ethylamine, 1.2 eq pivaloyl chloride, 1.1 eq Lewis Acid, 1.0-1.05 eq (S)-4- benzyloxazolidin-2-one, and 8 volumes of solvent for 12-24 h at -15-25 °C. % Yield based on HPLC area% of the crude reaction mixture.

Claims

CLAIMSWe claim:

1. A method for the preparation of an Lp(a) inhibitor compound of the formula:wherein the method comprises the steps of:(a) combining a pyrrolidine compound of the formula:comprises Ci to Cio alkyl. C3 to C7 cycloalkyl, a four member to seven-member heterocycloalkyl, a G, to Cio aryl, a four member to seven-member heteroaryl, or combinations thereof;, , , , OTs, OTf, or OMs,to form a trialkylated compound of the formula:(b) combining the trialkylated compound with a hydroxide or an alkoxide to form an intermediate compound of the formula:(c) combining the intermediate compound with an acid to form the Lp(a) inhibitor compound.

2. The method of claim 1, wherein the method comprises the steps of:(a) combining a pyrrolidine compound of the formula:I, OTs, OTf, or OMs;to form a trialkylated compound of the formula:(b) combining the trialkylated compound with a hydroxide or an alkoxide to form an intermediate compound of the formula:(c) combining the intermediate compound with an acid to form muvalaplin.

3. The method of claim 1 or 2, wherein the method comprises the steps of: (a) combining a pyrrolidine compound of the formula:form a trialkylated compound of the formula:(b) combining the trialkylated compound with a hydroxide or an alkoxide to form an intermediate compound of the formula:(c) combining the intermediate compound with an acid to form muvalaplin.

4. A method for the preparation of an Lp(a) inhibitor compound of the formula:wherein the method comprises the steps of:(a) combining a pyrrolidine compound of the formula:, , , I, OTs, OTf, or OMs,to form a trialkylated compound of the formula:(b) combining the trialkylated compound with a peroxide to form a triacid compound of the formula:(c) combining the triacid compound with an acid to form the Lp(a) inhibitor compound.

5. A method for the preparation of an Lp(a) inhibitor compound of the formula:wherein the method comprises the steps of:(a) combining a pyrrolidine compound of the formula:Ci to Cio alkyl, C3 to C7 cycloalkyl, a four member to seven-member heterocycloalkyl, a Ce to C10 aryl, a four member to seven-member heteroaryl, or combinations thereof;form a trialkylated compound of the formula:(b) adding an acid to form the Lp(a) inhibitor compound.

6. The method of claim 5, wherein the method comprises the steps of:(a) combining a pyrrolidine compound of the formula:, wherein R comprises Ci to Cio alkyl, C3 to C7 cycloalkyl, a four member to seven-member heterocycloalkyl, a Ce to Cio aryl, a four member to seven-member heteroaryl, or combinations thereof;form a trialkylated compound of the formula:(b) adding an acid to form the Lp(a) inhibitor compound.

7. The method of claim 5 or 6, wherein R is z'Pr, Bn, or Ph.The method of any one of claims 3, 6, or 7. wherein theformed by:(1) combiningwith ammonium hydroxide and sodium carbonate in acetonitrile to form the tribenzoate compound of the formula:(2) combining the tribenzoate compound with lithium aluminum hydride to form a tribenzyl alcohol compound of the formula:(3) combining the tribenzyl alcohol compound with HBr and a bromide salt to form the compound of the formula:

9. The method of any one of claims 1 to 8, wherein step (a) further comprises adding a non-nucleophilic base.

10. The method of claim 9, wherein the non-nucleophilic base comprises sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldi silazide (KHMDS), lithiumhexamethyldisilazide (LiHMDS), lithium diisopropylamide (LDA), lithium dicyclohexylamide, or combinations thereof.

11. The method of any one of claims 1 to 10, wherein step (a) is performed at a temperature of from about -78 °C to about 20 °C.

12. The method of claim 11, wherein the temperature is from about -40 °C to about 15 °C.

13. The method of claim 12, wherein the temperature is from about -20 °C to about 10 °C.

14. The method of any one of claims 1 to 3 or 8 to 13, wherein the hydroxide of step (b) comprises NaOH, LiOH, KOH, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, or combinations thereof.

15. The method of claim 14, wherein the tetramethylammonium hydroxide is generated in situ from the combination of tetramethylammonium chloride and NaOH, LiOH, or KOH.

16. The method of claim 15, wherein the tetrabutylammonium hydroxide is generated in situ from the combination of tetrabutylammonium chloride and NaOH, LiOH, or KOH.

17. The method of any one of claims 1 to 3 or 8 to 13, wherein the alkoxide of step (b) is generated in situ from the combination of (1) an alcoholic solvent and (2) a carbonate base selected from the group consisting of K2CO3, Li2CO3, Na2CO3, CssCO3, and combinations thereof.

18. The method of any one of claims 1 to 3, or 8 to 13, wherein the alkoxide of step (b) is generated in situ from the combination of (1) an alcoholic solvent and (2) a hydroxide.

19. The method of claim 17 or 18, wherein the alcoholic solvent comprises methanol, ethanol, isopropanol, or propanol.

20. The method of any one of claims 1 to 4 or 8 to 19, wherein the acid of step (c) comprises HC1, H2SO4, H3PO4, or HBr.

21. The method of any one of claims 1 to 4 or 8 to 20, wherein step (c) is in water.

22. The method of any one of claims 1 to 4 or 8 to 21 , wherein step (c) comprises a nonpolar co-solvent.

23. The method of claim 22, wherein the nonpolar co-solvent comprises xylenes, o- xylene, m-xylene, -xylene. toluene, n-butyl ether, or cyclopentyl methyl ether.

24. The method of any one of claims 1 to 4 or 8 to 23, wherein step (c) is performed at a temperature of from about 90 °C to about 150 °C.

25. The method of any one of claims 5 to 7, wherein the acid of step (b) comprises HC1, II2SO4, II3PO4, or IIBr.

26. The method of any one of claims 5 to 7 or 25, wherein step (b) is in water.

27. The method of any one of claims 5 to 7, 25, or 26, wherein step (b) comprises a nonpolar co-solvent.

28. The method of claim 27, wherein the nonpolar co-solvent comprises xylenes, o-xylene, m-xylene, p-xylene, toluene, n-butyl ether, or cyclopentyl methyl ether.

29. The method of any one of claims 5 to 7 or 25 to 28, wherein step (b) is performed at a temperature of from about 90 °C to about 150 °C.

30. The method of claim 1 to 3 or 8 to 24, wherein the intermediate compound is crystalline.

31. The method of claim 30, wherein the intermediate compound is crystalline and is characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising peaks at 14.9°, 18.7°, and 19.0° ± 0.2° 20.

32. The method of claim 4 or 9 to 24, wherein the triacid compound is crystalline.

33. The method of claim 32, wherein the triacid compound is crystalline and is characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising peaks at 5.6°, 16.8°, 17.6°, 18.4°, 20.7°, and 22.5° ± 0.2° 20.

34. An intermediate compound for the preparation of an Lp(a) inhibitor compound, the intermediate compound of the formula:

35. The intermediate compound of claim 34, wherein the intermediate compound is crystalline.

36. The intermediate compound of claim 35, wherein the intermediate compound is slurried in an alcoholic solvent.

37. The intermediate compound of claim 26, wherein the alcoholic solvent is methanol.

38. The intermediate compound of any one of claims 35 to 37, wherein the intermediate compound is crystalline and is characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising peaks at 14.9°, 18.7°, and 19.0° ± 0.2° 20.

39. The intermediate compound of claim 38, wherein the intermediate compound is characterized by a powder x-ray diffraction pattern using Cu Ka radiation comprising peaks at 6.4°, 9.8°, 13.4°, 13.9°. 14.9°, 15.4°, 16.7°, 18.7°, and 19.0° ± 0.2° 20.

40. An intermediate compound for the preparation of an Lp(a) inhibitor compound, the intermediate compound of the formula:wherein R is z'Pr, Bn, or Ph.

41. The intermediate compound of claim 40, wherein the compound is of the formula:

42. A triacid compound for the preparation of an Lp(a) inhibitor compound, the triacid compound of the formula:

43. The triacid compound of claim 44, wherein the triacid compound is crystalline.

44. The triacid compound of claim 42 or 43, wherein the triacid compound is crystalline and is characterized by an powder x-ray diffraction pattern using Cu Ka radiation comprising peaks at 5.6° and 17.6° ± 0.2° 20.

45. The triacid compound of claim 44, wherein the triacid compound is crystalline and is characterized by an x-ray diffraction pattern using Cu Ka radiation comprising peaks at 5.6°, 16.8°, 17.6°, 18.4°, 20.7°, and 22.5° ± 0.2° 20.

46. A compound of the formula:wherein the compound is prepared the method of any one of claims 1 to 33.

47. A method for the preparation of an Lp(a) inhibitor compound of the formula:wherein the method comprises the steps of:(a) combining a pyrrolidine compound of the formula:comprises Ci to Cio alkyl, C3 to C7 cycloalkyl, a four member to seven-member heterocycloalkyl, a C to Cio aryl, a four member to seven-member heteroaryl, or combinations thereof;, , Br, I, OTs, OTf, or OMs, to form a trialkylated compound of the formula:(b) combining the trialkylated compound with a hydroxide or an alkoxide to form an intermediate compound of the formula:(c) combining the intermediate compound with an acid to form the Lp(a) inhibitor compound.

48. A method for the preparation of an Lp(a) inhibitor compound of the formula:wherein the method comprises the steps of:(a) combining a pyrrolidine compound of the formula:wherein R is iPr, Bn, or Ph;withX , wherein X is Cl, Br, T, OTs, OTf, or OMs,to form a trialkylated compound of the formula:(b) combining the trialkylated compound with a peroxide to form a triacid compound of the formula:(c) combining the triacid compound with an acid to form the Lp(a) inhibitor compound.

49. A method for the preparation of an Lp(a) inhibitor compound of the formula:wherein the method comprises the steps of:(a) combining a pyrrolidine compound of the formula:Ci to Cio alkyl, C3 to C7 cycloalkyl, a four member to seven-member heterocycloalkyl, a Ce to Cio aryl, a four member to seven-member heteroaryl, or combinations thereof;form a trialkylated compound of the formula:(b) adding an acid to form the Lp(a) inhibitor compound.

50. A crystalline compound of the formula:

51. The compound of claim 50, wherein the compound is characterized by an powder x-ray diffraction pattern using Cu Ka radiation comprising peaks at 6.6°, 13.2 °, and 20.7° ± 0.2° 20.

52. The compound of claim 50, wherein the compound is characterized by an x-ray diffraction pattern using Cu Ka radiation comprising peaks at 6.6°, 13.2°, 16.5°, 19.9°, 20.7°, 21.8 °, and 22.7° ± 0.2° 20.

53. The compound of claim 50, wherein the compound is characterized by an x-ray diffraction pattern using Cu Ka radiation comprising peaks at 6.6°, 13.2°, 13.9°, 16.5°, 18.3°, 19.9°, 20.7°, 21.8°, 22.7°, and 23.9° ± 0.2° 20.

54. A crystalline compound of the formula:

55. The compound of claim 54, wherein the compound is characterized by an powder x-ray diffraction pattern using Cu Ka radiation comprising peaks at 15.7°, 17.4°, and 21.2° ± 0.2° 20.

56. The compound of claim 54, wherein the compound is characterized by an x-ray diffraction pattern using Cu Ka radiation comprising peaks at 15.7°, 17.4°, 18.4°, 21.2°, 22.1°, and 22.5° ± 0.2° 20.

57. The compound of claim 54, wherein the compound is characterized by an x-ray diffraction pattern using Cu Ka radiation comprising peaks at 15.7°, 17.4°, 17.8°, 18.4°, 21.2°, 21.6°, 22.1°, 22.5°, 23.7°, and 25.4° ± 0.2° 20.

58. A crystalline compound of the formula:

59. The compound of claim 58, wherein the compound is characterized by an powder x-ray diffraction pattern using Cu Ka radiation comprising peaks at 14.0°, 21.0°, and 28.3° ± 0.2° 20.-SO- 60. The compound of claim 58, wherein the compound is characterized by an x-ray diffraction pattern using Cu Ka radiation comprising peaks at 14.0°, 20.3°, 21.0°, 21.4°, 21.8°, 22.8°, and 28.3° ± 0.2° 20.

61. The compound of claim 58, wherein the compound is characterized by an x-ray diffraction pattern using Cu Ka radiation comprising peaks at 14.0°, 16.5°, 20.3°, 21.0°, 21.4°, 21.8°, 22.8°, 23.5°, 26.2°, and 28.3° ± 0.2° 20.

62. A crystalline compound of the formula:

63. The compound of claim 62, wherein the compound is characterized by an powder x-ray diffraction pattern using Cu Ka radiation comprising peaks at 3.7°, 1 .5°, and 18.8° ± 0.2° 20.

64. The compound of claim 62, wherein the compound is characterized by an x-ray diffraction pattern using Cu Ka radiation comprising peaks at 3.7°, 9,9°, 13.5°, 14.9°, 18.8°, and 19.1° ± 0.2° 20.

65. The compound of claim 62, wherein the compound is characterized by an x-ray diffraction pattern using Cu Ka radiation comprising peaks at 3.7°, 6.5°, 9.9°, 13.5°, 14.9°, 16.4°, 16.7°, 18.8°, 19.1°, and 23.0 ° ± 0.2° 20.

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