Methods for producing triterpenoid derivatives

Abstract

In some aspects, the present disclosure provides methods for the preparation of omaveloxolone. Also provided herein are methods for the preparation of a compound having the Formula (III) wherein the variables are defined herein.

Description

METHODS FOR PRODUCING TRITERPENOID DERIVATIVES

[0001] This application claims the benefit of United States Provisional Application No. 63 / 516,483 filed July 28, 2023, the entire contents of which are hereby incorporated by reference.BACKGROUND OF THE INVENTIONI. Field of the Invention

[0002] The present invention relates generally to the field of chemistry, particularly organic chemistry and process chemistry. More particularly, it concerns methods for the synthesis of triterpenoid derivatives.II. Description of Related Art

[0003] The amorphous form (class 1) of omavel oxoIone (N- [(4aS,6aR,6bS, 8aR, 12aS, 14aR, 14bS)~ 11 -cyano-2,2,6a,6Z>,9,9, 12a-heptamethyl- 10, 14-dioxo- l,3,4,5,6,7,8,8a,14a,14&-decahydropicen-4a-yl]-2,2-difluoropropanamide; RTA 408; SKYCLARYS®) has been approved by the Food and Drug Administration (FDA) to treat Friedrich’s ataxia (FA) in adults and adolescents aged 16 and older. Omavel oxoIone and related triterpenoid analogs are potent known activators of nuclear factor erythroid-derived 2- related factor 2 (Nrf2) and are inhibitors of nuclear factor kappa-light-chain enhancer of activated B cells, inducing an anti-inflammatory and anti -oxi dative phenotype. Nrf2 signaling promotes anti -oxi dative mechanisms (Muthusamy et al., 2012), and Nrf2 activation can increase mitochondrial respiration (Holmstrom et al., 2013; Ludtmann et al., 2014).

[0004] Given the therapeutic use of omaveloxolone and related triterpenoid derivatives, improved methods of synthesizing triterpenoid derivatives are desirable. Presently known methods for forming triterpenoid derivatives and methods of use thereof have been disclosed in, for example, Fu and Gribble, 2013; Wong et al., 2016; Honda et al., 1997; Honda et al., 1998; Honda et al., 1999; Honda et al., 2000a; Honda et al., 2000b; Honda, et al., 2002; Suh et al. 1998; Suh et al., 1999; Place et al., 2003; Liby et al., 2005; and U.S. Patents 7,915,402; 7,943,778; 8,071,632; 8,124,799; 8,129,429; 8,338,618, 8,993,640, 9,102,681, 9,701,709, 9,512,094, 9,889,143, 10,093,614, and 10,556,858, which are incorporated herein by reference.Described herein are methods for synthesizing omaveloxolone and related triterpenoid derivatives, including those with improved yield, improved purity, improved efficiency, improved safety, improved environmental considerations, and / or otherwise enabling the improved industrial scale preparation of omaveloxolone and related triterpenoid derivatives.SUMMARY OF THE INVENTION

[0005] Provided herein are methods for the preparation of omaveloxolone and related compounds. In some aspects, the present disclosure provides a multi-step method for preparation of omaveloxolone from oleanolic acid, comprising the use of a compound of Formula I as a reagent in one or more steps, wherein Formula I is defined as:wherein:Ri, Ri', and Ri" are each independently hydrogen, halo, amino, cyano, or carboxy; or alkyl(c<8), cycloalkyl(c<8), alkenyl(c<8), alkynyl(c<8), aryl(c<8), aralkyl(c<8), heteroaryl(c<8), heteroaralkyl(c<8), alkoxy(c<8), cycloalkoxy(c<8), alkenyloxy(c<8), alkynyloxy(c<8), aryloxy(c<8), aralkoxy(c<8), heteroaryloxy(c<8), heteroaralkoxy(c<8), alkylamino(c<8), dialkylamino(c<8), amido(c<8), or a substituted version of any of these groups.

[0006] In some embodiments, Ri, Ri', and Ri" are each propyl. In some aspects, the method comprises reacting oleanolic acid with an alkylating agent in a reaction mixture to form Compound A, wherein Compound A is defined as:

[0007] In some embodiments, the reaction mixture further comprises potassium carbonate. In some embodiments, the reaction mixture further comprises 2-methyltetrahydrofuran. In some embodiments, the reaction mixture further comprises tetrabutyl ammonium bromide. In some embodiments, the alkylating agent is dimethyl sulfate. In some aspects, the reaction is carried out at a temperature of about 30°C. In certain aspects, the reaction is carried out for about 1.0h. In some aspects, the method further comprises contacting the reaction mixture with triethylamine at a second temperature of about 50°C for a second time period of about 3 h.

[0008] In some embodiments, the method further comprises reacting Compound A:with an oxidizing agent in a reaction mixture to form Compound B, wherein CompoundB is defined as:

[0009] In some embodiments, the oxidizing agent comprises meta-chloroperoxybenzoic acid. In some embodiments, the molar ratio of Compound A to the oxidizing agent is about 4:5. In some aspects, the reaction mixture comprises dichloromethane. In some embodiments, the reaction is carried out at a temperature of about 25°C. In some embodiments, the reaction is carried out at a time period of about 15 h. In some embodiments, the method further comprises contacting the reaction mixture with a solution of sodium bicarbonate and isolating the organic layer. In some embodiments, the method further comprises contacting the isolated organic layer with methanesulfonic acid.

[0010] In some aspects, the method further comprises reacting Compound B:with an oxidizing agent in a reaction mixture to form Compound C, wherein CompoundC is defined as:

[0011] In some embodiments, the oxidizing agent is pyridinium perbromide. In some embodiments, the reaction mixture comprises a molar ratio of Compound B to the oxidizing agent of about 1 : 1.4. In some embodiments, the reaction mixture further comprises toluene. In some embodiments, the method further comprises reacting Compound B with the oxidizing agent at a temperature of about 33°C. In some embodiments, the method further comprises reacting Compound B with the oxidizing agent for a reaction time period of about 2 h.

[0012] In some aspects, the method further comprises reacting Compound C:with an oxidizing agent in the presence of a compound of Formula I:in a reaction mixture to form Compound D, wherein Compound D is defined as:wherein:Ri, Ri', and Ri" are each independently hydrogen, halo, amino, cyano, or carboxy; or alkyl(c<8), cycloalkyl(c<8), alkenyl(c<8), alkynyl(c<8), aryl(c<8), aralkyl(c<8), heteroaryl(c<8), heteroaralkyl(c<8), alkoxy(c<8), cycloalkoxy(c<8), alkenyloxy(c<8), alkynyloxy(c<8), aryloxy(c<8), aralkoxy(c<8), heteroaryloxy(c<8), heteroaralkoxy(c<8), alkylamino(c<8), dialkylamino(c<8), amido(c<8), or a substituted version of any of these groups.

[0013] In some embodiments, Ri, Ri', and Ri" are each propyl. In some embodiments, the reaction mixture comprises a molar ratio of Compound C to the compound of Formula I of about 1 : 1.35. In some embodiments, the reaction mixture further comprises diisopropylethylamine. In some embodiments, the reaction mixture comprises a molar ratio of Compound C to diisopropylethylamine of about 1 : 1.6. In some embodiments, the oxidizing agent is dimethylsulfoxide. In some embodiments, the reaction mixture comprises a molar ratio of Compound C to dimethylsulfoxide of about 1 : 5.5. In some embodiments, the method further comprises reacting Compound C with the compound of Formula I under an inert atmosphere. In some aspects, the method comprises contacting Compound C with a solution comprising the compound of Formula I. In some embodiments, the concentration of the compound of Formula I in the solution is about 50% by weight. In some embodiments, the solution comprises ethyl acetate. In some embodiments, the reaction between Compound C and dimethylsulfoxide in the presence of the compound of Formula I is carried out at a temperature of about 25 °C. In some embodiments, the reaction between Compound C and dimethylsulfoxide in the presence the compound of Formula I is carried ourt for a reaction time period of about 3 h.

[0014] In some aspects, the present disclosure provides a method for the preparation of a compound of Formula III comprising obtaining a compound of Formula II:and reacting the compound of Formula II with an oxidizing agent in the presence of a compound of Formula I:in a reaction mixture to form a compound of Formula III:wherein:Ri, Ri', and Ri" are each independently hydrogen, halo, amino, cyano, or carboxy; or alkyl(c<8), cycloalkyl(c<8), alkenyl(c<8), alkynyl(c<8), aryl(c<8), aralkyl(c<8), heteroaryl(c<8), heteroaralkyl(c<8), alkoxy(c<8), cycloalkoxy(c<8), alkenyloxy(c<8), alkynyloxy(c<8), aryloxy(c<8), aralkoxy(c<8), heteroaryloxy(c<8), heteroaralkoxy(c<8), alkylamino(c<8), dialkylamino(c<8), amido(c<8), or a substituted version of any of these groups; andR2 is Ci-Cis-acyl or Ci-Cis-alkyl, wherein either of these groups is substituted or unsubstituted.

[0015] In some embodiments, Ri, Ri', and Ri" are each propyl. In some embodiments, R2 is Ci-Cis-acyl or substituted Ci-Cis-acyl. In certain embodiments, R2 is substituted Ci-Cis-acyl. In some embodiments, R2 is -CO2CH3. In some embodiments, the reaction mixture comprises a molar ratio of the compound of Formula II to the compound of Formula I from about 1 : 1 to about 1 :2. In some embodiments, the reaction mixture further comprises diisopropylethylamine. In some embodiments, the reaction mixture comprises a molar ratio of the compound of Formula II to diisopropylethylamine from about 1 : 1 to about 1 :2. In some embodiments, the reaction mixture further comprises dimethylsulfoxide. In some embodiments, the reaction mixture comprises a molar ratio of the compound of Formula II to dimethylsulfoxide of about 1 :6.8. In some embodiments, the method further comprises reactinga compound of Formula II with the compound of Formula I under an inert atmosphere. In some aspects, reacting the compound of Formula II with the compound of Formula I further comprises contacting the compound of Formula II with a solution comprising the compound of Formula I. In some embodiments, the concentration of the solution is about 50% by weight. In some embodiments, the solution further comprises ethyl acetate. In some embodiments, the method further comprises reacting the compound of Formula II with the compound of Formula I at a temperature of about 25 °C. In some embodiments, the method further comprises reacting the compound of Formula II with the compound of Formula I for a reaction time period of about 3 h.

[0016] In some aspects, the present disclosure provides a method for the preparation of Compound A comprising obtaining oleanolic acid, and reacting oleanolic acid with an alkylating agent in a reaction mixture to form Compound A:wherein the reaction mixture comprises a solvent that is immiscible with water.

[0017] In some embodiments, the reaction mixture further comprises a base, such as potassium carbonate. In some embodiments, the reaction mixture further comprises a phase-transfer catalyst, such as tetrabutylammonium bromide. In some embodiments, the alkylating agent is dimethyl sulfate. In some embodiments, the solvent comprises 2-methyltetrahydrofuran. In some aspects, the method further comprises an aqueous purification step. In some embodiments, the reaction is carried out at a temperature from about 0°C to about 100°C. In certain embodiments, the temperature is about 30°C. In some embodiments, the reaction is carried out for a reaction time period from about 0.5 h to about 3.0 h. In certain embodiments, the reaction time period is about 1.0 h. In some embodiments, Compound A is prepared in greater than 90% purity, as measured by high performance liquid chromatography. In certain embodiments, Compound A is prepared in greater than 95% purity, as measured by high performance liquid chromatography. In certain embodiments, Compound A is prepared in greater than 98% purity, as measured by high performance liquid chromatography.

[0018] In some aspects, the present disclosure provides a method for the preparation of Compound C, comprising obtaining Compound B:and reacting Compound B with pyridinium perbromide in a reaction mixture to form Compound C:

[0019] In some embodiments, the molar ratio of Compound B to pyridinium perbromide is about 1 : 1.4. In some embodiments, the reaction mixture comprises a solvent. In certain embodiments, the solvent is immiscible with water. In some embodiments, the solvent comprises toluene. In some embodiments, the reaction is carried out at a reaction time period from about 1 h to about 4 h. In certain embodiments, the reaction time period is about 2 h. In some embodiments, the reaction is carried out at a temperature from about 0°C to about 100°C. In certain embodiments, the temperature is about 33°C. In some embodiments, Compound C is prepared in greater than 90% purity, as measured by high performance liquid chromatography. In certain embodiments, Compound C is prepared in greater than 95% purity, as measured by high performance liquid chromatography. In certain embodiments, Compound C is prepared in greater than 98% purity, as measured by high performance liquid chromatography.

[0020] In some aspects, the present disclosure provides a method for the preparation of omaveloxolone comprising:(a) reactingwith dimethyl sulfate and potassium carbonate in the presence of tetrabutylammonium bromide to form(b) reactingwith meta-chloroperoxybenzoic acid to form(c) reactingwith pyridinium perbromide to form(d) reactingwithdiisopropylethylamine and dimethylsulfoxide to form(e) reactingwith sodium methoxide to form(f) reactingwith hydroxylamine and hydrochloric acid to form(g) reactingwith sodium methoxide to form(h) reactingwithto form(i) reactingwith pyridine to form(j) reactingunder conditions suitable to form(k) reactingwith diphenylphosphoryl azide and triethylamine to form(1) heatingto form(m) reactingunder conditions suitable to form(n) reactingwithto form omaveloxolone.BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0022] FIG. 1 shows a scheme of Compound D (methyl (4aS,6aR,6bS,8aR,12aS,14aR,14bS)- 2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,14,14a,14b- octadecahydropicene-4a(2H)-carboxylate) synthesis using Oleanolic Acid ((4aS,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl- 1,3, 4, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10,1 l,12,12a,12b,13,14b-octadecahydropicene-4a(2H)-carboxylic acid) as a starting material. Compound A (methyl (4aS,6aS,6bR,8aR,10S,12aR,14bS)-10- hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,12b,13,14b- octadecahydropicene-4a(2H)-carboxylate) is prepared from Oleanolic Acid using Me2SO4, K2CO3, TBABr, 2-MeTHF and water. Compound B (methyl (4aS,6aR,6bR,8aR,10S,12aR,14aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14- oxoicosahydropicene-4a(2H)-carboxylate) is prepared from Compound A using mCPBA, DCM, then MsOH. Compound C (methyl (4aS,6aR,6bS,8aR,10S,12aS,14aR,14bS)-10- hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14-oxo- l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,14,14a,14b-octadecahydropicene-4a(2H)-carboxylate) is prepared from Compound B using PyH*Brs and PhMe. Compound D is prepared from Compound C using T3P, DMSO, DIPEA and EtOAc.

[0023] FIG. 2 shows a scheme of omaveloxolone (N-[(4aS,6aR,6bS,8aR,12aS,14aR,14bS)~ 1 l-cyano-2,2,6a,6Z>,9,9,12a-heptamethyl-10,14-dioxo-l,3,4,5,6,7,8,8a,14a,14Z>- decahydropicen-4a-yl]-2,2-difluoropropanamide) synthesis using Compound D as a starting material. Compound E (methyl (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-l l-formyl- 2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,14,14a,14b- octadecahydropicene-4a(2H)-carboxylate) is prepared from Compound D using NaOMe, ethyl formate, EtOH and HC1. Compound F (methyl (4aS,6aR,6bS,8aR,13aS,15aR,15bS)- 2,2,6a,6b,9,9,13a-heptamethyl-15-oxo-l,3,4,5,6,6a,6b,7,8,8a,9,13,13a,15,15a,15b- hexadecahydropiceno[2,3-d]isoxazole-4a(2H)-carboxylate) is prepared from Compound E using NH2OH:HC1, DCM, H2O and MeOH. Compound G (methyl (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-l l-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,14,14a,14b-octadecahydropicene-4a(2H)-carboxylate) is prepared from Compound F using NaOMe, MeOH, DCM and HC1. Compound H (methyl (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-l l-bromo-l l-cyano-2,2,6a,6b,9,9,12a-heptamethyl- 10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,14,14a,14b-octadecahydropicene-4a(2H)- carboxylate) is prepared from Compound G using l,3-dibromo-5,5-dimethylimidazolidine- 2, 4-dione and DMF. Compound J (methyl (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-l l-cyano- 2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b- hexadecahydropicene-4a(2H)-carboxylate) is prepared from Compound H using pyridine, DMF, DCM, H2O and EtOH. Compound K ((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-l l-cyano- 2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b- hexadecahydropicene-4a(2H)-carboxylic acid) is prepared from Compound J using LiBr and DMAc. Compound L ((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-l l-cyano-2,2,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicene- 4a(2H)-carbonyl azide) is prepared from Compound K using DPP A, EtsN and toluene. Compound N ((4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-amino-4,4,6a,6b,l l,l l,14b- heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,12b,13,14b- octadecahydropicene-2-carbonitrile) is prepared from Compound M ((4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-isocyanato-4,4,6a,6b,l l,l l,14b-heptamethyl-3,13- di oxo-3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10,1 l,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile) using H3PO4, H2O, toluene, K2CO3, H2O and EtOAc. Omaveloxolone is prepared from Compound N using 2,2-difluoropropanoic acid, T3P, DIPEA, EtOAC, EtOAc / n-heptane and acetone / IP A / H2O .DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0024] In one aspect of the present disclosure, there are provided new methods for the preparation of triterpenoid derivatives, such as omaveloxolone (RTA-408). In some embodiments, the present methods may be used for the preparation of ursolic acid or oleanolic acid derivatives. In some embodiments, the triterpenoid derivatives are oleanolic acid derivatives. In other embodiments, the present methods may be useful for the preparation of omaveloxolone or related triterpenoid derivatives (see Schemes 1 and 2 below). In other embodiments, the present methods may be useful for the preparation of CDDO (RTA 401), which may then be further converted to omaveloxolone as described in U.S. Patent 8,993,640, which is incorporated herein by reference in its entirety. In some embodiments, the present methods may be useful for the preparation of methyl (4aS,6aR,6bS,SaR,12aS,14aR,14bS)-l l- cyano-2, 2,6a, 6A, 9,9, 12a-heptamethyl- l 0, 14-di oxo- l , 3, 4, 5, 6,7,8, 8a, l4a, l4A- decahydropicene-4a-carboxylate (RTA 402) and / or N-[(4aS,6aR,6bS,SaR,12aS,14aR,14bS)~ I I -cyano-2,2,6 ,6A,9,9, l 2a-heptamethyl-l 0,14-dioxo-l ,3,4,5,6,7,8,8 ,14 , 14A- decahydropicen-4a-yl]-2,2-difluoropropanamide (omaveloxolone) as shown in Schemes 1 and 2. In some embodiments, the present methods provide improvements in the method toward installing the triterpenoid skeleton of bardoxolone methyl and omaveloxolone. The present methods disclose improvements in the synthesis of triterpenoid compounds that may be further derivatized into different triterpenoid derivatives.Scheme 1.p 90-95% yield 88%yield Compound ( >98.5% purity >95% purity -80% yield >93% assay 98% assay >98% purity 96% assayScheme 2.

[0025] In some aspects, the preparation of triterpenoid derivatives and intermediate compounds in the synthesis of triterpenoid derivatives according to the methods provided herein increases the accessibility of triterpenoid derivatives, for example for therapeutic use or for use in studies related to drug development. In some embodiments, the methods described in the sections that follow, taken together or individually, are advantageous for the formation of the target compounds described below, particularly the industrial scale formation of the triterpenoid derivatives described below. In some embodiments, the presently disclosed methods comprise improved purification methods for triterpenoid derivatives or intermediate compounds in the synthesis of triterpenoid derivatives, particularly improved methods for the industrial scale purification of such compounds. In some embodiments, the presently disclosed methods comprise improved isolation methods for triterpenoid derivatives or intermediate compounds in the synthesis of triterpenoid derivatives, particularly improved methods for the industrial scale isolation of such compounds.

[0026] The presently disclosed methods may be used, as mentioned, to form triterpenoid derivatives. Synthetic triterpenoid derivatives, including oleanolic acid derivatives bardoxolone methyl and omaveloxolone, have been shown to be inhibitors of cellular inflammatory processes, such as the induction by IFN-y of inducible nitric oxide synthase (iNOS) and co COX-2 in mouse macrophages. Compounds derived from oleanolic acid have been shown to affect the function of multiple protein targets and thereby modulate the activity of several important cellular signaling pathways related to oxidative stress, cell cycle control, and inflammation. For example, the presently disclosed methods may be used to form bardoxolone methyl, or triterpenoid derivatives which are intermediates in the synthetic pathway to bardoxolone methyl or other triterpenoid derivative target compounds. Bardoxolone methyl has been evaluated in phase II and III clinical trials for the treatment and prevention of diabetic nephropathy and chronic kidney disease. The presently disclosed methods may be used to form omaveloxolone, or triterpenoid derivatives which are intermediates in a synthetic pathway to omaveloxolone or other triterpenoid derivative target compounds (see Scheme 1, Scheme 2 and U.S. Patent 8,993,640, which is incorporated herein by reference). Omaveloxolone has been evaluated in phase I and phase II clinical trials for the treatment of Friedrich’s ataxia. The present disclosure provides improved methods for forming such compounds, or for forming intermediates in the synthetic pathway towards such compounds, and therefore improves access to these important therapeutic compounds. Presently known methods for forming triterpenoid derivatives and methods of use thereof havebeen disclosed in, for example, Fu and Gribble, 2013; Wong et al., 2016; Honda et al., 1997; Honda et al., 1998; Honda et al., 1999; Honda et al., 2000a; Honda et al., 2000b; Honda, et al., 2002; Suh et al. 1998; Suh et al., 1999; Place et al., 2003; Liby et al., 2005; and U.S. Patents 7,915,402; 7,943,778; 8,071,632; 8,124,799; 8,129,429; 8,338,618, 8,993,640, 9,102,681, 9,701,709, 9,512,094, 9,889,143, 10,093,614, and 10,556,858, which are incorporated herein by reference. Advantages of the presently disclosed methods in comparison to these references are discussed in further detail below.

[0027] In some aspects, the methods provided herein may involve, for example, increasing the yield of compound D (methyl (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-2,2,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,14,14a,14b- octadecahydropicene-4a(2H)-carboxylate) or a compound of formula IV, improving the purity of compound D or a compound of formula IV, increasing the efficiency of making compound D or a compound of formula IV, simplifying the synthetic procedure of compound D or a compound of formula IV, making the reaction conditions milder for manufacturing compound D or a compound of formula IV, increasing the safety of making compound D or a compound of formula IV, reduced reaction time or manufacturing time of compound D or a compound of formula IV, reducing the number of intermediates when making compound D or a compound of formula IV, reducing the use or production of undesirable side products when making compound D or a compound of formula IV, and / or reducing cost in preparing compound D or a compound of formula IV comparison to previous methods.

[0028] The present disclosure provides alternative methods for preparing triterpenoid derivatives that may be favorable over existing methods. The presently disclosed methods may reduce the cost or time to form an acceptable combination of yield and purity of target triterpenoid derivatives, may reduce the cost or time to purify target triterpenoid derivatives, or may reduce the cost or time to isolate target triterpenoid derivatives. The presently disclosed methods may, for example, reduce the formation of unwanted byproducts in the formation, purification, or isolation of target triterpenoid compounds, reduce the number of steps in the formation of a target triterpenoid compound, simplify the procurement of goods for the formation, purification, or isolation of target triterpenoid derivatives, or reduce the cost of goods for the formation, purification, or isolation of target triterpenoid derivatives in comparison to known methods. In some embodiments, the present methods are safer than, or require simpler reaction procedures than previous methods. The present methods may be favorable at an industrial scale in comparison to known methods, such as comprise reactionsthat are conducted under mild reaction conditions, reduce manufacturing time or cycle time, or use compounds which are lower in cost than those used in known methods. These examples of the advantageous attributes should not be construed to limit in any way the possible advantages of the presently disclosed methods.

[0029] In some embodiments, the presently disclosed methods result in higher yields, either by mass or by percent yield, of triterpenoid derivatives in comparison to known methods. For example, the methods provided herein provide improved purity or yield for the chemical transformation of Compound A (methyl (4aS,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy- 2,2,6a,6b,9,9,12a-heptamethyl-l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,12b,13,14b- octadecahydropicene-4a(2H)-carboxylate) to Compound B (methyl (4aS,6aR,6bR,8aR,10S,12aR,14aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14- oxoicosahydropicene-4a(2H)-carboxylate). See FIG. 1. The present methods also provide improved purity or yield across several transformations (see for example the multi-step conversion of Oleanolic Acid to Compound D (methyl (4aS,6aR,6bS,8aR,12aS,14aR,14bS)- 2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,14,14a,14b- octadecahydropicene-4a(2H)-carboxylate) shown in FIG. 1). In some embodiments, the synthetic routes of the present methods have an advantage of improving purification of compounds of downstream reactions. In some embodiments, the presently disclosed methods produce a lower amount of unwanted byproducts or impurities in comparison to known methods. In some embodiments of the methods described below, the impurities in the crude product are more easily identifiable, which facilitates removal of impurities compared to corresponding known methods. In some embodiments, the present methods demonstrate reduced yield loss compared to corresponding known methods. In some embodiments, the isolated triterpenoid derivatives have a higher purity than those prepared according to corresponding known methods. In some embodiments, the present methods are safer than corresponding known methods. In some embodiments, the formation of triterpenoid derivatives according to the present methods is not limited by equipment requirements for the reactions, a non-limiting example of which is reactor size, in comparison to corresponding known methods. In some embodiments, the present methods have favorable experimental conditions, or allow for more flexibility in the experimental parameters with equal or improved yields and / or purity of target compound as compared to known methods. Non-limiting examples of experimental parameters include reaction temperature, reaction vessel size, reaction time, reaction pressure,reaction solvent, stoichiometry of the reaction, or reaction pH. Additional details in this regard are provided in the sections that follow and in the Examples.

[0030] The presently disclosed methods involve the use of compounds, including examples of classes of compounds, that are favorable over those used in known methods. Non-limiting examples of classes of compounds that may be used in the presently disclosed methods are acids, bases, oxidizing agents, and reducing agents. In some embodiments, the present methods disclose the use of embodiments of classes of compounds that are safer, lower in cost, easier to handle, less toxic, or more environmentally friendly than those used in known methods. In some embodiments, the compounds used in the presently disclosed methods are more easily removed if and when their removal is desired, or form byproducts which are more easily removed if and when desired than compounds used in known methods.

[0031] The presently disclosed methods in some embodiments allow for workup or isolation conditions that are favorable over known methods. In some embodiments, either crude or purified target compounds formed according to the present methods have improved physical morphologies. In some embodiments, the improved physical morphologies facilitate improved isolation of triterpenoid compounds. In some embodiments, the triterpenoid compounds formed or purified according to the current methods have improved filterability or improved filter times. In some embodiments, the solvents used in the workup or isolation of the target compounds according to the methods disclosed herein are favorable over known methods. In some embodiments, the present methods may reduce the amount of solvent required to isolate or purify the compounds. In some embodiments, the solvents used to purify or isolate compounds synthesized according to the present methods may be lower in cost, less toxic, or more environmentally friendly than solvents used in previous methods. In some embodiments, either or both the reaction solvent or the workup solvent used in methods disclosed herein may be removed in less time, using less energy, in a more environmentally friendly fashion, or at lower cost than the corresponding previous methods. In some embodiments, present methods disclose a solvent shared among formation, purification, or isolation steps in the preparation of a triterpenoid compound. In this way, the present methods reduce the cost and complexity of the preparation of triterpenoid compounds.

[0032] The presently disclosed methods may comprise reagents, solvents, or steps that form unwanted byproducts that are water soluble. Therefore, the present methods allow for alternative protocols to obtain pure target compounds. These protocols may offer benefits in any combination of the formation, purification, or isolation of triterpenoid derivativesaccording to the present methods, particularly at an industrial scale, non-limiting examples of which may be reduced cost, reduced production of waste, reduced time required, increased energy-efficiency, increased safety, or any combination of these benefits. Additional details may be found in the Examples section that follows.

[0033] In some aspects, the present disclosure provides a multi-step method for preparation of omaveloxolone from oleanolic acid, comprising the use of a compound of Formula I as a reagent in one or more steps, wherein Formula I is defined as:wherein:Ri, Ri', and Ri" are each independently hydrogen, halo, amino, cyano, or carboxy; or alkyl(c<8), cycloalkyl(c<8), alkenyl(c<8), alkynyl(c<8), aryl(c<8), aralkyl(c<8), heteroaryl(c<8), heteroaralkyl(c<8), alkoxy(c<8), cycloalkoxy(c<8), alkenyloxy(c<8), alkynyloxy(c<8), aryloxy(c<8), aralkoxy(c<8), heteroaryloxy(c<8), heteroaralkoxy(c<8), alkylamino(c<8), dialkylamino(c<8), amido(c<8), or a substituted version of any of these groups.

[0034] In some embodiments, the compound of Formula I is used as a reagent in two steps. In some embodiments, Ri, Ri', and Ri" are each independently alkyl(c<8) or substituted alkyl(c<8). In some embodiments, Ri, Ri', and Ri" are each alkyl(c<8), such as propyl.

[0035] In some embodiments, the method further comprises reacting oleanolic acid with an alkylating agent in a reaction mixture under conditions suitable to form Compound A, wherein Compound A is defined as:

[0036] In some embodiments, the reaction mixture further comprises a base, such as potassium carbonate. In some embodiments, the base is substantially free from sodium carbonate. In some embodiments, the reaction mixture further comprises a solvent, such as an organic solvent. In some embodiments, the organic solvent is substantially 2-methyltetrahydrofuran. In some embodiments, the organic solvent is substantially free from tetrahydrofuran.

[0037] In some embodiments, the reaction mixture further comprises a phase transfer catalyst, such as a quaternary ammonium salt. In some embodiments, the phase transfer catalyst is tetrabutylammonium bromide. In some embodiments, the alkylating agent is dimethyl sulfate. In some embodiments, the method further comprises reacting oleanolic acid with the alkylating agent at a first temperature from about 10°C to about 40°C. In certain embodiments, the first temperature is from about 25°C to about 35°C. In some embodiments, the first temperature is about 30°C.

[0038] In some embodiments, the method further comprises reacting oleanolic acid for a first reaction time period from about 0.5 hours to about 2.0 hours. In certain embodiments, the first reaction time period is from about 0.75 hours to about 1.25 hours. In some embodiments, the first reaction time period is about 1.0 hour. In some embodiments, the method further comprises contacting the reaction mixture with a quenching reagent at a second temperature for a second time period. In some embodiments, the quenching reagent is a base, such as a tertiary amine. In some embodiments, the quenching reagent is triethylamine.

[0039] In some embodiments, the second temperature is from about 40°C to about 60°C. In some embodiments, the second temperature is from about 45°C to about 55°C. In some embodiments, the second temperature is about 50°C. In some embodiments, the second time period is from about 2.0 h to about 6.0 h. In some embodiments, the second time period is from about 2.0 h to about 5.0 h. In some embodiments, the second time period is about 3.0 h. In some embodiments, the method produces at least about 1000 grams of Compound A. In certain embodiments, the method produces at least about 100 kilograms of Compound A. In further embodiments, the method produces at least about 400 kilograms of Compound A. In other embodiments, the method produces from about 500 kilograms to about 1500 kilograms of Compound A. In certain embodiments, the method produces about 1000 kilograms of Compound A.

[0040] In some embodiments, the reaction mixture further comprises a base, such as potassium carbonate. In some embodiments, the base is substantially free from sodium carbonate.

[0041] In some embodiments, the method further comprises reacting Compound A:with an oxidizing agent in a reaction mixture under conditions suitable to form Compound B, wherein Compound B is defined as:

[0042] In some embodiments, the oxidizing agent comprises a peroxybenzoic acid(c<i2), such as meta-chloroperoxybenzoic acid. In some embodiments, the oxidizing agent is substantially free from peracetic acid. In some embodiments, the reaction mixture comprises a molar ratio of Compound A to the oxidizing agent from about 2: 1 to about 1 :2. In certain embodiments, the molar ratio is from about 1 : 1 to about 2:3. In some embodiments, the molar ratio is about 4:5. In some embodiments, the reaction mixture further comprises a solvent, such as an organic solvent. In some embodiments, organic solvent is dichloromethane.

[0043] In some embodiments, the method further comprises reacting Compound A with the oxidizing agent at a temperature from about 10°C to about 40°C. In certain embodiments, the temperature is from about 20°C to about 30°C. In further embodiments, temperature is about 25°C.

[0044] In some embodiments, the method further comprises reacting Compound A with the oxidizing agent for a reaction time period of about 10 hours to about 20 hours. In some embodiments, the reaction time period is from about 13 hours to about 17 hours. In certain embodiments, the reaction time period is about 15 hours.

[0045] In some embodiments, the method further comprises contacting the reaction mixture with a solution of sodium bicarbonate and isolating the organic layer. In some embodiments,the method further comprises contacting the isolated organic layer with an alkylsulfonic(c<8) acid, such as methanesulfonic acid. In some embodiments, the method produces at least about 1000 grams of Compound B. In certain embodiments, the method produces at least about 100 kilograms of Compound B. In further embodiments, the method produces from about 325 kilograms to about 425 kilograms of Compound B. In still further embodiments, the method produces about 375 kilograms of Compound B.

[0046] In some embodiments, the method further comprises reacting Compound B:with an oxidizing agent in a reaction mixture under conditions suitable to form Compound C, wherein Compound C is defined as:

[0047] In some embodiments, the oxidizing agent is a perbromide, such as pyridinium perbromide. In some embodiments, the reaction mixture comprises a molar ratio of Compound B to the oxidizing agent from about 2: 1 to about 1 :5. In certain embodiments, the molar ratio is from about 1 : 1 to about 1 :2. In some embodiments, the reaction mixture further comprises a solvent, such as an organic solvent. In some embodiments, the organic solvent is toluene. In some embodiments, the reaction mixture is substantially free from molecular bromine. In some embodiments, the reaction mixture is substantially free from acetonitrile.

[0048] In some embodiments, the method further comprises reacting Compound B with the oxidizing agent at a temperature from about 20°C to about 40°C. In certain embodiments, the temperature is from about 28°C to about 38°C. In further embodiments, the temperature is about 33°C. In some embodiments, the method further comprises reacting Compound B withthe oxidizing agent for a reaction time period of about 1 hour to about 5 hours. In certain embodiments, the reaction time period is from about 2 hours to about 4 hours. In some embodiments, the reaction time period is about 2 hours. In some embodiments, the method produces at least about 1000 grams of Compound C. In certain embodiments, the method produces at least about 100 kilograms of Compound C. In some embodiments, the method produces from about 100 kilograms to about 500 kilograms of Compound C. In further embodiments, the method produces from about 300 kilograms to about 350 kilograms of Compound C. In yet further embodiments, the method produces about 320 kilograms of Compound C.

[0049] In some embodiments, the method further comprises reacting Compound C:with an oxidizing agent in the presence of a compound of Formula I:in a reaction mixture to form Compound D, wherein Compound D is defined as:wherein:

[0050] Ri, Ri', and Ri" are each independently hydrogen, halo, amino, cyano, or carboxy; or alkyl(c<8), cycloalkyl(c<8), alkenyl(c<8), alkynyl(c<8), aryl(c<8), aralkyl(c<8), heteroaryl(c<8), heteroaralkyl(c<8), alkoxy(c<8), cycloalkoxy(c<8), alkenyloxy(c<8), alkynyloxy(c<8), aryloxy(c<8),aralkoxy(c<8), heteroaryl oxy <c<8), heteroaralkoxy(c<8), alkylamino(c<8), dialkylamino(c<8), amido(c<8), or a substituted version of any of these groups.

[0051] In some embodiments, Ri, Ri', and Ri" are each independently alkyl(c<8) or substituted alkyl(c<8). In some embodiments, Ri, Ri', and Ri" are each alkyl(c<8), such as propyl. In some embodiments, the reaction mixture comprises a molar ratio of Compound C to the compound of Formula I from about 2: 1 to about 1 :5. In certain embodiments, the molar ratio is from about 1 : 1 to about 1 :2. In further embodiments, the molar ratio is about 1 : 1.6. In some embodiments, the molar ratio is about 1 : 1.35. In some embodiments, the reaction mixture further comprises a base. In some embodiments, the base is an amine, such as diisopropylethylamine.

[0052] In some aspects, the reaction mixture comprises a molar ratio of Compound C to the base from about 2: 1 to about 1 :5. In some of these aspects, the molar ratio is from about 1 : 1 to about 1 :2. In some aspects, the reaction mixture further comprises an oxidizing agent, such as dimethylsulfoxide. In some aspects, the reaction mixture comprises a molar ratio of Compound C to the oxidizing agent, wherein the molar ratio is from about 1 :5 to about 1 : 10. In certain aspects, the molar ratio is from about 1 :4 to about 1 :7. In further aspects, the molar ratio is about 1 :6.8. In certain aspects, the molar ratio is about 1 :5.5. In some aspects, the method further comprises reacting Compound C with the compound of Formula I under an inert atmosphere. In some aspects, the inert atmosphere is substantially nitrogen.

[0053] In some aspects, a solution comprising the compound of Formula I is used in the reaction between Compound C and the oxidizing agent, such as dimethylsulfoxide. In some embodiments, the concentration of the compound of Formula I in the solution is from about 30% to about 70% by weight. In certain embodiments, the concentration of the compound of Formula I in the solution is from about 40% to about 60% by weight. In further embodiments, the concentration of the compound of Formula I in the solution is about 50% by weight. In some embodiments, the solution comprises an organic solvent, such as ethyl acetate.

[0054] In some embodiments, the reaction between Compound C and the oxidizing agent in the presence of the compound of Formula I is carried out at a temperature from about -10 °C to about 50 °C. In certain embodiments, the temperature is from about -5°C to about 40 °C. In further embodiments, the temperature is from about 20 °C to about 30 °C. In yet further embodiments, the temperature is about 25 °C. In some embodiments, the reaction between Compound C and the oxidizing agent in the presence of the compound of Formula I is carried out for a reaction time period from about 0.5 hours to about 5 hours. In certain embodiments,the reaction time period is from about 2 hours to about 4 hours. In further embodiments, the reaction time period is about 3 hours. In some embodiments, the method produces at least about 1000 grams of Compound D (methyl (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-2,2,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,14,14a,14b- octadecahydropicene-4a(2H)-carboxylate). In certain embodiments, the method produces at least about 100 kilograms of Compound D. In further embodiments, the method produces from about 250 kilograms to about 500 kilograms of Compound D. In yet further embodiments, the method produces about 410 kilograms of Compound D.

[0055] In some embodiments, the reaction mixture does not substantially comprise an oxidant comprising iodine, such as potassium 2-iodo-5-methylbenzenesulfonate, Dess-Martin periodinane, or 2-iodoxybenzoic acid. In some embodiments, the reaction mixture does not substantially comprise Oxone® (potassium monopersulfate). In other embodiments, the reaction mixture does not substantially comprise toluene. In some embodiments, the method does not comprise a hydrogenation step.

[0056] In some aspects, the method further comprises reacting Compound D:with an acylating agent in a reaction mixture under conditions suitable to form Compound E, wherein Compound E is defined as:

[0057] In some embodiments, the reaction mixture further comprises a solvent, such as an organic solvent. In some embodiments, the solvent is substantially ethanol. In some embodiments, the acylating agent is ethyl formate. In some embodiments, the reaction mixturefurther comprises a base. In some embodiments, the base is sodium methoxide. In some embodiments, the method produces at least about 500 grams of Compound E. In certain embodiments, the method produces at least about 1000 grams of Compound E.

[0058] In some embodiments, the method further comprises reacting Compound E:in a reaction mixture under conditions suitable to form Compound F, wherein Compound F is defined as:

[0059] In some embodiments, the reaction mixture further comprises hydroxylamine. In some aspects, the method produces at least about 500 grams of Compound F. In certain aspects, the method produces at least about 1000 grams of Compound F. In further aspects, the method produces from about 50 kilograms to about 500 kilograms of Compound F. In yet further aspects, the method produces from about 150 kilograms to about 300 kilograms of Compound F. In further aspects, the method produces from about 175 kilograms to about 275 kilograms of Compound F. In still further aspects, the method produces from about 190 kilograms to about 235 kilograms of Compound F.

[0060] In some embodiments, the method further comprises reacting Compound F:in a reaction mixture under conditions suitable to form Compound G, wherein Compound G is defined as:

[0061] In some embodiments, the reaction mixture further comprises sodium methoxide. In some embodiments, the method produces at least about 500 grams of Compound G. In certain embodiments, the method produces at least about 1000 grams of Compound G.

[0062] In some embodiments, the method further comprises reacting Compound G:with a compound having the structure:in a reaction mixture under conditions suitable to form Compound H, wherein Compound H is defined as:

[0063] In some embodiments, the reaction mixture further comprises a solvent. In certain embodiments, the solvent is an organic solvent, such as N,N-dimethylformamide. In some embodiments, the method produces at least about 500 grams of Compound H. In certain embodiments, the method produces at least about 1000 grams of Compound H.

[0064] In some embodiments, the method further comprises reacting Compound H:in a reaction mixture under conditions suitable to form Compound J, wherein Compound J is defined as:

[0065] In some embodiments, the reaction mixture further comprises a solvent. In some embodiments, the solvent is an organic solvent, such as N,N-dimethylformamide. In some embodiments, the reaction mixture further comprises a base, such as pyridine. In some embodiments, the reaction produces at least about 500 grams of Compound J. In certain embodiments, the reaction produces at least about 1000 grams of Compound J. In further embodiments, the reaction produces from about 100 kilograms to about 500 kilograms of Compound J. In further embodiments, the reaction produces from about 100 kilograms to about 300 kilograms of Compound J. In yet further embodiments, the reaction produces from about125 kilograms to about 250 kilograms of Compound J. In still further embodiments, the reaction produces from about 150 kilograms to about 190 kilograms of Compound J.

[0066] In some embodiments, the method further comprises reacting Compound J:in a reaction mixture under conditions suitable to form Compound K, wherein Compound K is defined as:

[0067] In some aspects, the reaction mixture further comprises a solvent. In some aspects, the solvent is an organic solvent, such as dimethylacetamide. In some aspects, the reaction mixture further comprises lithium bromide. In some aspects, the method produces at least about 500 grams of Compound K. In certain aspects, the method produces at least about 1000 grams of Compound K. In further aspects, the method produces from about 10 kilograms to about 200 kilograms of Compound K. In yet further aspects, the method produces from about 50 kilograms to about 150 kilograms of Compound K. In some aspects, the method produces from about 85 kilograms to about 105 kilograms of Compound K.

[0068] In some aspects, the method further comprises reacting Compound K:in a reaction mixture under conditions suitable to form Compound L, wherein Compound L is defined as:

[0069] In some aspects, the reaction mixture further comprises a solvent. In some aspects, the solvent is an organic solvent, such as toluene. In some aspects, the reaction mixture further comprises an azide, such as diphenylphosphoryl azide. In some aspects, the reaction mixture further comprises triethylamine. In some aspects, the method produces at least about 500 grams of Compound L. In certain aspects, the method produces at least about 1000 grams of Compound L.

[0070] In some embodiments, the method further comprises reacting Compound L:in a reaction mixture under conditions suitable to form Compound M, wherein Compound M is defined as:

[0071] In some embodiments, the method comprises heating Compound L in a solvent. In some embodiments, the solution of Compound L is heated at a temperature from about 50 °C to about 100 °C. In some embodiments, the solution is heated at about 80 °C. In some embodiments, the solvent is an organic solvent, such as benzene. In some embodiments, themethod produces at least about 500 grams of Compound M. In certain embodiments, the method produces at least about 1000 grams of Compound M.

[0072] In some embodiments, the method further comprises reacting Compound M:in a reaction mixture under conditions suitable to form Compound N, wherein Compound N is defined as:

[0073] In some embodiments, the reaction mixture further comprises a solvent, such as an organic solvent. In some embodiments, the solvent is substantially toluene. In some embodiments, the reaction mixture further comprises an acid, such as phosphoric acid. In some embodiments, the reaction produces at least about 500 grams of Compound N. In certain embodiments, the method produces at least about 1000 grams of Compound N. In further embodiments, the method produces from about 25 kilograms to about 200 kilograms of Compound N. In yet further embodiments, the method produces from about 50 kilograms to about 150 kilograms of Compound N. In still further embodiments, the method produces from about 95 kilograms to about 115 kilograms of Compound N.

[0074] In some embodiments, the method further comprises reacting Compound N:with a compound having the structure:in the presence of a coupling agent of Formula I:in a reaction mixture under conditions suitable to form omaveloxolone, wherein:Ri, Ri', and Ri" are each independently hydrogen, halo, amino, cyano, or carboxy; or alkyl(c<8), cycloalkyl(c<8), alkenyl(c<8), alkynyl(c<8), aryl(c<8), aralkyl(c<8), heteroaryl(c<8), heteroaralkyl(c<8), alkoxy(c<8), cycloalkoxy(c<8), alkenyloxy(c<8), alkynyloxy(c<8), aryloxy(c<8), aralkoxy(c<8), heteroaryloxy(c<8), heteroaralkoxy(c<8), alkylamino(c<8), dialkylamino(c<8), amido(c<8), or a substituted version of any of these groups.

[0075] In some embodiments, Ri, Ri', and Ri" are each independently alkyl(c<8) or substituted alkyl(c<8). In some embodiments, Ri, Ri', and Ri" are each alkyl(c<8), such as propyl. In some embodiments, the reaction mixture further comprises a solvent, such as an organic solvent. In some embodiments, the solvent is substantially ethyl acetate. In some embodiments, the reaction mixture comprises a molar ratio of Compound N to the coupling agent of Formula I from about 2: 1 to about 1 :5. In certain embodiments, the molar ratio is from about 1 : 1 to about 1 :2. In further embodiments, the molar ratio is about 1 : 1.6. In some embodiments, the reaction mixture further comprises a base, such as an amine. In some embodiments, the amine is dii sopropy 1 ethyl amine .

[0076] In some embodiments, the reaction mixture comprises a molar ratio of Compound N to the base from about 2: 1 to about 1 :5. In certain embodiments, the molar ratio is from about 1 : 1 to about 1 :2. In further embodiments, the molar ratio is about 1 : 1.6. In some embodiments, the method further comprises reacting Compound N with the coupling agent of Formula I under an inert atmosphere. In some embodiments, the inert atmosphere is substantially nitrogen. In some embodiments, reacting Compound N and the coupling agent of Formula I further comprises contacting Compound N with a solution comprising the coupling agent of Formula I. In some embodiments, the method produces at least about 500 grams of omaveloxolone. Incertain embodiments, the method produces at least about 1000 grams of omavel oxoIone. In further embodiments, the method produces from about 50 kilograms to about 125 kilograms of omavel oxoIone. In yet further embodiments, the method produces from about 75 kilograms to about 95 kilograms of omaveloxolone.

[0077] In some aspects, the present disclosure describes a method for the preparation of a compound of Formula III comprising obtaining a compound of Formula II:or a salt thereof, and reacting the compound of Formula II with an oxidizing agent in the presence of a compound of Formula I:in a reaction mixture under conditions suitable to form a compound of Formula III:or a salt thereof, wherein:Ri, Ri', and Ri" are each independently hydrogen, halo, amino, cyano, or carboxy; or alkyl(c<8), cycloalkyl(c<8), alkenyl(c<8), alkynyl(c<8), aryl(c<8), aralkyl(c<8), heteroaryl(c<8), heteroaralkyl(c<8), alkoxy(c<8), cycloalkoxy(c<8), alkenyloxy(c<8), alkynyloxy(c<8), aryloxy(c<8), aralkoxy(c<8), heteroaryloxy(c<8), heteroaralkoxy(c<8), alkylamino(c<8), dialkylamino(c<8), amido(c<8), or a substituted version of any of these groups; and R2 is:Ci-Cis-acyl or Ci-Cis-alkyl, wherein either of these groups is substituted or unsubstituted.

[0078] In some embodiments, Ri, Ri', and Ri" are each independently alkyl(c<8) or substituted alkyl(c<8). In some embodiments, Ri, Ri', and Ri" are each alkyl(c<8), such as propyl. In some embodiments, R2 is Ci-Cis-acyl or substituted Ci-Cis-acyl. In certain embodiments, R2 is substituted Ci-Cis-acyl, such as -CO2CH3. In some embodiments, the reaction mixture comprises a molar ratio of the compound of Formula II to the compound of Formula I from about 2: 1 to about 1:5. In certain embodiments, the molar ratio is from about 1 : 1 to about 1 :2. In further embodiments, the molar ratio is about 1 : 1.6. In some embodiments, the reaction mixture further comprises a base. In some embodiments, the base is an amine, such as dii sopropy 1 ethyl amine .

[0079] In some embodiments, the reaction mixture comprises a molar ratio of the compound of Formula II to the base from about 2: 1 to about 1 :5. In certain embodiments, the molar ratio is from about 1 : 1 to about 1 :2. In further embodiments, the molar ratio is about 1 : 1.6. In some embodiments, the molar ratio is about 1 : 1.4. In some embodiments, the molar ratio is about 1 : 1.35. In some embodiments, the reaction mixture further comprises an oxidizing agent, such as dimethylsulfoxide. In some embodiments, the reaction mixture comprises a molar ratio of the compound of Formula II to the oxidizing agent, wherein the molar ratio is from about 1 :5 to about 1 : 10. In certain embodiments, the molar ratio is from about 1 :5 to about 1 :7. In further embodiments, the molar ratio is about 1 :6.8. In some embodiments, the molar ratio is about 1 :5.5.

[0080] In some embodiments, the method further comprises reacting a compound of Formula II with the compound of Formula I under an inert atmosphere. In some embodiments, the inert atmosphere is substantially nitrogen. In some embodiments, a solution comprising the compound of Formula I is used in the reaction of the compound of Formula II with the oxidizing agent. In some embodiments, the concentration of the compound of Formula I in the solution is from about 30% to about 70% by weight. In certain embodiments, the concentration of the compound of Formula I in the solution is from about 40% to about 60% by weight. In further embodiments, the concentration of the compound of Formula I in the solution is about 50% by weight. In some embodiments, the solution comprises a solvent. In some embodiments, the solvent is an organic solvent, such as ethyl acetate.

[0081] In some embodiments, the method further comprises reacting the compound of Formula II with the compound of Formula I at a temperature from about -10 °C to about 50 °C. In certain embodiments, the temperature is from about -5°C to about 40 °C. In further embodiments, the temperature is from about 20 °C to about 30 °C. In still further embodiments, the temperature is about 25 °C.

[0082] In some embodiments, the method further comprises reacting the compound of Formula II with the compound of Formula I for a reaction time period of from about 0.5 hours to about 5 hours. In certain embodiments, the reaction time period is from about 2 hours to about 4 hours. In further embodiments, the reaction time period is about 3 hours. In some embodiments, the method produces at least about 500 grams of the compound of Formula III. In certain embodiments, the method produces at least about 1000 grams of the compound of Formula III. In further embodiments, the method produces at least about 100 kilograms of the compound of Formula III. In yet further embodiments, the method produces from about 100 kilograms to about 500 kilograms of the compound of Formula III. In further embodiments, the method produces from about 200 kilograms to about 400 kilograms of the compound of Formula III. In certain embodiments, the method produces about 300 kilograms of the compound of Formula III.

[0083] In some embodiments, the present disclosure described a method for the preparation of omavel oxoIone comprising reacting Compound N:or a salt thereof with 2,2-difluoropropanoic acid and a coupling agent of Formula I:in a reaction mixture under conditions suitable to form omaveloxolone, or a pharmaceutically acceptable salt thereof, wherein:Ri, Ri', and Ri" are each independently hydrogen, halo, amino, cyano, or carboxy; or alkyl(c<8), cycloalkyl(c<8), alkenyl(c<8), alkynyl(c<8), aryl(c<8), aralkyl(c<8), heteroaryl(c<8), heteroaralkyl(c<8), alkoxy(c<8), cycloalkoxy(c<8), alkenyloxy(c<8), alkynyloxy(c<8), aryloxy(c<8), aralkoxy(c<8), heteroaryloxy(c<8), heteroaralkoxy(c<8), alkylamino(c<8), dialkylamino(c<8), amido(c<8), or a substituted version of any of these groups.

[0084] In some embodiments, Ri, Ri', and Ri" are each independently alkyl(c<8) or substituted alkyl(c<8). In some embodiments, Ri, Ri', and Ri" are each alkyl(c<8), such as propyl.

[0085] In some embodiments, the reaction mixture further comprises a solvent. In some embodiments, the solvent is an organic solvent, such as ethyl acetate. In some embodiments, the reaction mixture comprises a molar ratio of Compound N to the coupling agent of Formula I from about 2: 1 to about 1 :5. In some embodiments, the molar ratio is from about 1 : 1 to about 1 :2. In certain embodiments, the molar ratio is about 1 : 1.6. In further embodiments, the reaction mixture further comprises a base. In some embodiments, the base is an amine, such as dii sopropy 1 ethyl amine .

[0086] In some embodiments, the reaction mixture comprises a molar ratio of Compound N to the base from about 2: 1 to about 1 :5. In certain embodiments, the molar ratio is from about 1 : 1 to about 1 :2. In further embodiments, the molar ratio is about 1 : 1.6. In some embodiments, the method further comprises reacting Compound N with the coupling agent of Formula I under an inert atmosphere. In some embodiments, the inert atmosphere is substantially nitrogen. In some embodiments, reacting Compound N and the coupling agent of Formula I further comprises contacting Compound N with a solution comprising the coupling agent of Formula I.

[0087] In some embodiments, the method further comprises reacting Compound N with the coupling agent of Formula I under an inert atmosphere. In some embodiments, the method produces at least about 500 grams of omaveloxolone. In certain embodiments, the method produces at least about 1000 grams of omaveloxolone. In further embodiments, the method produces from about 50 kilograms to about 150 kilograms of omaveloxolone. In still further embodiments, the method produces from about 75 kilograms to about 95 kilograms of omaveloxolone.

[0088] In some aspects, the present disclosure provides a method for the preparation of omaveloxolone comprising:(a) reactingwith dimethyl sulfate and potassium carbonate in the presence of tetrabutyl ammonium bromide to make(b) reactingwith meta-chloroperoxybenzoic acid to make(c) reactingwith pyridinium perbromide to make5 (d) reactingwith dimethylsulfoxide in the presence ofand diisopropylethylamine to make(e) reactingwith sodium methoxide and diethyl formate to make(f) reactingwith hydroxylamine hydrochloride to make(g) reactingwith sodium methoxide to make(h) reactingwithto make(i) reactingwith pyridine to make(j) reactingwith lithium bromide to make(k) reactingwith diphenylphosphoryl azide and triethylamine to make(1) heatingto make(m) reactingwith phosphoric acid and potassium carbonate to make(n) reactingwithto make omaveloxolone.

[0089] The above examples of favorable attributes listed above are for illustration purposes and should not be construed to limit the observed or contemplated benefits associated with formation of target compounds or intermediates according to the methods disclosed herein.Any of the individual reactions disclosed in the present application may exhibit any combination of the benefits listed above. As mentioned above, the formation of compounds using methods disclosed herein may also have one or more other attributes deemed favorable to or by the practitioner, optionally in combination with any of the attributes listed in the paragraphs above.I. Formation of C3-oxo Triterpenoid Derivatives

[0089] In one aspect, the present disclosure provides new methods for the oxidation of C3-OH triterpenoid derivatives (see FIG. 1 for carbon atom numbering) to C3-oxo triterpenoidderivatives (see, as a non-limiting example, Step 4 or the formation of Compound D from Compound C of FIG. 1). In some embodiments, the presently disclosed methods are improved, favorable, or advantageous over known methods. In some embodiments, the methods disclosed herein are tolerant of other reactive functional groups that are present in the C3-0H triterpenoid derivative starting material. C3-0H triterpenoid derivatives may be prepared, for example, using the methods described in the section that follows or in the Examples section, or by other known methods.

[0090] The presently disclosed methods for the preparation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) involve, in some embodiments, the use of compounds of Formula V:(Formula V), wherein Rio, Rio', and Rio" are each independently hydrogen, halo, amino, cyano, or carboxy; or alkyl(c<8), alkenyl(c<8), alkynyl(c<8), aryl(c<8), aralkyl(c<8), heteroaryl(c<8), heteroaralkyl(c<8), alkoxy(c<8), alkenyloxy(c<8), alkynyloxy(c<8), aryloxy(c<8), aralkoxy(c<8), heteroaryl oxy (c<8), heteroaralkoxy(c<8), alkylamino(c<8), dialkylamino(c<8), amido(c<8), or a substituted version of any of these groups. The compounds of Formula V act, in combination with at least one reagent or compound known to a person of skill in the art, as an electrophilic target for the C3-0H group of the reactant triterpenoid derivative, wherein a subsequent deprotonation / elimination provides the C3-oxo triterpenoid derivative product. In some embodiments, Rio, Rio', and Rio" are alkyl(c<8), alkenyl(c<8), or alkynyl(c<8). In preferred embodiments, Rio, Rio', and Rio" are alkyl(c<8), such as propyl.

[0091] In some embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) to the compound of formula V is about 10: 1, about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3: l, about 2: l, about 1 : 1, about 1 :2, about 1 :3, about 1 :4, about 1 :5, about 1 :6, about 1 :7, about 1 :8, about 1 :9, about 1 : 10, or any range derivable therein.. In some embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) to the compound of formula V is between about 1 : 1 and 1 :2. Inpreferred embodiments, the molar ratio of the C3-0H triterpenoid derivative (e.g., compound C in FIG. 1) to the compound of formula V is about 1 : 1.6.

[0092] As discussed above, the compounds of Formula V may in some embodiments of the methods for the formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) disclosed herein be used in combination with at least one additional reagent or compound. In some embodiments, the additional reagent comprises an oxidant. In preferred embodiments, the oxidant is an alkyl sulfoxide. In some embodiments, the oxidant is dimethyl sulfoxide. In some embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) to the oxidant is about 20: 1, about 19: 1, about 18: 1, about 17: 1, about 16: 1, about 15: 1, about 14: 1, about 13: 1, about 12: 1, about 11 : 1, about 10: 1, about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3: 1, about 2:1, about 1 : 1, about 1 :2, about 1 :3, about 1 :4, about 1 :5, about 1 :6, about 1 :7, about 1 :8, about 1 :9, about 1 : 10, about 1 : 11, about 1 : 12, about 1 : 13, about 1 : 14, about 1 : 15, about 1 : 16, about 1 : 17, about 1 : 18, about 1 : 19, about 1 :20, or any range derivable therein. In some embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) to the oxidant is between about 1 :5 and about 1 : 10. In some preferred embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) to the oxidant is about 1 :6.8. In some preferred embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) to the oxidant is about 1 :5.5. The presently disclosed methods for the formation of C3-oxo triterpenoid derivatives (e.g., compound C in FIG. 1) that comprise, in one embodiment, use of compounds of Formula V with an oxidant have the advantage of suppressing formation of unwanted byproducts, such as bisenone triterpenoid derivatives that are formed in methods known to the art. In this way, the present methods provide an advantage in simplifying the complexity and cost of purifying and isolating C3-oxo triterpenoid derivatives. Further details on this advantage are provided below.

[0093] In some embodiments, the reaction mixture for the formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) according to the methods disclosed herein comprises a base. In some embodiments, the base is a poor nucleophile. In some embodiments, the base comprises a nitrogen atom. In some embodiments, the base is an amine, such as a tertiary amine. In some embodiments, the base is diisopropylethylamine, also known as Hunig’s base. In some embodiments the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) to the base is about 10: 1, about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3: 1, about 2: 1, about 1 : 1, about 1 :2, about 1 :3, about 1 :4, about 1 :5, about 1 :6, about1 :7, about 1 :8, about 1 :9, about 1 : 10, or any range derivable therein. In some embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) to the base is between about 2: 1 and about 1 :5. In some preferred embodiments, the molar ratio of the C3- OH triterpenoid derivative (e.g., compound C in FIG. 1) to the base is about 1 : 1.6. In some preferred embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) to the base is about 1 : 1.4. In some preferred embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) to the base is about 1 : 1.35.

[0094] The methods for preparing C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) disclosed herein are conducted in a solvent determined by the practitioner. In some embodiments, the formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) is conducted in an organic solvent. In preferred embodiments, the solvent is substantially ethyl acetate. In some embodiments, the solvents for the formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) according to the methods disclosed herein are advantageous for the industrial production of C3-oxo triterpenoid derivatives. For example, the solvents used in the present methods are more easily removed during the purification or isolation of the C3-oxo unsaturated triterpenoid derivative (e.g., compound D in FIG. 1), a lower volume of the solvents used according to the present methods is required, the solvents used in the present methods cost less, the solvents used in the present methods are less toxic, or have another favorable physical property as determined by the practitioner. In some embodiments, the solvents used in methods discussed in this section are advantageous in that they are used in other reactions described elsewhere in the application. In some embodiments, the solvent system disclosed herein facilitates the formation of particles with improved physical morphologies. For example, in some embodiments C3-oxo unsaturated triterpenoid derivatives (e.g., compound D in FIG. 1) formed or purified according to the present methods have improved physical morphologies, such as uniform or consistent particle size, and as such have improved efficiency of filtration or drying.

[0095] In some embodiments, the methods for forming C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) disclosed herein are conducted by dissolving C3-OH triterpenoid derivatives (e.g., compound C in FIG. 1) in a solvent and subsequently contacting the C3-OH triterpenoid derivatives (e.g., compound C in FIG. 1) with a compound of Formula V and, optionally, at least one additional reagent. In some embodiments, the compound of Formula V, the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1), and any other reagents are combined neat and the reaction is conducted. In some embodiments, the compound of FormulaV is combined with the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) and any other reagents, the compounds are dissolved in a solvent, and the reaction is conducted. In some embodiments, the present methods disclose contacting a solution of the C3-0H triterpenoid derivative (e.g., compound C in FIG. 1) with a solution of the compound of Formula V and adding any additional compounds or reagents, either neat or in solution, and the reaction is conducted. The solvent of a solution of the compound of Formula V according to the present methods may be any aqueous or organic solvent favorable to the practitioner. In some embodiments, the solvent of a solution of the compound of Formula V disclosed herein is an organic solvent. In some embodiments, the solvent of a solution of the compound of Formula V according to the present methods is ethyl acetate. In some embodiments, the concentration by weight of the solution of the compound of Formula V that contacts the C3- OH triterpenoid derivative (e.g., compound C in FIG. 1) according to the present methods is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, or any range derivable therein. In some embodiments, the concentration of the solution of the compound of Formula V that contacts the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) according to the present methods is between about 30% by weight and about 70% by weight. In some embodiments, the concentration of the solution of the compound of Formula V that contacts the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) according to the present methods is between about 40% by weight and about 60% by weight. In some embodiments, the concentration of the solution of the compound of Formula V that contacts the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) according to the present methods is about 50% by weight.

[0096] The methods for forming C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) disclosed herein may be conducted at any temperature which provides an acceptable combination of yield and purity of the C3-oxo triterpenoid derivative (e.g., compound D in FIG. 1) product in an acceptable period of time, as determined by the practitioner. A favorable temperature may be higher or lower than corresponding previous methods depending on the context. A favorable temperature may be closer to room temperature than corresponding previous methods. A reaction temperature may be favorable if, for example, maintenance of the reaction mixture at the reaction temperature requires less energy or has a reduced cost for energy supplied to maintain the temperature, or forms an acceptable combination of yield andpurity of target compound in less time in comparison to corresponding previous methods. The presently disclosed formation of C3-oxo triterpenoid derivatives may be carried out at about - 10°C, about -9°C, about -8°C, about -7°C, about -6°C, about -5°C, about -4°C, about -3°C, about -2°C, about -1°C, about 0°C, about 1°C, about 2°C, about 3°C, about 4°C, about 5°C, about 6°C, about 7°C, about 8°C, about 9°C, about 10°C, about 11°C, about 12°C, about 13 °C, about 14°C, about 15°C, about 16°C, about 17°C, about 18°C, about 19°C, about 20°C, about21°C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, about 30°C, about 31°C, about 32°C, about 33°C, about 34°C, about 35°C, about36°C, about 37°C, about 38°C, about 39°C, about 40°C, about 41 °C, about 42°C, about 43 °C, about 44°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, about 50°C, or any range derivable therein. In some embodiments, the present methods comprise forming C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) at a temperature between about -5°C and about 40°C. In some embodiments, the present methods comprise conducting the C3-0H triterpenoid derivative oxidation reaction (e.g., step 4 in FIG. 1) at a temperature between about -5°C and about 40°C. In some embodiments, the present methods comprise conducting the reaction forming C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) at a temperature between about 20°C and about 30°C. In some embodiments, the present methods comprise conducting the reaction forming C3-oxo triterpenoid derivatives at about 25°C. In some embodiments the present methods comprise conducting the reaction forming C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) at about room temperature.

[0097] As mentioned above, the present methods for formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) provide an acceptable combination of yield and purity of the C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) in an acceptable period of time, as determined by the practitioner. In some embodiments, the period of time required to achieve a combination of acceptable purity and yield according to methods disclosed herein is shorter than for corresponding previous methods, and as such may be particularly attractive for the industrial production of a C3-oxo triterpenoid derivative (e.g., compound D in FIG. 1). In some embodiments, the present methods allow for the formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) at higher yields or with increased purity in a period of time equivalent to those of corresponding known methods. The methods disclosed herein for forming C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) provide, in some embodiments, an acceptable combination of yield and purity of the C3-oxo triterpenoid derivative (e.g., compound D in FIG. 1) with acceptable purity in about 0.5 hours, about 1 hour,1.5 hours, about 2 hours, 2.5 hours, about 3 hours, 3.5 hours, about 4 hours, 4.5 hours, about 5 hours, 5.5 hours, about 6 hours, 6.5 hours, about 7 hours, 7.5 hours, about 8 hours, 8.5 hours, about 9 hours, 9.5 hours, about 10 hours, or any range derivable therein. In some embodiments, the present methods provide an acceptable combination of yield and purity of the C3-oxo triterpenoid derivative (e.g., compound D in FIG. 1) in a time period of between about 0.5 hours and about 5 hours. In some embodiments, the present methods provide an acceptable combination of yield and purity of the C3-oxo triterpenoid derivative (e.g., compound D in FIG. 1) in a time period of between about 2 hours and about 4 hours. In some embodiments, the present methods provide an acceptable combination of yield and purity of the C3-oxo triterpenoid derivative (e.g., compound D in FIG. 1) in about 3 hours. In some embodiments, the present methods comprise an additional period of time to provide an acceptable combination of yield and purity of the C3-oxo triterpenoid derivative product (e.g., compound D in FIG. 1) of about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, or any range derivable therein. In some embodiments, the additional period of time is between about 2 hours and about 4 hours. In some embodiments, the additional period of time is about 3 hours.

[0098] The presently disclosed methods for forming C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) may be conducted under atmospheric conditions that are favorable to the practitioner. The methods disclosed herein in some embodiments comprise a step conducted under reduced pressure compared to atmospheric pressure. In other embodiments, the methods disclosed herein may be conducted under atmospheric pressure. In some embodiments, the methods disclosed herein may be conducted under increased pressure compared to atmospheric pressure. In some embodiments, the present methods are conducted in reaction vessels that are open to atmosphere. In some embodiments, the present methods are conducted in an atmosphere that is substantially inert, such as under nitrogen or argon.

[0099] In some embodiments, C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) prepared according to the presently disclosed methods have improved purity over C3-oxo triterpenoid derivatives prepared according to previous methods. In some embodiments, C3- oxo triterpenoid derivatives (e.g., compound D in FIG. 1) prepared according to the presently disclosed methods have less impurities in comparison C3-oxo triterpenoid derivatives prepared according to previous methods. Less impurities may be measured in any combination of crude reaction intermediates, purified reaction intermediates, crude C3-oxo triterpenoid derivatives, or purified or isolated C3-oxo triterpenoid derivatives prepared according to the presentmethods. In some embodiments, the present methods have impurities in purified and isolated C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) of about 0.1% or lower. In this way, the present methods provide C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) with less impurity than C3-oxo triterpenoid derivatives prepared according to known methods. In some embodiments, formation of the undesired bis-enone triterpenoid derivative is suppressed.

[0100] The presently disclosure provides alternative methods for preparing C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) that are favorable over existing methods. The presently disclosed methods may reduce the cost or time to form an acceptable combination of yield and purity of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1), may reduce the cost or time to purify C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1), or may reduce the cost or time to isolate C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) . The presently disclosed methods may, for example, reduce the formation of unwanted byproducts in the formation, purification, or isolation of C3-oxo triterpenoid compounds (e.g., compound D in FIG. 1), reduce the number of steps in the formation of a C3-oxo triterpenoid compound (e.g., compound D in FIG. 1), simplify the procurement of goods for the formation, purification, or isolation of target triterpenoid derivatives, or reduce the cost of goods for the formation, purification, or isolation of target triterpenoid derivatives in comparison to known methods. In some embodiments, the present methods are safer than, or require simpler reaction procedures than previous methods, such as reduce the number of steps for the preparation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) or do not require a hydrogenation step to obtain an acceptable combination of yield and purity of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1). The present methods may be favorable at an industrial scale in comparison to known methods, such as comprise reactions that are conducted under mild reaction conditions or use compounds which are lower in cost than those used in known methods. These examples of the advantageous attributes should not be construed to limit in any way the possible advantages of the presently disclosed methods.

[0101] In some embodiments, the present methods for the preparation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) are advantageous in that they do not require the use of compounds, reagents, solvents, or reaction conditions that are unfavorable to the practitioner, such as for reasons that are provided as illustrative examples at the beginning of this section. In some embodiments, the presently disclosed methods for forming C3-oxotriterpenoid derivatives (e.g., compound D in FIG. 1) do not use an oxidant comprising iodine. Non-limiting examples of oxidants or oxidizing agents comprising iodine are potassium 2- iodo-5-methylbenzenesulfonate, Dess-Martin periodinane, or 2-iodoxybenzoic acid. In preferred embodiments, the reaction mixture for the formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) is substantially free from potassium 2-iodoxy-5- methylbenzenesulfonic acid or any precursor to potassium 2-iodoxy-5-methylbenzenesulfonic acid. In some embodiments, the present methods for the formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) do not use Oxone® (potassium monopersulfate). In some embodiments, the present methods for the formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) do not use a heterogeneous catalyst, such as palladium on activated carbon, as discussed below. In some embodiments, the present methods use a solvent for the formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) that is substantially free from acetonitrile. In some embodiments, the present methods use a solvent for the preparation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) that is substantially free from toluene.

[0102] In some embodiments, the present methods are advantageous in that they do not proceed via a reaction step, a type or class of reaction, or a reaction intermediate that is unfavorable to the practitioner, such as for reasons that are provided as illustrative examples at the beginning of this section. In previously attempted methods, the formation of undesired bis- enone triterpenoid derivatives necessitated a hydrogenation step to proceed towards formation of other triterpenoid derivatives in an economically feasible fashion (See FIG. 1). In some of the embodiments, the methods provided herein form less undesired bis-enone triterpenoid derivatives and do not require a hydrogenation step. Therefore, a two-step conversion according to known methods is accomplished in one step according to the present methods. Therefore, for at least this reason the present methods are advantageous in that they have reduced manufacturing cycle times. In addition, hydrogenation reactions may utilize flammable reagents or may be carried out at high temperature or pressure. As the presently disclosed methods do not require a hydrogenation step, the present methods are advantageous in that they have improved safety over known methods. With the experimental considerations outlined above, hydrogenation reactions may be required to be carried out in specialized reaction vessels. As the presently disclosed methods do not require a hydrogenation step, the present methods are additionally advantageous in that they do not require specialized equipment for carrying out hydrogenation reactions. For at least this reason, the presentmethods are favorable for use in the industrial scale production of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1). In these ways, the present methods reduce the complexity, cost, and mitigate other experimental and industrial limitations associated with the formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) by known methods. In some embodiments, the present methods for the formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) do not comprise a bis-enone intermediate. As the hydrogenation step according to known methods is conducted in toluene, the presently disclosed methods additionally remove the need for a difficult solvent exchange step. Thus, in some embodiments, the methods disclosed herein for the formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) do not comprise a difficult solvent exchange step. As described in example 1, there is a solvent exchange from ethyl acetate to methanol. Although a solvent exchange is still required, the exchange to methanol from ethyl acetate is operationally easier than going from toluene to methanol. The purification and isolation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) is, in some embodiments, conducted as a coevaporation between the solvent used in the C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) and at least another solvent, such as methanol. In this way, the present methods allow for simplified reaction solvent systems, which is particularly advantageous in the industrial production of C3-oxo triterpenoid derivatives.

[0103] As mentioned above, the present methods are useful for the industrial scale production or formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1). In some embodiments, the present methods produce or form at least 50 grams of C3-oxo triterpenoid derivative (e.g., compound D in FIG. 1). In some embodiments, the present methods produce or form about 100 g, about 250 g, about 500 g, about 750 g, or about 1000 g of C3-oxo triterpenoid derivative (e.g., compound D in FIG. 1), or any range derivable therein. In some embodiments, the present methods produce or form at least about 2 kg, about 5 kg, about 10 kg, about 20 kg, about 30 kg, about 40 kg, about 50 kg, about 60 kg, about 70 kg, about 80 kg, about 90 kg, or about 100 kg of C3-oxo triterpenoid derivative (e.g., compound D in FIG. 1), or any range derivable therein. In some embodiments, the present methods produce or form about 100 kg, about 120 kg, about 140 kg, about 160 kg, about 180 kg, about 200 kg, about 220 kg, about 240 kg, about 260 kg, about 280 kg, about 300 kg, about 320 kg, about 340 kg, about 360 kg, about 380 kg, or about 400 kg, about 420 kg, about 440 kg, about 460 kg, about 480 kg, about 500 kg, or any range derivable therein. In some embodiments, the present methods make or form a batch of C3-oxo triterpenoid derivative (e.g., compound D inFIG. 1) that is about 325 g. In some embodiments, the present methods may be used to make or form a batch of C3-oxo triterpenoid derivative (e.g., compound D in FIG. 1) that is greater than 500 kg.

[0104] In some embodiments, C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) isolated according to the presently disclosed methods have improved purity in comparison to corresponding known methods. In some embodiments, the purity of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) isolated according to the presently disclosed methods is about 94%, about 94.5%, about 95%, about 95.5%, about 96%, about 96.5%, about 97%, about 97.5%, about 98%, about 98.5%, about 99%, about 99.5%, or any range derivable therein. In some embodiments, the purity of C3-oxo triterpenoid triterpenoid derivatives (e.g., compound D in FIG. 1) isolated according to the presently disclosed methods is greater than 90%. In some embodiments, the purity of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) isolated according to the presently disclosed methods is about 94% to about 97%. In some embodiments, the purity of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) isolated according to the presently disclosed methods is about 96.5% to about 99.5%. In some embodiments, the purity is at least about 98%. In some embodiments, the purity is about 99%.

[0105] In some embodiments, C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) isolated according to the presently disclosed methods have improved yield in comparison to corresponding known methods as calculated for the formation of C3-oxo triterpenoid derivatives from C3-hydroxy triterpenoid derivatives (which may also correspond to the C9-C11 unsaturated triterpenoid derivatives described in a section that follows). In some embodiments, the yield of the reaction of C3 -hydroxy triterpenoid derivatives (e.g., compound C in FIG. 1) to form C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or any range derivable therein. In some embodiments, the yield of the reaction of C3 -hydroxy triterpenoid derivatives (e.g., compound C in FIG. 1) to form C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) is greater than 67%. In some embodiments, the yield of the reaction of C3-hydroxy triterpenoid derivatives (e.g., compound C in FIG. 1) to form C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) is about 85% to about 95%. In some embodiments, the yield of the reaction of C3-hydroxy triterpenoid derivatives (e.g., compound D in FIG. 1) to form C3-oxo triterpenoid derivatives(e.g., compound D in FIG. 1) is about 85% to about 92%. In some embodiments, the yield is about 87%.

[0106] In some embodiments, reactions forming C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) according to the presently disclosed methods have improved yield in comparison to corresponding known methods as calculated for the multi-step transformation of oleanolic acid (corresponding to the starting material for the formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) described in a section that follows) to C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1). In some embodiments, the yield of the multi-step reaction to form C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, or any range derivable therein. In some embodiments, the yield of the reaction to form C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) is greater than 35%. In some embodiments, the yield of the reaction to form C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) is about 45% to about 55%. In some embodiments, the yield of the reaction of C3-hydroxy triterpenoid derivatives (e.g., compound C in FIG. 1) to form C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) is about 47% to about 60%. In some embodiments, the yield is about 56%.II. Formation of C9-C11 Unsaturated Triterpenoid Derivatives

[0107] One of the advantages of some of the methods provided herein is that they do not involve protection and subsequent deprotection of the hydroxy group and thus save a number of steps, which results in a more efficient process. Provided herein are new methods for the installation of a double bond in triterpenoid derivatives between atoms 9 and 11 (see, as a non-limiting example, Compound C in FIG. 1). The starting material for the reaction discussed in this section is referred to herein as a C9-C11 saturated triterpenoid derivative, which in some embodiments is the C12-oxo triterpenoid derivatives described in the section that follows. A triterpenoid derivative possessing a C9-C11 double bond as prepared in presently disclosed methods discussed in this section is referred to herein as a C9-C11 unsaturated triterpenoid derivative. In some embodiments, the presently disclosed methods are improved or advantageous over previous methods. In some embodiments, the methods disclosed herein are tolerant of other reactive functional groups that are present in the C9-C11saturated triterpenoid derivative starting material. The C9-C11 saturated triterpenoid derivative may be prepared using the methods described below and in the Examples section. Any of the presently disclosed methods may be further modified and optimized using the principles and techniques of organic chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (2007), which is incorporated herein by reference.

[0108] The presently disclosed methods for transforming C9-C 11 saturated triterpenoid derivatives (e.g., compound B in FIG. 1) into C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) involve the use of an oxidant. In some embodiments, the oxidant used in the formation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) provides advantages for the industrial scale formation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) in comparison to corresponding known methods. For example, the oxidant may be less costly, procured more easily, safer to use, or may be removed at a later stage more easily than reagents used in corresponding known methods. The oxidant used in the formation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) has, according to the present invention, the benefit of having greater availability on an industrial or at a commercial scale than oxidants used in previous methods. In some embodiments, the oxidant used for the formation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) provides advantageous control over impurity formation, such as reduced impurity formation. In some embodiments, the present methods have the advantage of removing reagents from the processing stream, non-limiting examples of which are hydrobromic acid, a solution of hydrobromic acid, sodium methoxide, or molecular bromine. In some embodiments, the oxidant in formation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) is at least as strong an oxidizing agent as bromine. In some embodiments, the oxidizing agent functions as a source of bromine. In some embodiments, the oxidant is advantageous in that it is more easily handled or provides greater stoichiometric control over the addition of bromine as compared to corresponding known methods for forming C9-C11 unsaturated triterpenoid derivatives. In some embodiments, the oxidizing agent is pyridinium perbromide. In some embodiments, the oxidant is essentially free from molecular bromine. In some embodiments the molar ratio of C9-C11 saturated triterpenoid derivatives (e.g., compound B in FIG. 1) to oxidizing agent is about 10: 1, about 9: 1, about 8: l, about 7: l, about 6: 1, about 5: l, about 4: l, about 3: l, about 2:l, about 1 : 1, about 1 :2, about 1 :3, about 1 :4, about 1 :5, about 1 :6, about 1 :7, about 1 :8, about 1 :9, about 1 : 10, orany range derivable therein. In preferred embodiments, the molar ratio of C9-C11 saturated triterpenoid derivatives (e.g., compound B in FIG. 1) to oxidizing agent is between about 2: 1 and 1 : 1 or, more preferably, between about 1.15: 1 and about 1.01 : 1. In some embodiments, the molar ratio of C9-C11 saturated triterpenoid derivatives to oxidizing agent is about 1 : 1.09.

[0109] The methods disclosed herein for the preparation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) are conducted in a solvent determined by the practitioner. In some embodiments, the solvent or solvents used in the preparation of C9- C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) according to the present methods are advantageous in comparison to corresponding known methods, particularly with respect to the industrial scale preparation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1), for reasons that may include those mentioned at the beginning of this section. In some embodiments, the formation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) is conducted in an organic solvent. In some embodiments, the organic solvent is an organic solvent that is immiscible with water. The water-immiscible solvent of the presently disclosed methods to form C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) facilitates improved isolation or purification of the target compounds. More particularly, use of a water-immiscible solvent facilitates aqueous purification steps which are more effective at removing water soluble by-products and impurities and which are favorable over previous methods, which commonly utilize solvents that are miscible with water. In preferred embodiments, the solvent used in the formation of the C9-C11 unsaturated triterpenoid derivative (e.g., compound C in FIG. 1) comprises toluene. Toluene forms an azeotrope with water, providing a further improvement over known methods in that water may be removed more efficiently in the course of isolating the target C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1). In addition, the presently disclosed use of toluene as the solvent for the formation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) prevents or reduces the formation of impurities, such as imidates, that are observed to be formed in corresponding known methods. As such, the solvent used in the formation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) according to present methods is additionally advantageous in that it is essentially free of compounds, including solvents, which may form undesired byproducts. In some embodiments, the solvent for C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) is essentially free from acetonitrile. In some embodiments, the solvent system disclosed herein facilitates the formation of particles with improved physical morphologies.For example, in some embodiments the C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) formed according to the present methods have improved physical morphologies, such as a particle size which is uniform or consistent, and as such have improved efficiency of filtration or drying.

[0110] In some embodiments, the present methods for the preparation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) are advantageous in that they do not require the use of compounds, reagents, solvents, or reaction conditions that are unfavorable to the practitioner, such as for reasons that are provided as illustrative examples at the beginning of this section. The present methods for the preparation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) are advantageous in that additional reagents or steps which are required in known methods to remove such impurities are unnecessary and eliminated in the presently disclosed methods. As mentioned above, the oxidant of presently disclosed methods for the formation C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) is advantageous in that it prevents or reduces the formation of an imidate impurity. Thus, in some embodiments, the present methods for the preparation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) do not comprise treatment of any crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) with an alkoxide, such as sodium methoxide, as used in current methods to remove such impurities. The present methods therefore simplify and are attractive for the preparation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1), particularly at a commercial or industrial scale. In some embodiments, the present methods do not require protection or deprotection of functional groups present in the starting molecule which may be necessary according to methods known to the art. In this way, the presently disclosed methods have less steps and so are simpler, have improved manufacturing times, or are more efficient than similar previous methods.

[0111] It should be recognized that the incorporation of additional steps into methods for purifying or isolating C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) may be advantageous for a variety of reasons, such as increased purity of resulting isolated compound. To that end, the present methods in some embodiments comprise an aqueous wash of crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1), such as a wash with aqueous NaOH. Such washes may have efficient or improved removal of impurities, such as acid adducts of crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1). The present methods for purifying or isolating C9-C11 unsaturatedtriterpenoid derivatives may comprise a wash with aqueous NaCl. In some embodiments, washing of crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) with about 2.5% aqueous NaOH or about 15% aqueous NaCl removes impurities and unwanted byproducts of the reaction that forms C9-C11 unsaturated triterpenoid derivatives. Therefore, embodiments of the present methods comprising such washes are associated with improved purity of isolated C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1). In some embodiments, the present methods comprise an aqueous wash of crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) using a solution of about 2.5% NaOH in water followed by an aqueous wash using a solution of about 15% NaCl in water. In this way, the purification of crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) according to the present methods results in improved purity of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) due to the improved removal of impurities and unwanted byproducts.

[0112] In some embodiments, the present methods for the purification and isolation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) involve crystallization of crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1). In some embodiments, the present methods are advantageous in that the process times are shortened, the cycle time to manufacture is reduced, or less waste is generated. In some embodiments, the solvent for the presently disclosed crystallization of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) is at least one organic solvent. In preferred embodiments, the solvent is toluene and n-heptane. In this way, the present methods provide C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) in higher yield and with higher purity than corresponding known methods. Higher purity is especially advantageous in consideration of the commercial or industrial production of other triterpenoid derivatives described in the present application; less impurity present in isolated C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) results in less impurity present for reactions where C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) may be the starting compound (see, for example, the preceding section). The present methods improve upon the purification procedures of known methods for preparing C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1). For example, the presently disclosed methods for preparing C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) do not comprise a recrystallization of crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) in a mixture of methanol and water or optional secondrecrystallization in a mixture of methanol and tetrahydrofuran and water. The present methods for preparing C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) comprise purification via the above-mentioned crystallization using toluene / n-heptane, optionally followed by reslurry or recrystallization in toluene / n-heptane. The methods described herein (see also the Examples section) reduce the level of impurities in a sample of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1), for example of nonpolar impurities such as 15-OH triterpenoid derivatives, in comparison to known methods. In some embodiments, the present methods reduce the level of impurities below the limit of detection. Therefore, the presently disclosed methods are improved in the removal of non-polar impurities from crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) in comparison to known methods. The purification of crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) according to the present methods is thus improved over known methods as the presently disclosed purification methods use solvents which are shared with those used in the reaction forming C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1). As such, the present methods simplify the overall preparation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) without unacceptable loss in yield or purity of the purified or isolated C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1).

[0113] In some embodiments, the methods for formation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) are conducted by dissolving the C9-C11 saturated triterpenoid derivatives (e.g., compound B in FIG. 1) in a solvent and contacting the C9-C11 saturated triterpenoid derivatives (e.g., compound B in FIG. 1) with an oxidizing agent and, optionally, at least one additional reagent. In some embodiments, the present methods comprise combining the oxidizing agent with the C9-C11 saturated triterpenoid derivative (e.g., compound B in FIG. 1) and any other reagents, and conducting the reaction. In some embodiments, the present methods comprise combining the oxidizing agent neat with the C9- Cl l saturated triterpenoid derivative (e.g., compound B in FIG. 1) and any other reagents, dissolving the combined compounds in a solvent, and conducting the reaction. In some embodiments, the present methods comprise contacting a solution of the C9-C11 saturated triterpenoid derivative (e.g., compound B in FIG. 1) with a solution of the oxidizing agent, optionally wherein additional reagents are added either neat or in the form of a solution to form the reaction mixture, and conducting the reaction. In some embodiments, the solvents for the formation of a C9-C11 unsaturated triterpenoid derivative (e.g., compound C in FIG. 1)according to the methods disclosed herein are advantageous for the industrial production of the C9-C11 unsaturated triterpenoid derivative. For example, the solvents used in the present methods are more easily removed during the purification or isolation of the C9-C11 unsaturated triterpenoid derivative (e.g., compound C in FIG. 1), a lower volume of the solvents used according to the present methods is required, the solvents used in the present methods cost less, the solvents used in the present methods are less toxic, or have another favorable physical property as determined by the practitioner. In some embodiments, the solvents used in methods discussed in this section are advantageous in that they are used in other reactions described elsewhere in the application.

[0114] The presently disclosed methods for the formation of C9-C11 unsaturated triterpenoid derivative (e.g., compound C in FIG. 1) disclosed herein may be conducted at any temperature which provides an acceptable combination of yield and purity of the C9-C11 unsaturated triterpenoid derivative product (e.g., compound C in FIG. 1) in an acceptable period of time, as determined by the practitioner. A favorable temperature may be higher or lower than corresponding previous methods depending on the context. A favorable temperature may be closer to room temperature than corresponding previous methods. A reaction temperature may be favorable if, for example, maintenance of the reaction mixture at the reaction temperature requires less energy or has a reduced cost for energy supplied to maintain the temperature, or forms an acceptable combination of yield and purity of target compound in less time in comparison to corresponding previous methods. In some embodiments, the reaction temperature for the formation of C9-C11 unsaturated triterpenoid derivative (e.g., compound C in FIG. 1) is favorable for the industrial scale formation of the target C9-C11 unsaturated triterpenoid derivative (e.g., compound C in FIG. 1). The reaction may be carried out at about -10°C, about -9°C, about -8°C, about -7°C, about -6°C, about -5°C, about -4°C, about -3 °C, about -2°C, about -1°C, about 0°C, about 1°C, about 2°C, about 3 °C, about 4°C, about 5°C, about 6°C, about 7°C, about 8°C, about 9°C, about 10°C, about 11°C, about 12°C, about 13°C, about 14°C, about 15°C, about 16°C, about 17°C, about 18°C, about 19°C, about20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, about 30°C, about 31°C, about 32°C, about 33°C, about 34°C, about35°C, about 36°C, about 37°C, about 38°C, about 39°C, about 40°C, about 41°C, about 42°C, about 43°C, about 44°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, about50°C, or any range derivable therein. In some embodiments, the present methods comprise conducting the formation of C9-C11 unsaturated triterpenoid derivative (e.g., compound C inFIG. 1) at a temperature between about 28°C and about 38°C. In some embodiments, the present methods comprise conducting the formation of the C9-C11 unsaturated triterpenoid derivative (e.g., compound C in FIG. 1) at about 33°C.

[0115] As mentioned above, the methods for forming C9-C11 unsaturated triterpenoid derivative (e.g., compound C in FIG. 1) disclosed herein provides an acceptable combination of yield and purity of the C9-C11 unsaturated triterpenoid derivative product (e.g., compound C in FIG. 1) in an acceptable period of time, as determined by the practitioner. In some embodiments, the period of time required to achieve a combination of acceptable purity and yield according to methods disclosed herein is shorter than for methods of producing a corresponding compound that are known in the art, and as such may be favorable for the industrial production of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1). In some embodiments, the present methods allow for the formation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) at higher yields or with increased purity in a period of time equivalent to those of corresponding known methods. The methods for forming C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) disclosed herein provide, in some embodiments, an acceptable combination of yield and purity of the C9- C11 unsaturated triterpenoid derivative (e.g., compound C in FIG. 1) in about 0.5 hours, about1 hour, 1.5 hours, about 2 hours, 2.5 hours, about 3 hours, 3.5 hours, about 4 hours, 4.5 hours, about 5 hours, 5.5 hours, about 6 hours, 6.5 hours, about 7 hours, 7.5 hours, about 8 hours, 8.5 hours, about 9 hours, 9.5 hours, about 10 hours, or any range derivable therein. In some embodiments, the present methods provide an acceptable combination of yield and purity of the C9-C11 unsaturated triterpenoid derivative product (e.g., compound C in FIG. 1) in a time period of between about 0.5 hours and about 5 hours. In some embodiments, the present methods provide an acceptable combination of yield and purity of the C9-C11 unsaturated triterpenoid derivative product (e.g., compound C in FIG. 1) in a time period of between about2 hours and about 4 hours. In some embodiments, the present methods provide an acceptable combination of yield and purity of the C9-C11 unsaturated triterpenoid derivative product (e.g., compound C in FIG. 1) in about 2 hours. In some embodiments, the present methods comprise an additional period of time to provide an acceptable combination of yield and purity of the C9-C11 unsaturated triterpenoid derivative product (e.g., compound C in FIG. 1) of about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, or any range derivable therein. In someembodiments, the additional period of time is between about 0.5 hours and about 3 hours. In some embodiments, the additional period of time is about 1 hour.

[0116] The presently disclosed methods to form C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) are conducted under atmospheric conditions that are favorable to the practitioner. The methods disclosed herein may comprise a step conducted under reduced pressure compared to atmospheric pressure. In some embodiments, the methods disclosed herein may be conducted under atmospheric pressure. In some embodiments, the methods disclosed herein may be conducted under increased pressure compared to atmospheric pressure. In some embodiments, the present methods are conducted in reaction vessels that are open to atmosphere. In some embodiments, the present methods are conducted in an atmosphere that is substantially inert, such as under nitrogen or argon.

[0117] In some embodiments, the methods described in this section are advantageous in that the purification of the crude product or the isolation of the pure product is improved over known methods. In some embodiments, the present methods for the preparation of C9- Cl l unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) involve a purification step of an intermediate structure. In some embodiments, crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) formed according to the present methods have less impurities than the corresponding crude product formed according to known methods. In some embodiments, the present methods remove more, either by percentage or by mass, impurities present in crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1). In some embodiments, impurities that are present in crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) formed according to the present method (also known as the impurity profile) may be removed more easily, at lower cost, more quickly, or using less raw materials than the corresponding purification of crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) according to known methods. In some embodiments, the present methods are advantageous in that less impurities, for example due to lower formation or due to more efficient removal during purification as described elsewhere in this section, are carried into subsequent reactions, thereby reducing the complexity of subsequent purification steps.

[0118] In some embodiments, the presently disclosed methods for the formation of C9- Cl l unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) have higher yields or provide higher purity C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) than the corresponding known methods. In some embodiments, C9-C11 unsaturatedtriterpenoid derivatives (e.g., compound C in FIG. 1) formed, purified, or isolated according to the presently disclosed methods have about 50% yield, 55% yield, 60% yield, 65% yield, 70% yield, 75% yield, 80% yield, 85% yield, 90% yield, 95% yield, or any range derivable therein. In some embodiments, the present methods provide C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) from about 62% yield to about 82% yield. In some embodiments, the present methods provide C12-oxo triterpenoid derivatives in greater than about 75% yield. In some embodiments, the present methods provide C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) from about 80% yield to about 90% yield. In some embodiments, the present methods provide C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) in 85% yield. The purity of crude or purified C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) may be characterized by an assay, for example an HPLC assay. The crude or purified C9-C11 unsaturated triterpenoid derivative (e.g., compound C in FIG. 1) sample may comprise the target compound as well as organic or inorganic impurities, water, or residual solvents. Higher assay results correspond to higher purity, and in some embodiments higher assay results therefore provide a quantification of the improvement of the presently disclosed methods over those known in the art. In other embodiments, the presently disclosed methods may be improved over previous methods despite providing C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) with lower assay results based on any of the variables described elsewhere in this section. In some embodiments, C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) formed, purified, or isolated according to the presently disclosed methods have improved assay results in comparison to corresponding known methods. In some embodiments, the assay result for C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) formed, purified, or isolated according to the presently disclosed methods is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or any range derivable therein. In some embodiments, the assay result for C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) formed, purified, or isolated according to the presently disclosed methods is about 90% to about 99%. In some embodiments, the assay result for C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) formed, purified, or isolated according to the presently disclosed methods is about 94% to about 99%. In preferred embodiments, the assay result is about 98%. In some embodiments, C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) isolated according to the presently disclosed methods have improved purity in comparison tocorresponding known methods. In some embodiments, the purity of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) isolated according to the presently disclosed methods is at least about 95%. In some embodiments, the purity of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) isolated according to the presently disclosed methods is about 94%, about 94.5%, about 95%, about 95.5%, about 96%, about 96.5%, about 97%, about 97.5%, about 98%, about 98.5%, about 99%, about 99.5%, or any range derivable therein. In some embodiments, the purity of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) isolated according to the presently disclosed methods is greater than 90%. In some embodiments, the purity of C9-C 11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) isolated according to the presently disclosed methods is about 94% to about 97%. In some embodiments, the purity of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) isolated according to the presently disclosed methods is about 96.5% to about 99.5%. In some embodiments, the purity is at least 98%, such as 99%. In some embodiments, the purity is about 98%.III. Formation of C12-oxo Triterpenoid Derivatives (C12)

[0119] In some embodiments, the present disclosure provides new methods for the preparation of compounds with an oxo group at atom 12 of triterpenoid derivatives (see, as a non-limiting example, Step 2 or the preparation of compound B from compound A of FIG. 1). Accordingly, the present methods disclose the formation, purification, and isolation of C12- oxo triterpenoid derivatives (e.g., compound B in FIG. 1). The methods discussed in this section are related to the conversion of a C12-C13 unsaturated triterpenoid derivatives (e.g., compound A in FIG. 1) into C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1). In some embodiments, the presently disclosed methods for preparing C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) are improved, favorable, or advantageous over previous methods. In some embodiments, the methods disclosed herein are tolerant of other reactive functional groups that are present in the C12-C13 unsaturated triterpenoid derivative starting material (e.g., compound A in FIG. 1). The C12-C13 unsaturated triterpenoid derivative (e.g., compound A in FIG. 1) may be prepared using the methods described below and in the Examples section.

[0120] In some embodiments, the presently disclosed methods for preparing C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) are advantageous in that they do not require the use of compounds, reagents, solvents, or reaction conditions for the formation,purification or isolation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) that are unfavorable to the practitioner, such as for reasons that are provided as illustrative examples at the beginning of this section. In some embodiments, the presently disclosed methods for preparing C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) are advantageous in that they do not proceed via certain reaction steps, intermediates, or pathways that are disadvantageous. In some embodiments, the present methods do not require protection or deprotection of functional groups present in the starting molecule which may be necessary according to methods known to the art. In this way, the presently disclosed methods have less steps and so are simpler, have improved manufacturing times, or are more efficient than similar previous methods.

[0121] The presently disclosed methods for the formation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) involve the use of an oxidant. In some embodiments, the oxidant is a peracid (also known as a peroxyacid). In some embodiments, the oxidant is an organic peracid, such as a peroxycarboxylic acid. In preferred embodiments, the oxidant is meto-chloroperoxybenzoic acid. In some embodiments, the present methods for formation of Cl 2-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) involve the use of a sulfonic acid. In some embodiments, the sulfonic acid is an alkylsulfonic acid, alkenylsulfonic acid, cycloalkylsulfonic acid, heterocycloalkylsulfonic acid, -alkanediyl-heterocycloalkylsulfonic acid, -alkanediyl-arylsulfonic acid, or arylsulfonic acid. Non-limiting examples of sulfonic acids that may be used in the present methods for the formation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) are methanesulfonic acid, ethanesulfonic acid, 1- propanesulfonic acid, 1 -octanesulfonic acid, cyclohexanesulfonic acid, 2-mesitylenesulfonic acid, benzenesulfonic acid, dodecylbenzenesulfonic acid, or a camphorsulfonic acid. In some embodiments, the sulfonic acid is a substituted version of the groups listed above, such as trifluoromethanesulfonic acid, aminomethanesulfonic acid, PFOS, 4-hydroxybenzenesulfonic acid, 3 -hydroxypropane- 1 -sulfonic acid, In some embodiments, the sulfonic acid is a salt or a hydrate of any of the above-mentioned groups or compounds. As mentioned above, in some embodiments the compounds, including oxidants, used in the presently disclosed preparation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) are advantageous in that they do not comprise compounds used in corresponding known methods. For example, in some embodiments, the reaction mixture for the formation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) is essentially free from peracetic acid. The absence of peracetic acid in the reaction mixture results in a lower amount of undesired acetylated byproducts, and as suchimproves the purification and isolation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) in comparison to corresponding known methods, as discussed further below. Due at least to the embodiments outlined above, the present methods represent an improvement in yield and purity of isolated C12-oxo triterpenoid derivatives over corresponding known methods.

[0122] In some embodiments, the molar ratio of the C12-C13 unsaturated triterpenoid derivative (e.g., compound A in FIG. 1) to the oxidant is about 5: 1, about 4.5: 1, about 3: 1, about 3.5: 1, about 3: 1, about 2.5: 1, about 2: 1, about 1.5: 1, about 1 : 1, about 1 :2, about 1 :2.5, about 1 :3, about 1 :3.5, about 1 :4, about 1 :4.5, about 1 :5, or any range derivable therein. In some embodiments, the molar ratio of the C12-C13 unsaturated triterpenoid derivative (e.g., compound A in FIG. 1) to the oxidant is between about 3: 1 and about 1 : 1. In some embodiments, the molar ratio of the C12-C13 unsaturated triterpenoid derivative (e.g., compound A in FIG. 1) to the oxidant is about 2.3: 1

[0123] The methods disclosed herein for the preparation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) are conducted in a solvent determined by the practitioner. As mentioned above, in some embodiments the solvents used in the presently disclosed preparation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) are advantageous in that they do not comprise solvents used in corresponding known methods. For example, in some embodiments, the solvent for forming C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) is essentially free from acetic acid. The absence of acetic acid in the reaction mixture results in a lower amount of undesired acetylated byproducts, and as such improves the purification and isolation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) in comparison to corresponding known methods, as discussed further below. In some embodiments, the formation C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) is conducted in an organic solvent. In some embodiments, the solvent for the formation C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) comprises dichloromethane. In some embodiments, the solvent for the formation C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) comprises toluene. In preferred embodiments, the solvent or solvents used in the purification or isolation of the C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) comprises toluene. In some embodiments, the solvent or solvents used in the purification, or isolation of the C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) comprise water or methanol. In some embodiments, the solvent system disclosed herein facilitates the formation of particles with improved physical morphologies. For example, in someembodiments the C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) formed or purified according to the present methods have improved physical morphologies, such as a particle size which is uniform or consistent, and as such have improved efficiency of filtration or drying.

[0124] In some embodiments, the methods for formation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) are conducted by dissolving the C12-C13 unsaturated triterpenoid derivatives (e.g., compound A in FIG. 1) in a solvent and contacting the C12-oxo triterpenoid derivatives with an oxidizing agent and, optionally, at least one additional reagent. In some embodiments, the present methods comprise combining the oxidizing agent neat with the C12-C13 unsaturated triterpenoid derivatives (e.g., compound A in FIG. 1) and any other reagents and conducting the reaction. In some embodiments, the present methods comprise combining the oxidizing agent neat with the C12-C13 unsaturated triterpenoid derivatives (e.g., compound A in FIG. 1) and any other reagents, dissolving the combined compounds in a solvent, and conducting the reaction. In some embodiments, the present methods comprise contacting a solution of the C12-C13 unsaturated triterpenoid derivatives (e.g., compound A in FIG. 1) with a solution of the oxidizing agent, optionally wherein additional reagents are added either neat or in the form of a solution to form the reaction mixture and conducting the reaction. In some embodiments, the solvents for the formation of a C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) according to the methods disclosed herein are advantageous for the industrial production of the C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) . For example, the solvents used in the present methods are more easily removed during the purification or isolation of the C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) , a lower volume of the solvents used according to the present methods is required, the solvents used in the present methods cost less, the solvents used in the present methods are less toxic, or have another favorable physical property as determined by the practitioner. In some embodiments, the solvents used in methods discussed in this section are advantageous in that they are used in other reactions described elsewhere in the application.

[0125] The methods for forming C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) disclosed herein may be conducted at any temperature which provides an acceptable combination of yield and purity of the C12-oxo triterpenoid derivative product (e.g., compound B in FIG. 1) in an acceptable period of time, as determined by the practitioner. A favorable temperature may be higher or lower than corresponding previous methods depending on the context. A favorable temperature may be closer to room temperature than correspondingprevious methods. A reaction temperature may be favorable if, for example, maintenance of the reaction mixture at the reaction temperature requires less energy or has a reduced cost for energy supplied to maintain the temperature, or forms an acceptable combination of yield and purity of target compound in less time in comparison to corresponding previous methods. The presently disclosed formation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) may be carried out at about -10°C, about -9°C, about -8°C, about -7°C, about -6°C, about - 5°C, about -4°C, about -3°C, about -2°C, about -1°C, about 0°C, about 1°C, about 2°C, about 3 °C, about 4°C, about 5 °C, about 6°C, about 7°C, about 8°C, about 9°C, about 10°C, about 11°C, about 12°C, about 13°C, about 14°C, about 15°C, about 16°C, about 17°C, about 18°C, about 19°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about26°C, about 27°C, about 28°C, about 29°C, about 30°C, about 31°C, about 32°C, about 33°C, about 34°C, about 35°C, about 36°C, about 37°C, about 38°C, about 39°C, about 40°C, about41°C, about 42°C, about 43°C, about 44°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, about 50°C, or any range derivable therein. In some embodiments, the present methods comprise conducting the reaction forming C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) at a temperature between about -5°C and about 40°C. In some embodiments, the present methods comprise conducting the reaction forming C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) at a temperature between about 20°C and about 30°C. In some embodiments, the present methods comprise conducting the reaction forming C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) at about 25°C. In some embodiments the present methods comprise conducting the reaction forming C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) at about room temperature.

[0126] As mentioned above, the present methods for formation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) provide an acceptable combination of yield and purity of the C 12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) in an acceptable period of time, as determined by the practitioner. In some embodiments, the period of time required to achieve a combination of acceptable purity and yield according to methods disclosed herein is shorter than for corresponding previous methods, and as such may be particularly attractive for the industrial production of C 12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) . In some embodiments, the present methods allow for the formation of C 12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) at higher yields or with increased purity in a period of time equivalent to those of corresponding known methods. The methods disclosed herein for forming C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) provide, in someembodiments, an acceptable combination of yield and purity of the C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) in about 5 hours, 5.5 hours, about 6 hours, 6.5 hours, about 7 hours, 7.5 hours, about 8 hours, 8.5 hours, about 9 hours, 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 12.5 hours, about 13 hours, about 13.5 hours, about 14 hours, about 14.5 hours, about 15 hours, about 15.5 hours, about 16 hours, about 16.5 hours, about 17 hours, about 17.5 hours, about 18 hours, about 18.5 hours, about 19 hours, about 19.5 hours, about 20 hours, about 21 hours, about 21.5 hours, about 22 hours, about 22.5 hours, about 23 hours, about 23.5 hours, about 24 hours, about 24.5 hours, about 25 hours, or any range derivable therein. In some embodiments, the present methods provide an acceptable combination of yield and purity of the C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) in a time period of between about 10 hours and about 20 hours. In some embodiments, the present methods provide an acceptable combination of yield and purity of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) in a time period of between about 13 hours and about 17 hours. In some embodiments, the present methods provide an acceptable combination of yield and purity of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) in about 15 hours. In some embodiments, the present methods comprise an additional period of time to provide an acceptable combination of yield and purity of the C12-oxo triterpenoid derivative product (e.g., compound B in FIG. 1) of about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hour, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, or any range derivable therein. In some embodiments, the additional period of time is between about 1 hour and about 3 hours. In some embodiments, the additional period of time is about 2 hours.

[0127] The presently disclosed methods for forming C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) may be conducted under atmospheric conditions that are favorable to the practitioner. The methods disclosed herein in some embodiments comprise a step conducted under reduced pressure compared to atmospheric pressure. In other embodiments, the methods disclosed herein may be conducted under atmospheric pressure. In some embodiments, the methods disclosed herein may be conducted under increased pressure compared to atmospheric pressure. In some embodiments, the present methods are conducted in reaction vessels that are open to atmosphere. In some embodiments, the present methods are conducted in an atmosphere that is substantially inert, such as under nitrogen or argon.

[0128] In some embodiments, the methods described herein for the preparation of C12- oxo triterpenoid derivatives (e.g., compound B in FIG. 1) are advantageous in that thepurification of crude product or the isolation of pure product is improved over known methods. The improvements may be related to details mentioned above. In some embodiments, the present methods for the preparation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) comprise a purification step which improves the provision of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1). The purification step may, for example, purify reaction intermediates prior to a next reaction. The purification step may, for example, remove unreacted oxidant or other unwanted byproducts. A purification step of a of reaction intermediate according to the present methods in some embodiments comprises a washing step, such as an aqueous wash. In some embodiments the aqueous wash comprises use of an aqueous sodium bicarbonate solution. In some embodiments, the purification and isolation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) according to the present methods comprises a crystallization step. In some embodiments, the solvent for the crystallization step comprises an organic solvent and water, such as an alcohol and water. In preferred embodiments, the presently disclosed methods for preparing C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) comprise a crystallization step wherein the crystallization solvent is isopropanol and water. In some embodiments, the solvent for the crystallization step comprises a mixture of organic compounds, such as toluene and heptanes. In some embodiments, the preparation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) is improved in that purification steps used in corresponding known methods may be eliminated. In some embodiments, the present methods for the purification and isolation of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) do not comprise a water precipitation step. In these ways, the present methods reduce the time required to purify C12- oxo triterpenoid derivatives (e.g., compound B in FIG. 1) and increase the purity of isolated C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) in comparison with known methods.

[0129] In some embodiments, C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) formed according to the present methods have less impurities than the corresponding crude product formed according to known methods. In some embodiments, the presently disclosed methods for forming C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) produce less unwanted byproducts than corresponding known methods. In some embodiments, the presently disclosed methods are advantageous in that a lower amount of undesired byproducts, such as acetylated C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1), are formed in the course of the reaction. In this way, subsequent reactions wherein the C12-oxotriterpenoid derivatives (e.g., compound B in FIG. 1) are the starting material have a reduced need for remediation monitoring for acetylated C12-oxo triterpenoid derivatives. In this way, the presently disclosed methods are associated with reduced cost or complexity of industrial production of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1). In some embodiments, the present methods remove more impurities, either by percentage or by mass, that may be present in crude C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1). In some embodiments, impurities that are present in the crude C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) formed according to the present method may be removed more easily, at lower cost, more quickly, or using less raw materials than the corresponding purification of crude C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) according to known methods. For any of the reasons provided above, in some embodiments the presently disclosed methods for forming C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) with higher purity as compared to known methods.

[0130] In some embodiments, the presently disclosed methods for the formation of Cl 2-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) have higher yields or provide higher purity Cl 2-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) than the corresponding known methods. In some embodiments C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) formed, purified, or isolated according to the presently disclosed methods have about 50% yield, 55% yield, 60% yield, 65% yield, 70% yield, 75% yield, 80% yield, 85% yield, 90% yield, 95% yield, or any range derivable therein. In some embodiments, the present methods provide C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) in greater than about 81% yield. In some embodiments, the present methods provide Cl 2-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) from about 70% yield to about 80% yield. In some embodiments, the present methods provide C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) in about 74% yield. In some embodiments, Cl 2-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) formed, purified, or isolated according to the presently disclosed methods have improved assay results in comparison to corresponding known methods. The purity of crude or purified Cl 2-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) may be characterized by an assay, for example an HPLC assay. The sample containing crude or purified C12-oxo triterpenoid derivative (e.g., compound B in FIG. 1) may further comprise, for example, organic or inorganic impurities, water, or residual solvents. Higher assay results correspond to higher purity, and in some embodiments higher assay results therefore provide a quantification of the improvement of the presently disclosed methods overthose known in the art. In other embodiments, the presently disclosed methods may be improved over previous methods despite providing C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) with lower assay results based on any of the variables described elsewhere in this section. In some embodiments, C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) formed, purified, or isolated according to the presently disclosed methods have improved assay results in comparison to corresponding known methods. In some embodiments, the assay result for C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) formed, purified, or isolated according to the presently disclosed methods is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or any range derivable therein. In some embodiments, the assay result for C12-oxo triterpenoid derivatives formed, purified, or isolated according to the presently disclosed methods is about 97% to about 99%. In preferred embodiments, the assay result is about 98%. In some embodiments, C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) isolated according to the presently disclosed methods have improved purity in comparison to corresponding known methods. In some embodiments, the purity of C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) isolated according to the presently disclosed methods is about 85%, about 85.5%, about 86%, about 86.5%, about 87%, about 87.5%, about 88%, about 88.5%, about 89%, about 89.5%, about 90%, about 90.5%, about 91%, about 91.5%, about 92%, about 92.5%, about 93%, about 93.5%, about 94%, about 94.5%, about 95%, about 95.5%, about 96%, about 96.5%, about 97%, about 97.5%, about 98%, about 98.5%, about 99%, about 99.5%, or any range derivable therein. In some embodiments, the purity is greater than about 90%. In some embodiments, the purity of C12- oxo triterpenoid derivatives (e.g., compound B in FIG. 1) isolated according to the presently disclosed methods is about 89% to about 95%. In some embodiments, the purity is at least about 95%, such as 96%. In some embodiments, the purity is about 95%.IV. Formation of C17 Ester Triterpenoid Derivatives (C17-C(O)OR)

[0131] The present disclosure provides new methods for the conversion of Cl 7- carboxylic acid triterpenoid derivatives (e.g., oleanolic acid) to C17-ester triterpenoid derivatives (e.g. compound A in FIG. 1). In some embodiments, the presently disclosed methods are improved or advantageous over previous methods, details of which are described below. In some embodiments, the methods disclosed herein are tolerant of other reactive functional groups that are present in the C17-carboxylic acid triterpenoid derivative startingmaterial. The C17-carboxylic acid triterpenoid derivatives that are starting materials in certain embodiments of the presently disclosed methods may be isolated or prepared by previous methods.

[0132] It should be recognized that the incorporation of additional steps into methods for purifying or isolating C17-carboxylic acid triterpenoid derivatives may be advantageous for a variety of reasons, such as increased purity of resulting isolated compounds or compounds formed from subsequent reaction of the isolated C17-carboxylic acid triterpenoid derivatives. For example, known methods of forming C12-oxo triterpenoid derivatives (e.g., compound B in FIG. 1) as described above may not involve isolation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1). However, the presently disclosed methods are favorable over such existing methods in that isolation of C17-ester intermediates is associated with improved impurities (that is, lower impurities or improved impurity profile) in subsequent downstream reactions as compared to known methods.

[0133] The methods disclosed herein for the preparation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) are conducted in a solvent determined by the practitioner. As mentioned above, in some embodiments the solvents used in the presently disclosed preparation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) are advantageous in that they do not comprise solvents used in corresponding known methods. In some embodiments, the formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) is conducted in an organic solvent. In some embodiments, the organic solvent is an organic solvent that is immiscible with water. The water-immiscible solvent of some embodiments of the presently disclosed methods to form C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) facilitates improved isolation or purification of the target compounds. More particularly, use of a water-immiscible solvent facilitates aqueous purification steps that are more effective at removing water soluble by-products and impurities and thus are favorable over previous methods that commonly utilize solvents miscible with water. In some embodiments, the presently disclosed solvents facilitate improved removal of undesired inorganic by-products from crude C17-ester triterpenoid derivative (e.g., compound A in FIG. 1) compositions. In some embodiments, crude C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) formed according to the current methods are more efficiently purified than C17-ester triterpenoid derivatives formed according to known methods. In preferred embodiments, the solvent used in the formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) comprises 2-methyltetrahydrofuran. In some embodiments, thesolvent system disclosed herein facilitates the formation of particles with improved physical morphologies. For example, in some embodiments the C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) formed or purified according to the present methods have improved physical morphologies, such as a particle size which is uniform or consistent, and as such have improved efficiency of filtration or drying.

[0134] The presently disclosed methods for transforming C17-carboxylic acid triterpenoid derivatives (e.g., oleanolic acid) into C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) involve the use of a base. In some embodiments, the base used in the formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) provides advantages for the industrial scale formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) in comparison to corresponding known methods. For example, the base may be less costly, procured more easily, safer to use, or may be removed at a later stage more easily than reagents used in corresponding known methods. The base used in the formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) has, according to the present invention, the benefit of having greater availability on an industrial or at a commercial scale than bases used in previous methods. In some embodiments, the base used for the presently disclosed formation of Cl 7-ester triterpenoid derivatives (e.g., compound A in FIG. 1) provides advantageous control over impurity formation, such as reduced impurity formation. In some embodiments, the base of the presently disclosed methods has higher solubility in the reaction solvent as compared to present methods. Therefore, in some embodiments the present disclosure provides methods with increased reaction concentrations, thereby improving the efficiency and increasing throughput of the manufacturing process, reducing manufacturing times. In some embodiments, the base according to the methods described herein comprises potassium carbonate. In some embodiments, the base does not comprise sodium carbonate or is substantially free from sodium carbonate.

[0135] In some embodiments the molar ratio of C17-carboxylic acid triterpenoid derivatives (e.g., oleanolic acid) to base is about 10: 1, about 9: 1, about 8:1, about 7: 1, about 6: 1, about 5: l, about 4: 1, about 3: l, about 2: l, about 1 : 1, about 1 :2, about 1 :3, about 1 :4, about 1 :5, about 1 :6, about 1 :7, about 1 :8, about 1 :9, about 1 : 10, or any range derivable therein. In preferred embodiments, the molar ratio of C17-carboxylic acid triterpenoid derivatives (e.g., oleanolic acid) to the base is between about 1 : 1 and 1 :2 or, more preferably, between about 1 : 1.40 and about 1 : 1.60. In some embodiments, the molar ratio of C17-carboxylic acid triterpenoid derivatives (e.g., oleanolic acid) to base is about 1 : 1.50.

[0136] The presently disclosed methods for transforming C17-carboxylic acid triterpenoid derivatives (e.g., oleanolic acid) into C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) involve the use of a quenching reagent. The quenching reagent may, for example, react with excess or residual unreacted reagents to prevent formation of impurity, facilitate removal of unreacted starting material, or prevent undesired reactions of reagents in subsequent reactions. In some embodiments, the presently disclosed methods provide quenching reagents which are favorable over quenching reagents that are used in previous methods. In some embodiments, quenching reagents of the presently disclosed methods are more efficient than known quenching reagents. In some embodiments, the use of quenching reagents as disclosed herein is associated with improved (that is, lower levels of impurities or improved impurity profile) impurities in subsequent reaction mixtures or product isolates. In some embodiments, the use of quenching reagents as disclosed herein is associated with lower levels of methylating reagents, such as for example dimethyl sulfate or derivatives thereof. In some embodiments, the quenching reagent comprises a base. In some embodiments, the quenching reagent comprises an amine, such as a tertiary amine. In some embodiments, the quenching reagent comprises triethylamine. In some embodiments, the quenching reagent is substantially free from acetic acid.

[0137] In some embodiments, the quenching reagent used in the formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) provides advantages for the industrial scale formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) in comparison to corresponding known methods. For example, the quenching reagent may be less costly, procured more easily, safer to use, or may be removed at a later stage more easily than reagents used in corresponding known methods. The quenching reagent used in the formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) has, according to the present invention, may have the benefit of having greater availability on an industrial or at a commercial scale than bases used in previous methods. In some embodiments, the quenching reagent used for the presently disclosed formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) provides advantageous control over impurity formation, such as reduced impurity formation.

[0138] In some embodiments the molar ratio of C17-carboxylic acid triterpenoid derivatives (e.g., oleanolic acid) to quenching reagent is about 10: 1, about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3: l, about 2: l, about 1 : 1, about 1 :2, about 1 :3, about 1 :4, about 1 :5, about 1 :6, about 1 :7, about 1 :8, about 1 :9, about 1 : 10, or any range derivabletherein. In preferred embodiments, the molar ratio of C17-carboxylic acid triterpenoid derivatives (e.g., oleanolic acid) to quenching reagent is between about 4:1 and 1 : 1 or, more preferably, between about 3: 1 and about 2: 1. In some embodiments, the molar ratio of Cl 7- carboxylic acid triterpenoid derivatives (e.g., oleanolic acid) to quenching is about 2.85: 1.

[0139] The methods for forming C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) disclosed herein may be conducted at any temperature which provides an acceptable combination of yield and purity of the C17-ester triterpenoid derivative product (e.g., compound A in FIG. 1) in an acceptable period of time, as determined by the practitioner. A favorable temperature may be higher or lower than corresponding previous methods depending on the context. A favorable temperature may be closer to room temperature than corresponding previous methods. A reaction temperature may be favorable if, for example, maintenance of the reaction mixture at the reaction temperature requires less energy or has a reduced cost for energy supplied to maintain the temperature or forms an acceptable combination of yield and purity of target compound in less time in comparison to corresponding previous methods. The presently disclosed formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) may be carried out at about -10°C, about -9°C, about -8°C, about -7°C, about -6°C, about - 5°C, about -4°C, about -3°C, about -2°C, about -1°C, about 0°C, about 1°C, about 2°C, about 3 °C, about 4°C, about 5 °C, about 6°C, about 7°C, about 8°C, about 9°C, about 10°C, about 11°C, about 12°C, about 13°C, about 14°C, about 15°C, about 16°C, about 17°C, about 18°C, about 19°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about26°C, about 27°C, about 28°C, about 29°C, about 30°C, about 31°C, about 32°C, about 33°C, about 34°C, about 35°C, about 36°C, about 37°C, about 38°C, about 39°C, about 40°C, about41°C, about 42°C, about 43°C, about 44°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, about 50°C, or any range derivable therein. In some embodiments, the present methods comprise conducting the reaction forming C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) at a temperature between about 15°C and about 50°C. In some embodiments, the present methods comprise conducting the reaction forming C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) at a temperature between about 20°C and about 40°C. In some embodiments, the present methods comprise conducting the reaction forming C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) at about 30°C. In some embodiments the present methods comprise conducting the reaction forming C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) at about room temperature.

[0140] As mentioned above, the present methods for formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) provide an acceptable combination of yield and purity of the C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) in an acceptable period of time, as determined by the practitioner. In some embodiments, the period of time required to achieve a combination of acceptable purity and yield according to methods disclosed herein is shorter than for corresponding previous methods, and as such may be particularly attractive for the industrial production of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1). In some embodiments, the present methods allow for the formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) at higher yields or with increased purity in a period of time equivalent to those of corresponding known methods. The methods disclosed herein for forming C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) provide, in some embodiments, an acceptable combination of yield and purity of the C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) in about 0.25 hours, about 0.5 hour, about 0.75 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, or any range derivable therein. In some embodiments, the present methods provide an acceptable combination of yield and purity of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) in a time period of between about 0.5 hours and about 3 hours. In some embodiments, the present methods provide an acceptable combination of yield and purity of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) in a time period of between about 0.75 hours and about 2 hours. In some embodiments, the present methods provide an acceptable combination of yield and purity of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) in about 1 hour.

[0141] In some embodiments, the presently disclosed methods for the formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) have higher yields or provide higher purity C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) than the corresponding known methods. In some embodiments, C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) formed, purified, or isolated according to the presently disclosed methods have about 50% yield, 55% yield, 60% yield, 65% yield, 70% yield, 75% yield, 80% yield, 85% yield, 90% yield, 95% yield, or any range derivable therein. In some embodiments, the present methods provide C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) inyields from about 60% yield to about 98% yield. In some embodiments, the present methods provide C17-ester triterpenoid derivatives in greater than about 85% yield. In some embodiments, the present methods provide C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) from about 85% yield to about 95% yield. In some embodiments, the present methods provide C17-ester triterpenoid derivatives in about 87% yield.

[0142] The purity of crude or purified C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) may be characterized by an assay, for example an HPLC assay. The crude or purified C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) sample may comprise the target compound as well as organic or inorganic impurities, water, or residual solvents. Higher assay results correspond to higher purity, and in some embodiments higher assay results therefore provide a quantification of the improvement of the presently disclosed methods over those known in the art. In other embodiments, the presently disclosed methods may be improved over previous methods despite providing C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) with lower assay results based on any of the variables described elsewhere in this section. In some embodiments, C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) formed, purified, or isolated according to the presently disclosed methods have improved assay results in comparison to corresponding known methods. In some embodiments, the assay result for C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) formed, purified, or isolated according to the presently disclosed methods is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or any range derivable therein. In some embodiments, the assay result for C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) formed, purified, or isolated according to the presently disclosed methods is about 90% to about 99%. In some embodiments, the assay result for C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) formed, purified, or isolated according to the presently disclosed methods is about 94% to about 99%. In preferred embodiments, the assay result is about 98%.

[0143] In some embodiments, C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) isolated according to the presently disclosed methods have improved purity in comparison to corresponding known methods. In some embodiments, the purity of C17-ester unsaturated triterpenoid derivatives (e.g., compound A in FIG. 1) isolated according to the presently disclosed methods is at least about 95%. In some embodiments, the purity of Cl 7- ester unsaturated triterpenoid derivatives (e.g., compound A in FIG. 1) isolated according tothe presently disclosed methods is about 94%, about 94.5%, about 95%, about 95.5%, about 96%, about 96.5%, about 97%, about 97.5%, about 98%, about 98.5%, about 99%, about 99.5%, or any range derivable therein. In some embodiments, the purity of C17-ester unsaturated triterpenoid derivatives (e.g., compound A in FIG. 1) isolated according to the presently disclosed methods is greater than 90%. In some embodiments, the purity of C17-ester unsaturated triterpenoid derivatives (e.g., compound A in FIG. 1) isolated according to the presently disclosed methods is about 94% to about 97%. In some embodiments, the purity of C17-ester unsaturated triterpenoid derivatives (e.g., compound A in FIG. 1) isolated according to the presently disclosed methods is about 96.5% to about 99.5%. In some embodiments, the purity is at least 98%, such as 99%. In some embodiments, the purity is about 98%.

[0144] In some embodiments, the synthetic steps provided herein may be used to provide improved yield, improved purity, improved efficiency, improved safety, improved environmental considerations, and / or otherwise may improve the industrial scale preparation of triterpenoid derivatives. In some embodiments, the methods of the present disclosure may be used to provide improvements over previous synthesis methods. For example, the methods of the present disclosure may provide improvements over the methods of Fu and Gribble, 2013; Wong et al., 2016; Honda et al., 1997; Honda et al., 1998; Honda et al., 1999; Honda et al., 2000a; Honda et al., 2000b; Honda, et al., 2002; Suh et al. 1998; Suh et al., 1999; Place et al., 2003; Liby et al., 2005; and U.S. Patents 7,915,402; 7,943,778; 8,071,632; 8,124,799; 8,129,429; 8,338,618, 8,993,640, 9,102,681, 9,701,709, 9,512,094, 9,889,143, 10,093,614, and 10,556,858, which are incorporated herein by reference.

[0145] In some aspects, the presently disclosed methods for forming C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) are advantageous with regard to industrial application, as they do not use an oxidant comprising iodine, such as potassium 2-iodo-5- methylbenzenesulfonate, Dess-Martin periodinane, or 2-iodoxybenzoic acid. In contrast, several of the previous synthesis methods describe the use of a reagent comprising iodine, particularly 2-iodoxybenzoic acid (IBX) (Fu and Gribble, 2013; Honda et al., 2000a). See Schemes 3 and 4 below, which outline the synthesis of (4aS)6a / ?,6& ,8a / ?,12a ,14a / ?,14AS)- 1 l-cyano-2,2,6a,6Z>,9,9,12a-heptamethyl-10,14-dioxo-l,3,4,5,6,7,8,8a,14a,14Z>- decahydropicene-4a-carboxylate (RTA 402) from oleanolic acid, using IBX for the formation of the forming C3-oxo triterpenoid. However, the use of IBX in industrial applications is limited, as IBX suffers from major safety concerns related to its violent decomposition under impact and / or heating (Satam et al., 2010). Moreover, IBX was reported to be impact sensitiveand explosive once heated above 200 °C; therefore, storing and distributing larger amounts of IBX for industrial application is both risky and impractical (Devadas et al., 2020).

[0146] In some aspects, the present methods for the formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) do not use Oxone® (potassium monopersulfate). Oxone® (potassium monopersulfate) is widely employed as an oxidant in the preparation of IBX (Nair, 2020; Frigerio; 1999); however, this approach is not applicable on a larger scale. There are numerous issues connected with Oxone® (potassium monopersulfate), including both inherent instability leading to safety concerns and low oxidation capacity (Amano et al., 2006).

[0147] In other aspects, the present methods are useful for the industrial scale production or formation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1), as they do not require a hydrogenation step. Several previous methods (Fu and Gribble, Honda et al., 2000a; Wong et al., 2016) describe a bis-enone intermediate (see Schemes 3, 4 and 5); however, the hydrogenation reaction in these syntheses requires a specialized reaction vessel. As the presently disclosed methods do not require special equipment to perform this step, the present methods may reduce the complexity, cost, and mitigate other experimental and industrial limitations associated with the formation of C3-oxo triterpenoid derivatives by known methods.

[0148] Furthermore, as the hydrogenation step according to the methods described in Schemes 3, 4 and 5 are conducted in toluene, the presently disclosed methods additionally remove the need for a difficult solvent exchange step. The purification and isolation of C3-oxo triterpenoid derivatives (e.g., compound D in FIG. 1) is, in some embodiments, conducted as a co-evaporation between the solvent used in the C3-oxo triterpenoid derivatives and at least another solvent, such as methanol. Thus, in some embodiments, the methods disclosed herein for the formation of C3-oxo triterpenoid derivatives do not comprise a difficult solvent exchange step. As the present methods allow for simplified reaction solvent systems, they are particularly advantageous in the industrial production of C3-oxo triterpenoid derivatives.

[0149] In some embodiments, the methods provided herein do not involve protection and subsequent deprotection of the hydroxy group, resulting in a more efficient process. Therefore, the present methods simplify the preparation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1), particularly at a commercial or industrial scale. In contrast, several methods known to the art require protection or deprotection of functionalgroups present in the starting molecule (Honda et al., 1998; Wong et al., 2016; Honda et al., 2000). See, for example, Schemes 5-7. Thus, the presently disclosed methods may have less steps, improved manufacturing times, or higher efficiency than previous methods shown in Schemes 3-7 below.Scheme 3.Scheme 4,Scheme 5,Scheme 6,Scheme 7,V. Definitions

[0150] When used in the context of a chemical group: “hydrogen” means -H; “hydroxy” means -OH; “oxo” means =0; “carbonyl” means -C(=O)-; “carboxy” means -C(=O)OH (also written as -COOH or -CO2H); “halo” means independently -F, -Cl, -Br or -I; “amino” means -NH2; “hydroxyamino” means -NHOH; “nitro” means -NO2; imino means =NH; “cyano” means -CN; “isocyanyl” means -N=C=O; “azido” means -N3; in a monovalent context “phosphate” means -OP(O)(OH)2 or a deprotonated form thereof; in a divalent context “phosphate” means -OP(O)(OH)O- or a deprotonated form thereof; “mercapto” means -SH; and “thio” means =S; “thiocarbonyl” means -C(=S)-; “sulfonyl” means -S(O)2~; and “sulfinyl” means -S(O)-.

[0151] In the context of chemical formulas, the symbol means a single bond, “=” means a double bond, and “=” means triple bond. The symbol “ - ” represents an optional bond, which if present is either single or double. The symbol “==” represents a single bond or a double bond. Thus, the formulacovers, for example,and. And it is understood that no one such ring atom forms part of more than one double bond. Furthermore, it is noted that the covalent bond symbol when connecting one or two stereogenic atoms, does not indicate any preferred stereochemistry. Instead, it covers all stereoisomers as well as mixtures thereof. The symbol ”, when drawn perpendicularly [— CH3across a bond (e.g. , * for methyl) indicates a point of attachment of the group. It is noted that the point of attachment is typically only identified in this manner for larger groups in order to assist the reader in unambiguously identifying a point of attachment. The symbolmeans a single bond where the group attached to the thick end of the wedge is “out of the page.” The symbol “,"1111” means a single bond where the group attached to the thick end of the wedge is “into the page”. The symbol ” means a single bond where the geometry around a double bond e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended. Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper.

[0152] For the chemical groups and compound classes, the number of carbon atoms in the group or class is as indicated as follows: “Cn” or “C=n” defines the exact number (n) of carbon atoms in the group / class. “C<n” defines the maximum number (n) of carbon atoms that can be in the group / class, with the minimum number as small as possible for the group / class in question. For example, it is understood that the minimum number of carbon atoms in the groups “alkyl(c<8)”, “alkanediyl(c<8)”, “heteroaryl(c<8)”, and “acyl(c<8)” is one, the minimum number of carbon atoms in the groups “alkenyl(c<8)”, “alkynyl(c<8)”, and “heterocycloalkyl(c<8)” is two, the minimum number of carbon atoms in the group “cycloalkyl(c<8)” is three, and the minimum number of carbon atoms in the groups “aryl(c<8)” and “arenediyl(c<8)” is six. “Cn-n'” defines both the minimum (n) and maximum number (n') of carbon atoms in the group. Thus, “alkyl(C2-io)” designates those alkyl groups having from 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical groups or class it modifies and it may or may not be enclosed in parenthesis, without signifying any change in meaning. Thus, the terms “Ci-C4-alkyl”, “Ci-4-alkyl”, “Cl-4-alkyl”, “alkyl(ci-4)”, and “alkyl(C<4)” are all synonymous. Except as noted below, every carbon atom is counted to determine whether the group or compound falls with the specified number of carbon atoms. For example, the group dihexylamino is an example of a dialkylamino(ci2) group; however, it is not an example of a dialkylamino(C6) group. Likewise, phenylethyl is an example of an aralkyl(c=8) group. When any of the chemical groups or compound classes defined herein is modified by the term “substituted”, any carbon atom in the moiety replacing the hydrogen atom is not counted. Thus methoxyhexyl, which has a total of seven carbon atoms, is an example of a substituted alkyl(ci- 6). Unless specified otherwise, any chemical group or compound class listed in a claim set without a carbon atom limit has a carbon atom limit of less than or equal to twelve.

[0153] The term “saturated” when used to modify a compound or chemical group means the compound or chemical group has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of substituted versions of saturated groups, one or more carbon oxygen double bond or a carbon nitrogen double bond may be present. And when such a bond is present, then carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine / enamine tautomerism are not precluded. When the term “saturated” is used to modify a solution of a substance, it means that no more of that substance can dissolve in that solution.

[0154] The term “aliphatic” signifies that the compound or chemical group so modified is an acyclic or cyclic, but non-aromatic compound or group. In aliphatic compounds / groups, the carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds / groups can be saturated, that is joined by single carbon- carbon bonds (alkanes / alkyl), or unsaturated, with one or more carbon-carbon double bonds (alkenes / alkenyl) or with one or more carbon-carbon triple bonds (alkynes / alkynyl).

[0155] The term “aromatic” signifies that the compound or chemical group so modified has a planar unsaturated ring of atoms with 4zz +2 electrons in a fully conjugated cyclic TI system. An aromatic compound or chemical group may be depicted as a single resonance structure; however, depiction of one resonance structure is taken to also refer to any other resonance structure. For example:

[0156] Aromatic compounds may also be depicted using a circle to represent the delocalized nature of the electrons in the fully conjugated cyclic TI system, two non-limiting examples of which are shown below:

[0157] The term “alkyl” refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen. The groups -CH3 (Me), -CH2CH3 (Et), -CH2CH2CH3 (zz-Pr or propyl), -CH(CH3)2(z-Pr, Pr or isopropyl), -CH2CH2CH2CH3 (zz-Bu), -CH(CH3)CH2CH3 ( ec-butyl),-CH2CH(CH3)2(isobutyl), -C(CH3)3 (tert-butyl, / -butyl, / -Bu or 'Bu), and -CH2C(CH3)3 (neo- pentyl) are non-limiting examples of alkyl groups. The term “alkanediyl” refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups -CEfe- (methylene), -CH2CH2-, - CH2C(CH3)2CH2- , and -CH2CH2CH2- are non-limiting examples of alkanediyl groups. The term “alkylidene” refers to the divalent group =CRR' in which R and R' are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include: =CH2, =CH(CH2CH3), and =C(CH3)2. An “alkane” refers to the class of compounds having the formula H-R, wherein R is alkyl as this term is defined above.

[0158] The term “cycloalkyl” refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, said carbon atom forming part of one or more nonaromatic ring structures, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused, bridged, or spirocyclic. Non-limiting examples include: -CH(CH2)2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to a carbon atom of the non-aromatic ring structure. The term “cycloalkanediyl” refers to a divalent saturated aliphatic group with two carbon atoms as points of attachment, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groupjs anonlimiting example of cycloalkanediyl group. A “cycloalkane” refers to the class of compounds having the formula H-R, wherein R is cycloalkyl as this term is defined above.

[0159] The term “alkenyl” refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: -CH=CH2 (vinyl), -CH=CHCH3, -CH=CHCH2CH3, -CH2CH=CH2(allyl), -CH2CH=CHCH3, and -CH=CHCH=CH2. The term “alkenediyl” refers to a divalent unsaturated aliphatic group, with two carbon atoms as points of attachment, a linear or branched acyclic structure, at least one nonaromatic carboncarbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. The groups -CH=CH-, -CH=C(CH3)CH2- -CH=CHCH2- and - CH2CH=CHCH2- are non-limiting examples of alkenediyl groups. It is noted that while the alkenediyl group is aliphatic, once connected at both ends, this group is not precluded from forming part of an aromatic structure. The terms “alkene” and “olefin” are synonymous and refer to the class of compounds having the formula H-R, wherein R is alkenyl as this term is defined above. Similarly, the terms “terminal alkene” and “a-olefin” are synonymous and refer to an alkene having just one carbon-carbon double bond, wherein that bond is part of a vinyl group at an end of the molecule.

[0160] The term “alkynyl” refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not preclude the presence of one or more non-aromatic carbon-carbon doublebonds. The groups -C=CH, -OCCH3, and -CH2OCCH3 are non-limiting examples of alkynyl groups. An “alkyne” refers to the class of compounds having the formula H-R, wherein R is alkynyl.

[0161] The term “aryl” refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more aromatic ring structures, each with six ring atoms that are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. As used herein, the term aryl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C6H4CH2CH3 (ethylphenyl), naphthyl, and a monovalent group derived from biphenyl (e.g., 4-phenylphenyl). The term “arenediyl” refers to a divalent aromatic group with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structures, each with six ring atoms that are all carbon, and wherein the divalent group consists of no atoms other than carbon and hydrogen. As used herein, the term arenediyl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. Non-limiting examples of arenediyl groups include:An “arene” refers to the class of compounds having the formula H-R, wherein R is aryl as that term is defined above. Benzene and toluene are non-limiting examples of arenes.

[0162] The term “aralkyl” refers to the monovalent group -alkanediyl-aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.

[0163] The term “heteroaryl” refers to a monovalent aromatic group with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the aromatic ring structure(s) is nitrogen, oxygen orsulfur, and wherein the heteroaryl group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings are fused; however, the term heteroaryl does not preclude the presence of one or more alkyl or aryl groups (carbon number limitation permitting) attached to one or more ring atoms. Non-limiting examples of heteroaryl groups include benzoxazolyl, benzimidazolyl, furanyl, imidazolyl (Im), indolyl, indazolyl, isoxazolyl, methylpyridinyl, oxazolyl, oxadiazolyl, phenylpyridinyl, pyridinyl (pyridyl), pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term “N-heteroaryl” refers to a heteroaryl group with a nitrogen atom as the point of attachment. A “heteroarene” refers to the class of compounds having the formula H-R, wherein R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes.

[0164] The term “heterocycloalkyl” refers to a monovalent non-aromatic group with a carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more non-aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the non-aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the heterocycloalkyl group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings may be fused, bridged, or spirocyclic. As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to one or more ring atoms. Also, the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, tetrahydropyridinyl, pyranyl, oxiranyl, and oxetanyl. The term “A-heterocycloalkyl” refers to a heterocycloalkyl group with a nitrogen atom as the point of attachment. A-pyrrolidinyl is an example of such a group.

[0165] The term “acyl” refers to the group -C(O)R, in which R is a hydrogen, alkyl, cycloalkyl, or aryl as those terms are defined above. The groups, -CHO, -C(O)CH3 (acetyl, Ac), -C(O)CH2CH3, -C(O)CH(CH3)2, -C(O)CH(CH2)2, -C(O)C6H5, and -C(O)C6H4CH3are non-limiting examples of acyl groups. A “thioacyl” is defined in an analogous manner, except that the oxygen atom of the group -C(O)R has been replaced with a sulfur atom, -C(S)R. The term “aldehyde” corresponds to an alkyl group, as defined above, attached to a -CHO group.

[0166] The term “alkoxy” refers to the group -OR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: -OCH3 (methoxy), -OCH2CH3 (ethoxy), -OCH2CH2CH3, -OCH(CH3)2 (isopropoxy), or -OC(CH3)3 (tert-butoxy). The terms “cycloalkoxy”, “alkenyloxy”, “alkynyloxy”, “aryloxy”, “aralkoxy”, “heteroaryloxy”, “heterocycloalkoxy”, “heteroaralkoxy”, “alkylsilyloxy” and “acyloxy”, when used without the “substituted” modifier, refers to groups, defined as -OR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, heteroaralkyl, alkylsilyl and acyl, respectively. The terms “alkylthio” and “acylthio” refers to the group -SR, in which R is an alkyl group and acyl, respectively. The term “alkylsulfonyl” refers to the group -SO2R, in which R is an alkyl group. The term “alcohol” corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group. The term “ether” corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with an alkoxy group.

[0167] The term “alkylamino” refers to the group -NHR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: -NHCH3 and -NHCH2CH3. The term “dialkylamino” refers to the group -NRR', in which R and R' can be the same or different alkyl groups. Non-limiting examples of dialkylamino groups include: -N(CH3)2 and -N(CH3)(CH2CH3). The term “amido” (acylamino), when used without the “substituted” modifier, refers to the group -NHR, in which R is acyl, as that term is defined above. A nonlimiting example of an amido group is -NHC(O)CH3.

[0168] The term “heteroaralkyl” refers to the monovalent group -alkanediyl-heteroaryl, in which the terms alkanediyl and heteroaryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: pyridinylmethyl and 2-quinolinyl-ethyl.

[0169] When a chemical group is used with the “substituted” modifier, one or more hydrogen atom has been replaced, independently at each instance, by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CO2CH2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. For example, the following groups are non-limiting examples of substituted alkyl groups: -CH2OH, -CH2CI, -CF3, -CH2CN, -CH2C(O)OH, -CH2C(O)OCH3, -CH2C(O)NH2, -CH2C(O)CH3, -CH2OCH3, -CH2OC(O)CH3, -CH2NH2, -CH2N(CH3)2, and -CH2CH2CI. The term “haloalkyl” is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to halo (i.e. -F, -Cl, -Br, or -I) such that no otheratoms aside from carbon, hydrogen and halogen are present. The group, -CH2CI is a nonlimiting example of a haloalkyl. The term “fluoroalkyl” is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to fluoro such that no other atoms aside from carbon, hydrogen and fluorine are present. The groups -CH2F, -CF3, and -CH2CF3 are nonlimiting examples of fluoroalkyl groups. Non-limiting examples of substituted aralkyls are: (3-chlorophenyl)-methyl, and 2-chloro-2-phenyl-eth-l-yl. The groups, -C(O)CH2CF3, -CO2H (carboxyl), -CO2CH3 (methylcarboxyl), -CO2CH2CH3, -C(0)NH2 (carbamoyl), and -CON(CHS)2, are non-limiting examples of substituted acyl groups. The groups -NHC(0)0CH3 and -NHC(0)NHCH3 are non-limiting examples of substituted amido groups.

[0170] An “isomer” of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs.

[0171] A “salt” as used herein is not particularly limited. A salt of a compound of the present invention means a salt routinely used in the organic chemical field. A salt of a compound comprising a carboxyl group may, as a non-limiting example, be a base-addition salt of the carboxyl group. A salt of a compound comprising a amino group or basic heterocyclic group may, as a non-limiting example, be a acid-addition salt of the amino or basic heterocyclic group. Examples of the base-addition salt include: alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammo-nium salts; and organic amine salts such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, etha-nolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, and N,N'-dibenzylethylenediamine salt. Examples of the acid-addition salt include: inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, and perchlorate; organic acid salts such as acetate, formate, maleate, fumarate, tartrate, citrate, ascorbate, and trifluoro-acetate; and sulfonates such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate. According to the present definitions, a “salt” as used herein may be a pharmaceutically acceptable salt. “Pharmaceutically acceptable salts” means salts of compounds disclosed herein which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2 ethanedisulfonic acid, 2 hydroxyethanesulfonic acid, 2 naphthalenesulfonic acid, 3 phenylpropionic acid, 4,4' methylenebis(3 hydroxy 2 ene-1 carboxylic acid), 4 methylbicyclo[2.2.2]oct 2 ene-1 carboxylic acid, acetic acid, aliphatic mono- and dicarboxylicacids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o (4 hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002). In some embodiments, the salts of the compounds of the present invention have an advantage in that they may have useful pharmacological, physical, or chemical properties over compounds known in the prior art, whether for use in the indications stated herein or otherwise. In some embodiments, the compounds and formulas provided herein exist in salt or non-salt form. With regard to the salt form(s), in some embodiments the particular anion or cation forming a part of any salt form of a compound or formula provided herein is not critical.

[0172] A “stereoisomer” or “optical isomer” is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs. “Enantiomers” are stereoisomers of a given compound that are mirror images of each other, like left and right hands. “Diastereomers” are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic andinorganic compounds. A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral carbon), the total number of hypothetically possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, S form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures. As used herein, the phrase “substantially free from other stereoisomers” means that the composition contains < 15%, more preferably < 10%, even more preferably < 5%, or most preferably < 1% of another stereoisomer(s).

[0173] As used herein, “essentially free,” in terms of a specified component, is used to mean that none of the specified component has been purposefully formulated into a composition and / or is present only as a contaminant or in trace amounts. The total amount of the specified component resulting from any unintended contamination of a composition is therefore well below 0.05%, preferably below 0.01%. Most preferred is a composition in which no amount of the specified component can be detected with standard analytical methods.

[0174] As used herein, “substantially free,” in terms of a specified component, is used to mean that the total amount of the specified component is < 15%, preferably < 10%, and even more preferably < 5%.

[0175] As used herein the specification, “a” or “an” may mean one or more. The use of the word “a” or “an,” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0176] The use of the term “or” in the claims is used to mean “and / or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.” As used herein “another” may mean at least a second or more.

[0177] The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps.

[0178] As used herein, the term "water-immiscible solvent" refers to any non-aqueous or hydrophobic solvent which separates from solution into two distinct phases when mixed with water. The water-immiscible liquid is generally non-polar, with the non-limiting examples of the water immiscible liquid including terpenes, 2-methyltetrahydrofuran, sesquiterpenes, butanone, butyl acetate, heptane, hexane, toluene, dichloromethane, cyclohexane, petroleum ether (60-80), petroleum ether (80-100), petroleum ether (100-120), dibutyl ether, dipentyl ether, hexadecane, tetrachloroethylene, 1,1,1 -tri chloroethane, or other water-immiscible liquids well known in the art.

[0179] Other abbreviations used herein are as follows: DMSO, dimethyl sulfoxide; DMF, dimethylformamide; MeOH, methanol; EtOH, ethanol; EtOAc, ethyl acetate; THF, tetrahydrofuran; NaOMe, sodium methoxide; Me2SO4, dimethyl sulfate; K2CO3, potassium carbonate; TBABr, tetrabutylammonium bromide; 2-MeTHF, 2-methyltetrahydrofuran; mCPBA, m-chloroperbenzoic acid; DCM, dichloromethane; MsOH, methanesulfonic acid; PhMe, toluene; T3P, propylphosphonic acid anhydride; DIPEA, diisopropylethylamine; LiBr, lithium bromide; NaCl, sodium chloride; DMAc, N,N-dimethylacetamide; DPPA, diphenylphosphoryl azide; NaOH, sodium hydroxide; H3PO4, phosphoric acid; IPA, isopropanol; IBX, 2-iodoxybenzoic acid; NaHCCE, sodium bicarbonate; KF, critical in-process control; ID, identification method; IR, infrared spectroscopy; HPLC, high performance liquid chromatography; TEA or EtsN, tri ethylamine; LCMS, liquid chromatography mass spectrometry; ppm, parts per million; ICP-MS, inductively coupled plasma mass spectrometry; GCMS, gas chromatography mass spectrometry; GC, gas chromatography; MW, molecular weight; Py HB or PyH*Br3, pyridinium tribromide; IM 1-9, impurity compounds 1-9; LC, liquid chromatography; RRT, relative retention time; DMS, dimethyl sulfate.

[0180] TEA, triethylamine; NO, nitric oxide; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; IFNy or IFN-y, interferon-y; FA, Friedrich’s ataxia; Nrf2, nuclear factor erythroid-derived 2-related factor 2.

[0181] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the inherent variation in the method being employed to determine the value, the variation that exists among the study subjects, or a value that is within 10% of a stated value. Table 1. Intermediate Compounds

[0182] The above definitions supersede any conflicting definition in any reference that is incorporated by reference herein. The fact that certain terms are defined, however, should not be considered as indicative that any term that is undefined is indefinite. Rather, all terms used are believed to describe the invention in terms such that one of ordinary skill can appreciate the scope and practice the present invention.VI. ExamplesThe following examples are included to demonstrate preferred embodiments of the invention.It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.Example 1 - Formation of C3-oxo Triterpenoid DerivativesTable 2: Preparation of product D from C

[0183] Ethyl acetate (EtOAc; 6.6-7.6X), C (0.99-1.01X) and dimethyl sulfoxide (DMSO; 0.84-0.94X) is charged to a reactor, and the content is adjusted to - 5 °C. Propylphosphonic acid anhydride (T3P) solution (50% w / w in ethyl acetate, 1.72-1.84X) is charged to the reactor maintaining the temperature at -5 - 5 °C. The reaction mixture is then stirred at - 5 °C for no less than 2.0 h. Diisopropylethylamine (DIPEA; 0.41-0.45X) is charged to the reactor maintaining the temperature at - 5 °C. Ethyl acetate (EtOAc; 0.10-0.20X) is charged to the reactor maintaining a temperature at -5-5 °C. The content is adjusted to 20-30 °C and the temperature is maintained at 20-30 °C for no less than 2.0 h until the reaction is determined to be complete. Purified water (4.75-5.25X) is then charged to the reactor and thetemperature is maintained at 20-30 °C for no less than 1.0 h. The mixture is stirred for no less than 1.0 h at 20-30 °C. Agitation is stopped, and the mixture is allowed to settle for no less than 1.0 h at 20-30 °C before separation and removal of the bottom aqueous layer. IN sodium hydroxide (NaOH; 4.73-5.33X) aqueous solution is charged to the reactor maintaining the temperature at 20-30 °C and the biphasic mixture is agitated for no less than 1.0 h at 20-30 °C. Agitation is stopped, and the mixture is allowed to settle for no less than 1.0 h at 20-30 °C before separation and removal of the bottom aqueous layer. 8% sodium bicarbonate (NaHCCh) aqueous solution (4.75-5.25X) is charged to the reactor maintaining the temperature at 20-30 °C and the biphasic mixture is agitated for no less than 1.0 h at 20-30 °C. Agitation is stopped, and the mixture is allowed to settle for no less than 1.0 h at 20-30 °C before separation and removal of the bottom aqueous layer. 8% sodium bicarbonate (NaHCCh) aqueous solution (4.75-5.25X) is charged to the reactor maintaining the temperature at 20-30 °C and the biphasic mixture is agitated no less than no less than 1.0 h at 20-30 °C. Agitation is stopped, and the mixture is allowed to settle for no less than 1.0 h at 20-30 °C before separation and removal of the bottom aqueous layer. Purified water (4.75-5.25X) is charged to the reactor maintaining the temperature at 20-30 °C and the biphasic mixture is agitated for no less than 1.0 h at 20-30 °C. Agitation is stopped, and the mixture is allowed to settle for no less than 1.0 h at 20-30 °C before separation and removal of the bottom aqueous layer. The contents of the reactor are concentrated under vacuum to 2.0 V at a temperature of no more than 45 °C. Purified water (0.14-0.16X) is charged to the reactor. Methanol (3.75-4.15X) is charged to the reactor. The contents of the reactor are concentrated under vacuum to 2.0 V at a temperature of no more than 45 °C. Methanol (3.75-4.15X) is charged to the reactor. The contents of the reactor are concentrated under vacuum to 2.0 V at a temperature of no more than 45 °C. The temperature is then adjusted to 20-30 °C and methanol (5.63-6.23X) is charged to the reactor. The water content is then checked by Karl Fischer to confirm water content of the filtrate is in the range of 0.5-2.0%. The content is adjusted to no less than 64 °C (refluxing). The contents are stirred at the temperature no less than 64 °C (refluxing) for no less than 20 min to ensure that the solid has dissolved completely. The mixture is then cooled to - 5 °C over a period of no less than 6 h and then aged for an additional no less than 6.0 h. The resulting slurry is filtered, and the wet cake is washed with methanol / water (7 / 3, w / w; 0.7-1.3X). The product D is dried under vacuum at 45-55 °C for no less than 16 h (average yield 87%). Yield summaries and the testing report for Compound D are shown in Tables 3 and 4 below.Table 3: Yield summaries for Compound D (methyl (4aS,6aR,6bS,8aR,12aS,14aR,14bS)- 2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,14,14a,14b- octadecahydropicene-4a(2H)-carboxylate)Table 4: Testing Report for Compound D (methyl (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,14,14a,14b- octadecahydropicene-4a(2H)-carboxylate)Example 2 - Formation of C9-C11 Unsaturated TriterpenoidsTable 5: Preparation of product C from B

[0184] Toluene (14.0-14.8X) and B (0.99- 1.0 IX) are charged into a reactor, and the batch temperature is adjusted to 28 - 38 °C and stirred for no less than 0.5 h to dissolve the solid clearly. The batch is cooled to a temperature between 20-30 °C. Pyridinium tribromide (PyHBr?; 0.89-0.95X) is charged into the reactor, maintaining the temperature at 20-35 °C, followed by a rinse forward with toluene (1.2-1 ,4X). The reaction mixture is then stirred at 20- 35 °C for no less than 9 h until the reaction is determined to be complete. The batch temperature is adjusted to 25-35 °C. 10% sodium sulfite solution (4.7-5.3X) is then charged into the reactor, maintaining the temperature at 25-35 °C. The mixture is stirred for no less than 2.0 h to quench any remaining oxidant. Agitation is stopped, and the mixture is allowed to settle for no less than 2.0 h before separation and removal of the bottom aqueous layer. 2.5% sodium hydroxide (NaOH) aqueous solution (5.42-6.58X) is charged into the reaction and the biphasic mixture is agitated for no less than 2.0 h at 25-35 °C. Agitation is stopped, and the mixture is allowed to settle for no less than 2.0 h before separation and removal of the bottom aqueous layer. 15%sodium chloride (NaCl) aqueous solution (4.73-5.27X) is charged to the reaction and the biphasic mixture is agitated for no less than 2.0 h at 25-35 °C. Agitation is stopped, and the mixture is allowed to settle for no less than 2.0 h before separation and removal of the bottom aqueous layer. Purified water (3.5-4.5X) is charged to the reaction and the biphasic mixture is agitated for no less than 2.0 h at 25-35 °C. Agitation is stopped, and the mixture is allowed to settle for no less than 2.0 h before separation and removal of the bottom aqueous layer. The contents of the reactor are then concentrated under vacuum to 7.5 V at a temperature of no more than 55 °C. The temperature of the concentrated solution is adjusted to 65-75 °C and maintained at a temperature of 65-75 °C for no less than 0.5 h. The contents are then cooled to 45-55 °C before being concentrated under vacuum to 4.5 V at a temperature of no more than 55 °C. The contents are adjusted 45-55 °C and stirred for no less than 1.0 h at 45-55 °C. n- Heptane (8.4-9.4X) is added over a period of no less than 5.0 h while maintaining a temperature of 45-55 °C. After stirring for no less than 1 h at 45-55 °C, the mixture is then cooled to 0 - 10 °C over a period of no less than 4h and then aged for an additional no less than 4h. The resulting slurry is filtered, and the wet cake is washed with n-heptane (0.68-1.36X). The wet cake and toluene (6.1-7. OX) are charged to a reactor, and the contents are adjusted to 65-75 °C and stirred for no less than 0.5h. The contents are then cooled to 45-55 °C before being concentrated under vacuum to 4.5 V at a temperature of no more than 55 °C. The contents are adjusted 45-55 °C and stirred for no less than l.Oh at 45-55 °C. / / -Heptane (8.4-9.4X) is added over a period of no less than 5. Oh while maintaining a temperature of 45-55 °C. After stirring for no less than 1 h at 45-55 °C, the mixture is then cooled to 0 - 10 °C over a period of no less than 4h and then aged for an additional no less than 4h. The resulting slurry is filtered, and the wet cake is washed with an n-heptane (0.68-1.36X). The resulting product C is dried under vacuum at 45-55 °C for no less than 10 h (average yield 85%). Yield summaries and the testing report as were obtained for batches 1-4 for Compound C are shown in Tables 6 and 7 below.Table 6: Yield summaries for Compound C (methyl (4aS,6aR,6bS,8aR,10S,12aS,14aR,14bS)- 10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14-oxo- l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,14,14a,14b-octadecahydropicene-4a(2H)-carboxylate)Table 7: Testing Report for Compound C (methyl (4aS,6aR,6bS,8aR,10S,12aS,14aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14-oxo- l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,14,14a,14b-octadecahydropicene-4a(2H)-carboxylate)Example 3 - Formation of C12-oxo Triterpenoid DerivativesTable 8: Preparation of product B from A

[0185] Dichloromethane (DCM; 11.5-12.5X) and A (0.99-1.01X) are charged to a reactor, and the temperature is adjusted to 10-30 °C. m-Chloroperbenzoic acid (m-CPBA; 0.44- 0.48X) is charged to the reactor while maintaining the temperature at 10 - 30 °C. A dichloromethane (1.2-1.4X) rinse is charged to the reactor. The reaction mixture is then stirred at 20-30 °C for no less than 13 h until the reaction is determined to be complete. 10% sodium sulfite solution (0.95-1.05X) is then charged to the reactor while maintaining the temperature at 20-30 °C. The mixture is stirred for no less than 0.5 h to quench the reaction. An 8% sodium hydrogen carbonate solution (3.75-4.25X) is then charged to the reactor while maintaining the temperature at 20-30 °C. The mixture is stirred for no less than 1.5 h. Agitation is stopped, and the mixture is allowed to settle for no less than 2.5 h before the bottom organic layer is separated and the upper aqueous layer is discarded. The organic layer is transferred back to the reactor, purified water (4.5-5.5X) is charged, and the biphasic mixture is agitated for no less than 1.5 h at 20-30 °C. Agitation is stopped, and the mixture is allowed to settle for no less than 3.5 h before the bottom organic layer is separated and the upper aqueous layer is discarded The organic layer is transferred back to the reactor and a methane sulfonic acid / dichloromethane solution (0.058-0.066X methane sulfonic acid; 0.62-0.70X dichloromethane) is charged while maintaining the temperature at 20-30 °C. The reaction mixture is then stirred at 20-30 °C for no less than 0.5 h until the reaction is determined to be complete. An 8% sodium hydrogen carbonate solution (4.75-5.25X) is then charged to the reactor maintaining the temperature at 20-30 °C. The mixture is stirred for no less than 1.5 h, agitation is stopped, and the mixture is allowed to settle for no less than 2.0 h before separating the bottom organic layer and discarding the upper aqueous layer. The organic layer is transferred back to the reactor, purified water(4.5-5.5X) is charged to the reactor and the biphasic mixture is agitated for no less than 1.5 h at 20-30 °C. Agitation is stopped, and the mixture is allowed to settle for no less than 3.0 h before the bottom organic layer is separated and the upper aqueous layer is discarded. The organic layer is transferred back to the reactor and the contents of the reactor are concentrated under vacuum to 3.0 V at a temperature of no more than 30 °C. The temperature of the concentrated solution aw adjusted to 20-30 °C and isopropanol (3.7-4. IX) is added over a period of no less than 5 h while maintaining a temperature of 20 - 30 °C. The resulting mixture is stirred at 20 - 30 °C for no less than 1.5 h before the contents of the reactor are concentrated under vacuum to 5.0 V at a temperature of no more than 55 °C. The temperature of the concentrated solution is adjusted to 45-55 °C and isopropanol (3.7-4. IX) is added over a period of no less than 3 h while maintaining a temperature of 45 - 55 °C. The contents of the reactor are concentrated under vacuum to 5.0 V at a temperature of no more than 55 °C. The temperature of the concentrated solution is adjusted to 45-55 °C and isopropanol (3.7-4. IX) is added over a period of no less than 2 h while maintaining a temperature of 45 - 55 °C. Purified water (0.9-1. IX) is then added over a period of no less than 3h while maintaining a temperature of 45-55 °C. After stirring for no less than 1 h at 45-55 °C, the mixture is then cooled to 15 - 25 °C over a period of no less than 3h and then aged for an additional no less than 4h. The resulting slurry is filtered, and the wet cake is washed with an isopropanol / water (9: 1, V / V; 1.8-2.2X) solution. The resulting product B is dried under vacuum at 45-55 °C for no less than 18 h (average yield 74%). Yield summaries and the testing report for Compound B are shown in Tables 9 and 10.1-10.2 below.Table 9: Yield summaries for Compound B (methyl(4aS,6aR,6bR,8aR,10S,12aR,14aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14- oxoicosahydropicene-4a(2H)-carboxylate)Table 10.1: Testing Report for Compound B (methyl(4aS,6aR,6bR,8aR,10S,12aR,14aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14- oxoicosahydropicene-4a(2H)-carboxylate)Table 10.2: Testing Report for Compound B (methyl(4aS,6aR,6bR,8aR,10S,12aR,14aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14- oxoicosahydropicene-4a(2H)-carboxylate)Example 4 - Formation of C17-ester Triterpenoid DerivativesTable 11: Preparation of product A from Oleanolic Acid

[0186] 2-methyltetrahydrofuran (2-MeTHF; 1.9-2. IX) and Oleanolic Acid (0.99- 1.01X) are charged to a reactor. The reactor is charged with an additional portion of 2- methyltetrahydrofuran (2.1-2.5X) and the temperature is adjusted to 25-35°C. 18-19% potassium carbonate solution (K2CO3; 2.23-2.69X) is charged to the reactor while maintaining the temperature at 25 - 35 °C. Tetrabutylammonium bromide (TBABr; 0.028-0.032X) is charged to the reactor. The reactor is rinsed with 2-methyltetrahydrofuran (0.05-0.15X) and the reaction mixture is then stirred at 25-35 °C for no less than 0.5 h. Dimethyl sulfate (DMS; 0.34- 0.38X) is charged to the reactor over no less than 1.0 h while maintaining the temperature at 25-35°C. The reactor is rinsed with 2-methyltetrahydrofuran (0.05-0.15X) and stirred while maintaining the temperature at 25-35°C for no less than 1.0 h. Triethylamine (TEA; 0.07- 0.09X) is charged to the reactor while maintaining the temperature at 25-35°C. The temperature of the reactor is adjusted to 45-55°C and the reaction mixture is stirred for no less than 4 h while maintaining the temperature at 45-55°C. The temperature of the reactor is adjusted to 25- 35°C. The reactor is charged with glacial acetic acid (0.12-0.16X) and stirred for no less than1 h while maintaining the temperature at 25-35°C. Agitation is stopped, and the mixture is allowed to settle for no less than 1.0 h before the bottom organic layer is separated and the upper aqueous layer is discarded. The organic layer is transferred back to the reactor and the reactor is charged with 21% sodium chloride solution (NaCl; 1.8-2. OX) while maintaining thetemperature at 25-35°C. The mixture is stirred for no less than 0.5 h before the bottom organic layer is separated and the upper aqueous layer is discarded. The organic layer is transferred back to the reactor and the contents of the reactor are concentrated under vacuum to 3.5 V at a temperature of no more than 50 °C. The temperature of the concentrated solution is adjusted to 45-55 °C and isopropanol (IP A; 0.35-0.45X) is added over a period of no less than 4 h while maintaining a temperature of 45-55 °C. The mixture is stirred at 45-55 °C for no less than 1.0 h. Isopropanol (IP A; 4.4-5. OX) is added over a period of no less than 4 h while maintaining a temperature of 45-55 °C. The mixture is stirred at 45-55 °C for no less than 1.0 h. Purified water (1.65-1.85X) is added over a period of no less than 3 h while maintaining a temperature of 45-55 °C. The temperature of the reactor is adjusted to 0-10 °C over a period of no less than 4.0 h and stirred for no less than 2.0 h. The resulting slurry is filtered, and the wet cake is washed with an isopropanol / water (3: 1, V / V; 1.5-1.7X) solution. The resulting product A is dried under vacuum at 50-60 °C for no less than 30 h (average yield 87%). Yield summaries are shown in Tables 12 and 13.1-13.2 below.Table 12: Yield summaries for Compound A (methyl (4aS,6aS,6bR,8aR,10S,12aR,14bS)-10- hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,12b,13,14b- octadecahydropicene-4a(2H)-carboxylate)Table 13.1. Testing Report for Compound A (methyl (4aS,6aS,6bR,8aR,10S,12aR,14bS)-10- hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,12b,13,14b- octadecahydropicene-4a(2H)-carboxylate)Table 13.2. Testing Report for Compound A (methyl (4aS,6aS,6bR,8aR,10S,12aR,14bS)-10- hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-l,3,4,5,6,6a,6b,7,8,8a,9,10,l l,12,12a,12b,13,14b- octadecahydropicene-4a(2H)-carboxylate)

[0187] All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.REFERENCES

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Claims

WHAT IS CLAIMED IS:

1. A multi-step method for preparation of omaveloxolone from oleanolic acid, comprising the use of a compound of Formula I as a reagent in one or more steps, wherein Formula I is defined as:wherein:Ri, Ri', and Ri" are each independently hydrogen, halo, amino, cyano, or carboxy; or alkyl(c<8), cycloalkyl(c<8), alkenyl(c<8), alkynyl(c<8), aryl(c<8), aralkyl(c<8), heteroaryl(c<8), heteroaralkyl(c<8), alkoxy(c<8), cycloalkoxy(c<8), alkenyloxy(c<8), alkynyloxy(c<8), aryloxy(c<8), aralkoxy(c<8), heteroaryloxy(c<8), heteroaralkoxy(c<8), alkylamino(c<8), dialkylamino(c<8), amido(c<8), or a substituted version of any of these groups.

2. The method of claim 1, wherein Ri, Ri', and Ri" are each propyl.

3. The method according to either claim 1 or claim 2, wherein the method comprises reacting oleanolic acid with an alkylating agent in a reaction mixture to form Compound A, wherein Compound A is defined as:

4. The method of claim 3, wherein the reaction mixture further comprises potassium carbonate.

5. The method according to either claim 3 or claim 4, wherein the reaction mixture further comprises 2-methyltetrahydrofuran.

6. The method according to any one of claims 3-5, wherein the reaction mixture further comprises tetrabutylammonium bromide.

7. The method according to any one of claims 3-6, wherein the alkylating agent is dimethyl sulfate.

8. The method according to any one of claims 3-7, wherein the reaction is carried out at a temperature of about 30°C.

9. The method according to any one of claims 3-8, wherein the reaction is carried out for about 1.0 h.

10. The method according to any one of claims 3-9, wherein the method further comprises contacting the reaction mixture with triethylamine at a second temperature of about 50°C for a second time period of about 3 h.

11. The method according to any one of claims 1-10, wherein the method further comprises reacting Compound A:with an oxidizing agent in a reaction mixture to form Compound B, wherein CompoundB is defined as:

12. The method of claim 11, wherein the oxidizing agent comprises meta-chloroperoxybenzoic acid.

13. The method according to either claim 11 or claim 12, wherein the molar ratio of Compound A to the oxidizing agent is about 4:5.

14. The method according to any one of claims 11-13, wherein the reaction mixture comprises dichloromethane.

15. The method according to any one of claims 11-14, wherein the reaction is carried out at a temperature of about 25°C.

16. The method according to any one of claims 11-15, wherein the reaction is carried out at a time period of about 15 h.

17. The method according to any one of claims 11-16, wherein the method further comprises contacting the reaction mixture with a solution of sodium bicarbonate and isolating the organic layer.

18. The method of claim 17, wherein the method further comprises contacting the isolated organic layer with methanesulfonic acid.

19. The method according to any one of claims 1-18, wherein the method further comprises reacting Compound B:with an oxidizing agent in a reaction mixture to form Compound C, wherein CompoundC is defined as:

20. The method of claim 19, wherein the oxidizing agent is pyridinium perbromide.

21. The method according to either claim 19 or claim 20, wherein the reaction mixture comprises a molar ratio of Compound B to the oxidizing agent of from about 1 : 1 to about 1 :2.

22. The method according to any one of claims 19-21, wherein the reaction mixture further comprises toluene.

23. The method according to any one of claims 19-22, wherein the method further comprises reacting Compound B with the oxidizing agent at a temperature of about 33°C.

24. The method according to any one of claims 19-23, wherein the method further comprises reacting Compound B with the oxidizing agent for a reaction time period of about 2 h.

25. The method according to any one of claims 1 -24, wherein the method further comprises reacting Compound C:with an oxidizing agent in the presence of a compound of Formula I:in a reaction mixture to form Compound D, wherein Compound D is defined as:wherein:Ri, Ri', and Ri" are each independently hydrogen, halo, amino, cyano, or carboxy; oralkyl(c<8), cycloalkyl(c<8), alkenyl(c<8), alkynyl(c<8), aryl(c<8), aralkyl(c<8), heteroaryl(c<8), heteroaralkyl(c<8), alkoxy(c<8), cycloalkoxy(c<8), alkenyloxy(c<8), alkynyloxy(c<8), aryloxy(c<8), aralkoxy(c<8), heteroaryloxy(c<8), heteroaralkoxy(c<8), alkylamino(c<8), dialkylamino(c<8), amido(c<8), or a substituted version of any of these groups.

26. The method of claim 25, wherein Ri, Ri', and Ri" are each propyl.

27. The method of either claim 25 or claim 26, wherein the reaction mixture comprises a molar ratio of Compound C to the compound of Formula I from about 1 : 1 to about 1 :2.

28. The method according to any one of claims 25-27, wherein the reaction mixture further comprises diisopropylethylamine.

29. The method of claim 28, wherein the reaction mixture comprises a molar ratio of Compound C to diisopropylethylamine from about 1 : 1 to about 1 :2.

30. The method according to any one of claims 25-29, wherein the oxidizing agent is dimethylsulfoxide.

31. The method of claim 30, wherein the reaction mixture comprises a molar ratio of Compound C to dimethylsulfoxide from about 1 :5 to about 1 :7.

32. The method according to any one of claims 25-31, wherein the method further comprises reacting Compound C with the compound of Formula I under an inert atmosphere.

33. The method according to any one of claims 25-32, wherein the method comprises contacting Compound C with a solution comprising the compound of Formula I.

34. The method of claim 33, wherein the concentration of the compound of Formula I in the solution is about 50% by weight.

35. The method according to any one of claims 25-34, wherein the solution comprises ethyl acetate.

36. The method according to any one of claims 25-35, wherein the reaction between Compound C and dimethylsulfoxide in the presence of the compound of Formula I is carried out at a temperature of about 25 °C.

37. The method according to any one of claims 25-36, wherein the reaction between Compound C and dimethylsulfoxide in the presence the compound of Formula I is carried ourt for a reaction time period of about 3 h.

38. A method for the preparation of a compound of Formula III comprising obtaining a compound of Formula II:and reacting the compound of Formula II with an oxidizing agent in the presence of a compound of Formula I:in a reaction mixture to form a compound of Formula III:wherein:Ri, Ri', and Ri" are each independently hydrogen, halo, amino, cyano, or carboxy; or alkyl(c<8), cycloalkyl(c<8), alkenyl(c<8), alkynyl(c<8), aryl(c<8), aralkyl(c<8), heteroaryl(c<8), heteroaralkyl(c<8), alkoxy(c<8), cycloalkoxy(c<8), alkenyloxy(c<8), alkynyloxy(c<8), aryloxy(c<8), aralkoxy(c<8), heteroaryloxy(c<8), heteroaralkoxy(c<8), alkylamino(c<8),dialkylamino(c<8), amido(c<8), or a substituted version of any of these groups; andR2 is:Ci-Cis-acyl or Ci-Cis-alkyl, wherein either of these groups is substituted or unsubstituted.

39. The method of claim 38, wherein Ri, Ri', and Ri" are each propyl.

40. The method of either claim 38 or claim 39, wherein R2 is Ci-Cis-acyl or substituted Ci-Cis-acyl.

41. The method of claim 40, wherein R2 is substituted Ci-Cis-acyl.

42. The method of claim 41, wherein R2 is -CO2CH3.

43. The method according to any one of claims 38-42, wherein the reaction mixture comprises a molar ratio of the compound of Formula II to the compound of Formula I from about 1 : 1 to about 1 :2.

44. The method according to any one of claims 38-43, wherein the reaction mixture further comprises diisopropylethylamine.

45. The method of claim 44, wherein the reaction mixture comprises a molar ratio of the compound of Formula II to diisopropylethylamine from about 1 : 1 to about 1 :2.

46. The method according to any one of claims 38-45, wherein the reaction mixture further comprises dimethylsulfoxide.

47. The method according to claim 46, wherein the reaction mixture comprises a molar ratio of the compound of Formula II to dimethylsulfoxide from about 1 :5 to about 1 :7.

48. The method according to any one of claims 38-47, wherein the method further comprises reacting a compound of Formula II with the compound of Formula I under an inert atmosphere.

49. The method according to any one of claims 38-48, wherein reacting the compound of Formula II with the compound of Formula I further comprises contacting the compound of Formula II with a solution comprising the compound of Formula I.

50. The method of claim 49, wherein the concentration of the solution is about 50% by weight.

51. The method according to any one of claims 38-50, wherein the solution further comprises ethyl acetate.

52. The method according to any one of claims 38-51, wherein the method further comprises reacting the compound of Formula II with the compound of Formula I at a temperature of about 25 °C.

53. The method according to any one of claims 38-52, wherein the method further comprises reacting the compound of Formula II with the compound of Formula I for a reaction time period of about 3 h.

54. A method for the preparation of Compound A comprising obtaining oleanolic acid, and reacting oleanolic acid with an alkylating agent in a reaction mixture to form Compound A:wherein the reaction mixture comprises a solvent that is immiscible with water.

55. The method of claim 54, wherein the reaction mixture further comprises a base.

56. The method of claim 55, wherein the base is potassium carbonate.

57. The method according to any one of claims 54-56, wherein the reaction mixture further comprises a phase-transfer catalyst.

58. The method of claim 57, wherein the phase-transfer catalyst is tetrabutylammonium bromide.

59. The method according to any one of claims 54-58, wherein the alkylating agent is dimethyl sulfate.

60. The method according to any one of claims 54-59, wherein the solvent comprises 2-methyltetrahydrofuran.

61. The method according to any one of claims 54-60, wherein the method further comprises an aqueous purification step.

62. The method according to any one of claims 54-61, wherein the reaction is carried out at a temperature from about 0°C to about 100°C.

63. The method of claim 62, wherein the temperature is about 30°C.

64. The method according to any one of claims 54-63, wherein the reaction is carried out for a reaction time period from about 0.5 h to about 3.0 h.

65. The method of claim 64, wherein the reaction time period is about 1.0 h.

66. The method according to any one of claims 54-65, wherein Compound A is prepared in greater than 90% purity, as measured by high performance liquid chromatography.

67. The method of claim 66, wherein Compound A is prepared in greater than 95% purity, as measured by high performance liquid chromatography.

68. The method of claim 67, wherein Compound A is prepared in greater than 98% purity, as measured by high performance liquid chromatography.

69. A method for the preparation of Compound C, comprising obtaining Compound B:and reacting Compound B with pyridinium perbromide in a reaction mixture to form Compound C:

70. The method of claim 69, wherein the molar ratio of Compound B to pyridinium perbromide is from about 1 : 1 to about 1 :2.

71. The method of either claim 69 or claim 70, wherein the reaction mixture comprises a solvent.

72. The method of claim 71, wherein the solvent is immiscible with water.

73. The method of claim 72, wherein the solvent comprises toluene.

74. The method according to any one of claims 69-73, wherein the reaction is carried out at a reaction time period from about 1 h to about 4 h.

75. The method of claim 74, wherein the reaction time period is about 2 h.

76. The method according to any one of claims 69-75, wherein the reaction is carried out at a temperature from about 0°C to about 100°C.

77. The method of claim 76, wherein the temperature is about 33°C.

78. The method according to any one of claims 69-77, wherein Compound C is prepared in greater than 90% purity, as measured by high performance liquid chromatography.

79. The method of claim 78, wherein Compound C is prepared in greater than 95% purity, as measured by high performance liquid chromatography.

80. The method of claim 79, wherein Compound C is prepared in greater than 98% purity, as measured by high performance liquid chromatography.

81. A method for the preparation of omavel oxoIone comprising:(a) reactingwith dimethyl sulfate and potassium carbonate in the presence of tetrabutylammonium bromide to form(b) reactingwith meta-chloroperoxybenzoic acid to form(c) reactingwith pyridinium perbromide to form(d) reactingwithdiisopropylethylamine and dimethylsulfoxide to form(e) reactingwith sodium methoxide to form(f) reactingwith hydroxylamine and hydrochloric acid to form(g) reactingwith sodium methoxide to formwith pyridine to form(j) reactingunder conditions suitable to form(k) reactingwith diphenylphosphoryl azide and triethylamine to form(1) heatingto form(m) reactingunder conditions suitable to form(n)to form omaveloxolone.

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