EP4642788A1 - Chemical synthesis methods and cddo/cddo-ea preparations - Google Patents

Abstract

Improved synthesis methods for providing a Compound #6, Compound #7 and various CDDO, CDDO derivatives and CDDO analogs, are provided. Product compositions comprising CDDO, CDDO-EA, CDDO-Me prepared according to the methods disclosed are also provided. Synthesis methods taking less than about 12 hours, or less than about 2 hours, that are scalable and provide commercially useful and economically suitable yield CDDO compound products are disclosed.

Description

Inventor: Shizue Mito Atty. Docket No.119526-000014 CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS GOVERNMENT LICENSE RIGHTS This invention was made with government support under NIH (National Institutes of Health) Grant SC2GM127272 awarded by the National Institute of General Medical Sciences (NIGMS). The government has certain rights in the invention. FIELD OF THE INVENTION The present invention is related to the field of chemical synthesis and pharmacologically active compounds. CROSS REFERENCE TO RELATED APPLICATION This application claims the benefit of United States provisional patent application number 63/436,082, filed December 29, 2022, which is hereby incorporated by reference as though fully set forth herein. BACKGROUND OF THE INVENTION Naturally occurring triterpenoids (TP) in plants are used for medicinal purposes in many Asian countries. Some ursolic and oleanolic acids (OAs) are reported to be anti- inflammatory and anti-carcinogenic (Huang et al., 1994; Nishino et al., 1988). However, the biological activity of these naturally-occurring molecules is relatively weak. The synthesis of various TP analogs have been described by several groups (Honda et al., 1997; Honda et al., 1998; Honda et al., 2000; Honda et al., 2002; Yates, 2007). The ongoing efforts for providing oleanolic and ursolic acid analogs that possessed improved anti-inflammatory and antiproliferative activity has led to the identification of particular 2-cyano-3,12-dioxooleane-1,9(11)-dien-28-oic acid (CDDO, RTA 402) TP compounds. Experimental studies focused on triterpenoids and their possible role in cytoprotective gene induction have been reported. In the case of inducing cytoprotective genes Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS through Keap1-Nrf2-antioxidant response element (ARE) signaling, a structure activity evaluation of 15 triterpenoids observed the importance of Michael acceptor groups on both the A and C rings, a nitrile group at C-2 of the A ring, and substituents at C-17. These studies reportedly identified sites of these compounds that resulted in a change in the pharmacodynamic action of certain of the triterpenoids examined (Yates et al., 2007). Synthesis methods for several TP analogs from oleanolic acid have been described (e.g., CDDO-MA, CDDO-Me, TP-225, CDDO-EA, CDDO-Im; See Honda et al., 1997, 1998, 1999, 2000a, 2000b, 2002; Suh et al., 1998; 1999; 2003; Place et al., 2003; Liby et al., 2005). While these TP analog synthesis protocols appeared promising, they have been reported to require extremely complicated multi-step processes (Honda et al., 2000a, 2000b), are time intensive, and lack in specificity for desired, sufficiently pure products, rendering the techniques inefficient and less suitable for commercially scalable production of pharmacologically active terpenoids. The difficult and time consuming alternative methods for preparing CDDO-Me from oleanolic acid presented in Honda et al., (2000a and 2000b), is described as requiring 24 hours for one step of the synthesis. This period of time for synthesis of CDDO-Me renders the process unsuited for the timely production of commercially useful quantities of desirable CDDO analogs and derivatives (CDDO-EA). Fu et al. (2013) reports a multi-step synthesis for producing bardoxolone methyl (CDDO-Me) from oleanolic acid, and proposes the method as being a scalable alternative approach to synthesizing CDDO-Me. CDDO-Me is a precursor compound in the synthesis of CDDO, CDDO-EA, and other CDDO derivatives and analogs. Unfortunately, the Fu et al. synthesis protocol has been found to yield an undesirable Compound #11 (Figure 6), and to fail to provide a properly brominated precursor compound (Compound #6) for synthesis to CDDO-Me (Compound #7) (Figure 6). A properly brominated Compound #6 is necessary for the subsequent synthesis of CDDO-Me (See Figure 6, Compound #7). Using the synthesis protocol of Fu et al., an undesirable over brominated precursor compound (Compound #11), that included an alpha- bromination, was produced (See Figure 6, Compound#11). This over brominated Compound #11, upon elimination, resulted in the formation of a tetrasubstituted olefine. This inappropriately over Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS brominated Compound #11 would not therefore yield the desired CDDO-Me (Compound #7), according to the next step of desired CDDO product reaction sequence (Figure 6, Compound #7, CuCN, KI/DMF), and would further not be useful in the overall efficient and specific synthesis of CDDO (Compound #8), Compound #9, or CDDO-EA (Compound #10). Overall, the chemical arts remain in need of an alternative and improved synthesis strategy for producing less diverse, specifically substituted compounds, and pharmacologically active terpenoid derivatives and desired precursor compounds, especially Compound #6 and CDDO-Me. The chemical arts remain in need of improved processes having shorter synthesis time requirements for preparing CDDO compounds, that are commercially scalable, efficient and more cost effective. SUMMARY OF THE INVENTION The present invention in a general and overall sense relates to improved chemical synthesis strategies for producing pharmacologically active preparations of specifically substituted terpenoid derivatives, such as CDDO, from oleanolic acid, in a significantly reduced period of time, such as in less than about 12 or about 24 hours. By way of example, the synthetic terpenoid compounds produced according to the presently improved methods comprise CDDO, CDDO-Me, CDDO-EA, CDDO-Im and other CDDO derivatives and analogs. Synthesis of the intermediate Compound #6, essential to all further synthesis of CDDO and its analogs, is efficiently produced in less than about 2 hours or less than about 12 hours. In some aspects, the synthesis method disclosed herein provides a commercially scalable process for synthesizing a pharmacologically active synthetic triterpenoid (CDDO, CDDO-EA, CDDO-Im, CDDO-Me), from oleanolic acid. In another aspect, a chemical synthesis method that provides for the production of the synthetic terpenoid, Compound #6, as well as CDDO-Me (Compound #7) (See Figure 5) is provided. In some embodiments, the chemical synthesis method provides for the commercial scale production of a terpenoid compound having a Formula I: Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS FORMULA I: In certain or heteroatom-unsubstituted C1 – C15 acyl. In other embodiments, the chemical synthesis methods provide for the efficient synthesis of any one or a combination of the following compounds:       In another aspect of this invention, improved chemical synthesis strategies provide for the more efficient production of synthetic triterpenoids having a structure of Formula II, shown below. FORMULA II: Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS In certain or a heteroatom-substituted C₁- C₅-alkylamino having at least one fluorine atom. In other embodiments, the Y is a heteroatom- substituted or heteroatom-unsubstituted C2-C4-alkylamino having at least one fluorine atom. In further embodiments, the invention provides pharmaceutically acceptable salts and hydrates of these synthetic triterpenoids. In yet further embodiments, the invention provides single enantiomers of these synthetic triterpenoids or their salts or hydrates that are substantially free from other optical isomers. In still further embodiments, racemic mixtures of these synthetic triterpenoids as well as their salts and hydrates are provided. Examples of other CDDO derivatives provided according to the present methods and compositions include CDDO-TFEA and CDDO-EA. The chemical structures of these compounds appear below: FORMULA III: In the method for synthesis of the CDDO-EA compound, the R¹ group is substituted to provide a CDDO-EA compound (TP-319). The CDDO-EA compound (Compound #10) is defined by the structure in Formula IV: Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS FORMULA IV: In yet another the compound of Formula V is provided. FORMULA V: for synthesizing the compound of Formula VI are provided. FORMULA VI: Novel Improved Synthesis of CDDO: Improved Methods Avoid Over Reacted Bromination, avoids Complex Mixture of Product Compounds, and Reduces Synthesis Time 14- fold. Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS In another aspect, an improved, more efficient chemical method for synthesizing a synthetic triterpenoid is provided. The methods provided here are improved over those conventional in the literature. The method conventional in the literature provides for a conversion of Oleanolic acid to an intermediate product #6 (with a high catalyst (HBr) eq ) (Fu et al., (2013)). The present process provides for use of a low catalytic amount of HBr. . The prior art process in Fu et al. results in production of a complex mixture of compounds, and random, undesired multi- brominated substitutions and/or sites of substitution groups, as well as alpha bromination occurs. Subsequent elimination resulted in a tetrasubstituted olefine. The methyl ester was hydrolyzed, and the corresponding carboxylic acid resulted. These incidents rendered the prior processes unacceptable. The present method provides a synthesis method that employs LiI to transform the methyl ester of the CDDO-Me to a carboxylic acid (CDDO) from substrate. The CDDO resulting was not a complex mixture. Chemical conversion from Oleanolic acid to a final product of CDDO- EA may take place either through the use of one or a mixture of substrates of an epoxide Compound (#4) and a ketone Compound (#5). The CDDO Compound #6 obtained as a result of the bromination step (HBr, Br2), may then be converted to CDDO-Me (Compound #7) in the synthesis step with CuCN, KI (DMF). The Compound #7 may then be processed (with LiI) to provide Compound #8 (CDDO). The Compound #8 is then subjected to (COCl)₂ to provide Compound #9. Compound #9 is then processed with EtNH2 to provide Compound #10 (CDDO-EA). A mixture of the epoxide and the ketone compound is brominated to provide a CDDO-Me of the desired structure, and this CDDO-Me product would then be processed to provide a CDDO #8 using lithium iodine (LiI). The bromination reaction was run with substrate of both the epoxide (#4) and the ketone (#5) compounds using a much reduced amount of the acid catalyst (acid catalyst, HBr) (less than about 1% weight equivalents per substrate weight). The weight equivalent of acid catalyst found effective in the present methods (HBr, 0.025 eq) were significantly less than the catalyst equivalent weight of the same catalyst reported in the literature of Fu et al., (2013) (HBr, 0.44 eq). In addition, while the prior methods required at least 24 hours for chemical synthesis of Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS bardoxolone methyl (CDDO-Me, Compound #7), the presently disclosed chemical synthesis pathway provides for a much shorter synthesis time of about 2 hours to synthesize CDDO-Me (Compound #7), compared to the literature reported time period of 24 hours (Fu et al., (2013)). The significantly reduced equivalent amount of acid catalyst required in the present synthesis scheme, the greater degree of specificity of reaction products, and the vastly shorted processing time (2 hours), provides a commercially-scalable technique for the synthesis and commercial manufacture of CDDO compounds, including CDDO-Me, as well as further synthesis to CDDO and CDDO-EA. (See Figure 6). This includes the synthesis of CDDO, CDDO-Me, and CDDO-EA products. A flow-chart of the chemical synthesis for the CDDO appears in Figure 6. The synthesis procedure for CDDO-EA is also presented in Example 6 (a CDDO-EA Batch #1) and Example7 (a CDDO-EA Batch #2). The CDDO-EA produced from each batch as described herein, were of essentially the same purity and biological activity. The anti-inflammatory properties of both batches of CDDO-EA produced was assessed as a function of the effectiveness of the CDDO- EA for blocking LPS-induced MCP-1 production in cell culture (macrophages). It was found that the effectiveness of the Batch #1 and the Batch #2 CDDO-EA was essentially the same (LPS = 112,235 pg/ml, Batch #1 CDDO-EA = 31,341 pg/ml MCP-1 production, Batch #2 CDDO-EA = 24,648 pg/ml MCP-1 production). This is an about 3.6 and a 4.6-fold difference in the decrease of MCP-1 production in cell culture, respectively, resulting from the Batch #1 CDDO-EA and the Batch #2 CDDO-EA. This establishes that the novel synthesis protocol developed in the present disclosure is reproducible and reliable. Figures 2A and 2B provide the spectral analysis of the products obtained in the synthesis according to the present synthesis techniques, employing less than 5% of the acidic catalyst. These data demonstrate that the presently disclosed synthesis methods provide CDDO analog and/or derivatives, such as CDDO-EA, in about a 2 hour period of time, at a temperature of 35 °C. The methods for synthesis of Compound #4, Compound #5, Compound #6, Compound #7 and Compound #10 are provided in Figures 5 and 6, as well as in the following Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS Examples. Definitions: In the following description, for purposes of explanation, specific numbers, materials and configurations are set forth in order to provide a thorough understanding of the invention. It will be apparent, however, to one having ordinary skill in the art that the invention may be practiced without these specific details. In some instances, well-known features may be omitted or simplified so as not to obscure the present invention. Furthermore, reference in the specification to phrases such as “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. The appearances of phrases such as “in one embodiment” in various places in the specification are not necessarily all referring to the same embodiment. Further, as the present inventive concept is susceptible to embodiments of many different forms, it is intended that the present disclosure be considered as an example of the principles of the present inventive concept and not intended to limit the present inventive concept to the specific embodiments shown and described. Any one of the features of the present inventive concept may be used separately or in combination with any other feature. References to the terms “embodiment,” “embodiments,” and/or the like in the description mean that the feature and/or features being referred to are included in, at least, one aspect of the description. Separate references to the terms “embodiment,” “embodiments,” and/or the like in the description do not necessarily refer to the same embodiment and are also not mutually exclusive unless so stated and/or except as will be readily apparent to those skilled in the art from the description. For example, a feature, structure, process, step, action, or the like described in one embodiment may also be included in other embodiments, but is not necessarily included. Thus, the present inventive concept may include a variety of combinations and/or integrations of the embodiments described herein. Additionally, all aspects of the present disclosure, as described herein, are not essential for its practice. Likewise, other systems, methods, features, and advantages of the present inventive concept will be, or become, apparent to one with skill in the art upon examination of the figures and the description. It is intended that all such additional systems, methods, features, and Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS advantages be included within this description, be within the scope of the present inventive concept, and be encompassed by the claims. Definitions: Any term of degree such as, but not limited to, the term “about” as used in the description and the appended claims, should be understood to include the recited values or a value that is three times greater or one third of the recited values. For example, about 3 cm includes all values from 1 mm to 9 cm. For example, terms of degree can refer to less than or equal to + 5%, such as less than or equal to + 2%, such as less than or equal to + 1%, such as less than or equal to + 0.5%, such as less than or equal to + 0.2%, such as less than or equal to + 0.1%, such as less than or equal to + 0.05%. The term “disease” is intended to be interpreted as any condition of a subject evidencing symptoms associated with a clinical determination of obesity, a medical determination of an overweight measurement, metabolic syndrome, cardiac disease, insulin insensitivity, hypoglycemia, type I or II diabetes, elevated blood pressure, glucose intolerance, and the like. In particular descriptions of the preparations and methods, the term “disease” may be intended to specifically indicate a subject having been determined to be clinically obese or overweight. The terms "comprising," "including" and "having" are used interchangeably in this disclosure. The terms "comprising," "including" and "having" mean to include, but not necessarily be limited to the things so described. The term, “synthetic”, as provided in a description of a chemical or compound, should be understood to mean a non-naturally occurring substance or compound, such as a substance of a compound that has been obtained from other than a naturally occurring cell or tissue in nature. The term “synthetic” may also refer to a substance of compound that has been chemically modified from the chemical structure of the substance or compound as it exists in its native unchanged state in nature. The terms “or” and “and/or,” as used herein, are to be interpreted as inclusive or meaning any one or any combination. Therefore, “A, B or C” or “A, B and/or C” mean any of the Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS following: “A,” “B” or “C”; “A and B”; “A and C”; “B and C”; “A, B and C.” An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive. As used herein, the term “amino” means —NH₂; the term “nitro” means —NO₂; the term “halo” designates —F, —Cl, —Br or —I; the term “mercapto” means —SH; the term “cyano” means —CN; the term “silyl” means —SiH3, and the term “hydroxy” means —OH. The term “heteroatom-substituted,” when used to modify a class of organic radicals (e.g., alkyl, aryl, acyl, etc.), means that one, or more than one, hydrogen atom of that radical has been replaced by a heteroatom, or a heteroatom containing group. Examples of heteroatoms and heteroatom containing groups include: hydroxy, cyano, alkoxy, ═O, ═S, —NO₂, —N(CH₃)₂, amino, or —SH. Specific heteroatom-substituted organic radicals are defined more fully below. The term “heteroatom-unsubstituted,” when used to modify a class of organic radicals (e.g., alkyl, aryl, acyl, etc.) means that none of the hydrogen atoms of that radical have been replaced with a heteroatom or a heteroatom containing group. Substitution of a hydrogen atom with a carbon atom, or a group consisting of only carbon and hydrogen atoms, is not sufficient to make a group heteroatom-substituted. For example, the group —C6H4C≡CH is an example of a heteroatom-unsubstituted aryl group, while —C₆H₄F is an example of a heteroatom-substituted aryl group. Specific heteroatom-unsubstituted organic radicals are defined more fully below. The term “alkyl” includes straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl(alicyclic) groups, alkyl heteroatom-substituted cycloalkyl groups, and cycloalkyl heteroatom-substituted alkyl groups. The term “heteroatom-unsubstituted C_n-alkyl” refers to a radical having a linear or branched, cyclic or acyclic structure, further having no carbon-carbon double or triple bonds, further having a total of n carbon atoms, all of which are nonaromatic, 3 or more hydrogen atoms, and no heteroatoms. For example, a heteroatom-unsubstituted C₁-C₁₀-alkyl has 1 to 10 carbon atoms. The groups, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, — CH(CH2)2 (cyclopropyl), —CH2CH2CH2CH3, —CH(CH3)CH2CH3, —CH2CH(CH3)2, — C(CH₃)₃, —CH₂C(CH₃)₃, cyclobutyl, cyclopentyl, and cyclohexyl, are all examples of heteroatom-unsubstituted alkyl groups. The term “heteroatom-substituted C_n-alkyl” refers to a Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS radical having a single saturated carbon atom as the point of attachment, no carbon-carbon double or triple bonds, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, all of which are nonaromatic, 0, 1, or more than one hydrogen atom, at least one heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a heteroatom-substituted C1-C10-alkyl has 1 to 10 carbon atoms. The following groups are all examples of heteroatom-substituted alkyl groups: trifluoromethyl, —CH₂F, —CH₂Cl, —CH₂Br, —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, — CH₂OCH₂CH₂CH₃, —CH₂OCH(CH₃)₂, —CH₂OCH(CH₂)₂, —CH₂OCH₂CF₃, —CH₂OCOCH₃, —CH2NH2, —CH2NHCH3, —CH2N(CH3)2, —CH2NHCH2CH3, —CH2N(CH3)CH2CH3, — CH₂NHCH₂CH₂CH₃, —CH₂NHCH(CH₃)₂, —CH₂NHCH(CH₂)₂, —CH₂N(CH₂CH₃)₂, — CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂Br, —CH₂CH₂I, —CH₂CH₂OH, —CH₂CH₂OCOCH₃, — CH2CH2NH2, —CH2CH2N(CH3)2, —CH2CH2NHCH2CH3, —CH2CH2N(CH3)CH2CH3, — CH2CH2NHCH2CH2CH3, —CH2CH2NHCH(CH3)2, —CH2CH2NHCH(CH2)2, — CH₂CH₂N(CH₂CH₃)₂, —CH₂CH₂NHCO₂C(CH₃)₃, and —CH₂Si(CH₃)₃. The term “heteroatom-unsubstituted Cn-alkenyl” refers to a radical having a linear or branched, cyclic or acyclic structure, further having at least one nonaromatic carbon-carbon double bond, but no carbon-carbon triple bonds, a total of n carbon atoms, three or more hydrogen atoms, and no heteroatoms. For example, a heteroatom-unsubstituted C₂-C₁₀-alkenyl has 2 to 10 carbon atoms. Heteroatom-unsubstituted alkenyl groups include: —CH═CH2, —CH═CHCH3, — CH═CHCH₂CH₃, —CH═CHCH₂CH₂CH₃, —CH═CHCH(CH₃)₂, —CH═CHCH(CH₂)₂, — CH₂CH═CH₂, —CH₂CH═CHCH₃, —CH₂CH═CHCH₂CH₃, —CH₂CH═CHCH₂CH₂CH₃, — CH2CH═CHCH(CH3)2, —CH2CH═CHCH(CH2)2, and —CH═CH—C6H5. The term “heteroatom-substituted Cn-alkenyl” refers to a radical having a single nonaromatic carbon atom as the point of attachment and at least one nonaromatic carbon-carbon double bond, but no carbon- carbon triple bonds, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, 0, 1, or more than one hydrogen atom, and at least one heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a heteroatom-substituted C₂-C₁₀-alkenyl has 2 to 10 carbon atoms. The groups, —CH═CHF, —CH═CHCl and —CH═CHBr, are examples of heteroatom-substituted alkenyl groups. Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS The term “heteroatom-unsubstituted C_n-alkynyl” refers to a radical having a linear or branched, cyclic or acyclic structure, further having at least one carbon-carbon triple bond, a total of n carbon atoms, at least one hydrogen atom, and no heteroatoms. For example, a heteroatom-unsubstituted C₂-C₁₀-alkynyl has 2 to 10 carbon atoms. The groups, —C≡CH, — C≡CCH3, and —C≡CC6H5 are examples of heteroatom-unsubstituted alkynyl groups. The term “heteroatom-substituted Cn-alkynyl” refers to a radical having a single nonaromatic carbon atom as the point of attachment and at least one carbon-carbon triple bond, further having a linear or branched, cyclic or acyclic structure, and having a total of n carbon atoms, 0, 1, or more than one hydrogen atom, and at least one heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a heteroatom-substituted C₂-C₁₀-alkynyl has 2 to 10 carbon atoms. The group, —C≡CSi(CH₃)₃, is an example of a heteroatom-substituted alkynyl group. The term “heteroatom-unsubstituted Cn-aryl” refers to a radical having a single carbon atom as a point of attachment, wherein the carbon atom is part of an aromatic ring structure containing only carbon atoms, further having a total of n carbon atoms, 5 or more hydrogen atoms, and no heteroatoms. For example, a heteroatom-unsubstituted C6-C10-aryl has 6 to 10 carbon atoms. Examples of heteroatom-unsubstituted aryl groups include phenyl, methylphenyl, (dimethyl)phenyl, —C₆H₄CH₂CH₃, —C₆H₄CH₂CH₂CH₃, —C₆H₄CH(CH₃)₂, —C₆H₄CH(CH₂)₂, —C6H3(CH3)CH2CH3, —C6H4CH═CH2, —C6H4CH═CHCH3, —C6H4C≡CH, —C6H4C≡CCH3, naphthyl, and the radical derived from biphenyl. The term “heteroatom-unsubstituted aryl” includes carbocyclic aryl groups, biaryl groups, and radicals derived from polycyclic fused hydrocarbons (PAHs). The term “heteroatom-substituted Cn-aryl” refers to a radical having either a single aromatic carbon atom or a single aromatic heteroatom as the point of attachment, further having a total of n carbon atoms, at least one hydrogen atom, and at least one heteroatom, further wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a heteroatom-unsubstituted C1-C10-heteroaryl has 1 to 10 carbon atoms. The term “heteroatom-substituted aryl” includes heteroaryl groups. It also includes those groups derived from the compounds: pyrrole, furan, thiophene, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Further examples of heteroatom-substituted aryl groups include the groups: —C₆H₄F, —C₆H₄Cl, — Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS C₆H₄Br, —C₆H₄I, —C₆H₄OH, —C₆H₄OCH₃, —C₆H₄OCH₂CH₃, —C₆H₄OCOCH₃, — C6H4OC6H5, —C6H4NH2, —C6H4NHCH3, —C6H4NHCH2CH3, —C6H4CH2Cl, —C6H4CH2Br, — C6H4CH2OH, —C6H4CH2OCOCH3, —C6H4CH2NH2, —C6H4N(CH3)2, —C6H4CH2CH2Cl, — C₆H₄CH₂CH₂OH, —C₆H₄CH₂CH₂OCOCH₃, —C₆H₄CH₂CH₂NH₂, —C₆H₄CH₂CH═CH₂, — C6H4CF3, —C6H4CN, —C6H4C≡CSi(CH3)3, —C6H4COH, —C6H4COCH3, —C6H4COCH2CH3, —C6H4COCH2CF3, —C6H4COC6H5, —C6H4CO2H, —C6H4CO2CH3, —C6H4CONH2, — C₆H₄CONHCH₃, —C₆H₄CON(CH₃)₂, furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, imidazoyl, quinolyl and indolyl. The term “heteroatom-unsubstituted Cn-aralkyl” refers to a radical having a single saturated carbon atom as the point of attachment, further having a total of n carbon atoms, wherein at least 6 of the carbon atoms form an aromatic ring structure containing only carbon atoms, 7 or more hydrogen atoms, and no heteroatoms. For example, a heteroatom-unsubstituted C7-C10- aralkyl has 7 to 10 carbon atoms. Examples of heteroatom-unsubstituted aralkyls include phenylmethyl(benzyl) and phenylethyl. The term “heteroatom-substituted C_n-aralkyl” refers to a radical having a single saturated carbon atom as the point of attachment, further having a total of n carbon atoms, 0, 1, or more than one hydrogen atom, and at least one heteroatom, wherein at least one of the carbon atoms is incorporated in an aromatic ring structure, further wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a heteroatom-substituted C2-C10-heteroaralkyl has 2 to 10 carbon atoms. The term “heteroatom-unsubstituted C_n-acyl” refers to a radical having a single carbon atom of a carbonyl group as the point of attachment, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, 1 or more hydrogen atoms, a total of one oxygen atom, and no additional heteroatoms. For example, a heteroatom-unsubstituted C₁-C₁₀-acyl has 1 to 10 carbon atoms. The groups, —COH, —COCH₃, —COCH₂CH₃, — COCH2CH2CH3, —COCH(CH3)2, —COCH(CH2)2, —COC6H5, —COC6H4CH3, — COC6H4CH2CH3, —COC6H4CH2CH2CH3, —COC6H4CH(CH3)2, —COC6H4CH(CH2)2, and — COC₆H₃(CH₃)₂, are examples of heteroatom-unsubstituted acyl groups. The term “heteroatom- substituted C_n-acyl” refers to a radical having a single carbon atom as the point of attachment, the carbon atom being part of a carbonyl group, further having a linear or branched, cyclic or acyclic Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS structure, further having a total of n carbon atoms, 0, 1, or more than one hydrogen atom, at least one additional heteroatom in addition to the oxygen of the carbonyl group, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a heteroatom-substituted C₁-C₁₀-acyl has 1 to 10 carbon atoms. The term heteroatom- substituted acyl includes carbamoyl, thiocarboxylate, and thiocarboxylic acid groups. The groups, —COCH2CF3, —CO2H, —CO2CH3, —CO2CH2CH3, —CO2CH2CH2CH3, —CO2CH(CH3)2, — CO₂CH(CH₂)₂, —CONH₂, —CONHCH₃, —CONHCH₂CH₃, —CONHCH₂CH₂CH₃, — CONHCH(CH₃)₂, —CONHCH(CH₂)₂, —CON(CH₃)₂, —CON(CH₂CH₃)CH₃, — CON(CH2CH3)2 and —CONHCH2CF3, are examples of heteroatom-substituted acyl groups. The term “heteroatom-unsubstituted C_n-alkoxy” refers to a group, having the structure —OR, in which R is a heteroatom-unsubstituted C_n-alkyl, as that term is defined above. Heteroatom-unsubstituted alkoxy groups include: —OCH3, —OCH2CH3, —OCH2CH2CH3, — OCH(CH3)2, and —OCH(CH2)2. The term “heteroatom-substituted Cn-alkoxy” refers to a group, having the structure —OR, in which R is a heteroatom-substituted C_n-alkyl, as that term is defined above. For example, —OCH2CF3 is a heteroatom-substituted alkoxy group. The term “heteroatom-unsubstituted Cn-alkenyloxy” refers to a group, having the structure —OR, in which R is a heteroatom-unsubstituted C_n-alkenyl, as that term is defined above. The term “heteroatom-substituted C_n-alkenyloxy” refers to a group, having the structure —OR, in which R is a heteroatom-substituted Cn-alkenyl, as that term is defined above. The term “heteroatom-unsubstituted C_n-alkynyloxy” refers to a group, having the structure —OR, in which R is a heteroatom-unsubstituted C_n-alkynyl, as that term is defined above. The term “heteroatom-substituted Cn-alkynyloxy” refers to a group, having the structure —OR, in which R is a heteroatom-substituted Cn-alkynyl, as that term is defined above. The term “heteroatom-unsubstituted C_n-aryloxy” refers to a group, having the structure —OAr, in which Ar is a heteroatom-unsubstituted Cn-aryl, as that term is defined above. An example of a heteroatom-unsubstituted aryloxy group is —OC6H5. The term “heteroatom- substituted C_n-aryloxy” refers to a group, having the structure —OAr, in which Ar is a heteroatom- substituted C_n-aryl, as that term is defined above. Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS The term “heteroatom-unsubstituted C_n-aralkyloxy” refers to a group, having the structure —ORAr, in which RAr is a heteroatom-unsubstituted Cn-aralkyl, as that term is defined above. The term “heteroatom-substituted Cn-aralkyloxy” refers to a group, having the structure — OR_Ar, in which R_Ar is a heteroatom-substituted C_n-aralkyl, as that term is defined above. The term “heteroatom-unsubstituted Cn-acyloxy” refers to a group, having the structure —OAc, in which Ac is a heteroatom-unsubstituted Cn-acyl, as that term is defined above. A heteroatom-unsubstituted acyloxy group includes alkylcarbonyloxy and arylcarbonyloxy groups. For example, —OCOCH₃ is an example of a heteroatom-unsubstituted acyloxy group. The term “heteroatom-substituted Cn-acyloxy” refers to a group, having the structure —OAc, in which Ac is a heteroatom-substituted C_n-acyl, as that term is defined above. A heteroatom-substituted acyloxy group includes alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and alkylthiocarbonyl groups. The term “heteroatom-unsubstituted Cn-alkylamino” refers to a radical having a single nitrogen atom as the point of attachment, further having one or two saturated carbon atoms attached to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, containing a total of n carbon atoms, all of which are nonaromatic, 4 or more hydrogen atoms, a total of 1 nitrogen atom, and no additional heteroatoms. For example, a heteroatom-unsubstituted C₁-C₁₀-alkylamino has 1 to 10 carbon atoms. The term “heteroatom-unsubstituted C_n-alkylamino” includes groups, having the structure —NHR, in which R is a heteroatom-unsubstituted Cn-alkyl, as that term is defined above. A heteroatom-unsubstituted alkylamino group would include — NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —NHCH(CH₂)₂, — NHCH2CH2CH2CH3, —NHCH(CH3)CH2CH3, —NHCH2CH(CH3)2, —NHC(CH3)3, —N(CH3)2, —N(CH3)CH2CH3, —N(CH2CH3)2, N-pyrrolidinyl, and N-piperidinyl. The term “heteroatom- substituted C_n-alkylamino” refers to a radical having a single nitrogen atom as the point of attachment, further having one or two saturated carbon atoms attached to the nitrogen atom, no carbon-carbon double or triple bonds, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, all of which are nonaromatic, 0, 1, or more than one hydrogen atom, and at least one additional heteroatom, that is, in addition to the nitrogen atom at the point of attachment, wherein each additional heteroatom is independently selected from the Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS group consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a heteroatom-substituted C₁-C₁₀- alkylamino has 1 to 10 carbon atoms. The term “heteroatom-substituted Cn-alkylamino” includes groups, having the structure —NHR, in which R is a heteroatom-substituted Cn-alkyl, as that term is defined above. The term “heteroatom-unsubstituted Cn-alkenylamino” refers to a radical having a single nitrogen atom as the point of attachment, further having one or two carbon atoms attached to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, containing at least one nonaromatic carbon-carbon double bond, a total of n carbon atoms, 4 or more hydrogen atoms, a total of one nitrogen atom, and no additional heteroatoms. For example, a heteroatom- unsubstituted C₂-C₁₀-alkenylamino has 2 to 10 carbon atoms. The term “heteroatom-unsubstituted C_n-alkenylamino” includes groups, having the structure —NHR, in which R is a heteroatom- unsubstituted Cn-alkenyl, as that term is defined above. Examples of heteroatom-unsubstituted Cn- alkenylamino groups also include dialkenylamino and alkyl(alkenyl)amino groups. The term “heteroatom-substituted C_n-alkenylamino” refers to a radical having a single nitrogen atom as the point of attachment and at least one nonaromatic carbon-carbon double bond, but no carbon-carbon triple bonds, further having one or two carbon atoms attached to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, 0, 1, or more than one hydrogen atom, and at least one additional heteroatom, that is, in addition to the nitrogen atom at the point of attachment, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a heteroatom- substituted C₂-C₁₀-alkenylamino has 2 to 10 carbon atoms. The term “heteroatom-substituted C_n- alkenylamino” includes groups, having the structure —NHR, in which R is a heteroatom- substituted Cn-alkenyl, as that term is defined above. The term “heteroatom-unsubstituted C_n-alkynylamino” refers to a radical having a single nitrogen atom as the point of attachment, further having one or two carbon atoms attached to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, containing at least one carbon-carbon triple bond, a total of n carbon atoms, at least one hydrogen atoms, a total of one nitrogen atom, and no additional heteroatoms. For example, a heteroatom-unsubstituted C₂- C10-alkynylamino has 2 to 10 carbon atoms. The term “heteroatom-unsubstituted Cn- Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS alkynylamino” includes groups, having the structure —NHR, in which R is a heteroatom- unsubstituted Cn-alkynyl, as that term is defined above. An alkynylamino group includes dialkynylamino and alkyl(alkynyl)amino groups. The term “heteroatom-substituted Cn- alkynylamino” refers to a radical having a single nitrogen atom as the point of attachment, further having one or two carbon atoms attached to the nitrogen atom, further having at least one nonaromatic carbon-carbon triple bond, further having a linear or branched, cyclic or acyclic structure, and further having a total of n carbon atoms, 0, 1, or more than one hydrogen atom, and at least one additional heteroatom, that is, in addition to the nitrogen atom at the point of attachment, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a heteroatom-substituted C₂-C₁₀- alkynylamino has 2 to 10 carbon atoms. The term “heteroatom-substituted C_n-alkynylamino” includes groups, having the structure —NHR, in which R is a heteroatom-substituted Cn-alkynyl, as that term is defined above. The term “heteroatom-unsubstituted C_n-arylamino” refers to a radical having a single nitrogen atom as the point of attachment, further having at least one aromatic ring structure attached to the nitrogen atom, wherein the aromatic ring structure contains only carbon atoms, further having a total of n carbon atoms, 6 or more hydrogen atoms, a total of one nitrogen atom, and no additional heteroatoms. For example, a heteroatom-unsubstituted C₆-C₁₀-arylamino has 6 to 10 carbon atoms. The term “heteroatom-unsubstituted Cn-arylamino” includes groups, having the structure —NHR, in which R is a heteroatom-unsubstituted C_n-aryl, as that term is defined above. A heteroatom-unsubstituted arylamino group includes diarylamino and alkyl(aryl)amino groups. The term “heteroatom-substituted Cn-arylamino” refers to a radical having a single nitrogen atom as the point of attachment, further having a total of n carbon atoms, at least one hydrogen atom, at least one additional heteroatoms, that is, in addition to the nitrogen atom at the point of attachment, wherein at least one of the carbon atoms is incorporated into one or more aromatic ring structures, further wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a heteroatom-substituted C₆-C₁₀-arylamino has 6 to 10 carbon atoms. The term “heteroatom-substituted C_n-arylamino” includes groups, having the structure —NHR, in which R is a heteroatom-substituted Cn-aryl, as Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS that term is defined above. A heteroatom-substituted arylamino group includes heteroarylamino groups. The term “heteroatom-unsubstituted Cn-aralkylamino” refers to a radical having a single nitrogen atom as the point of attachment, further having one or two saturated carbon atoms attached to the nitrogen atom, further having a total of n carbon atoms, wherein at least 6 of the carbon atoms form an aromatic ring structure containing only carbon atoms, 8 or more hydrogen atoms, a total of one nitrogen atom, and no additional heteroatoms. For example, a heteroatom- unsubstituted C₇-C₁₀-aralkylamino has 7 to 10 carbon atoms. The term “heteroatom-unsubstituted Cn-aralkylamino” includes groups, having the structure —NHR, in which R is a heteroatom- unsubstituted C_n-aralkyl, as that term is defined above. An aralkylamino group includes diaralkylamino groups. The term “heteroatom-substituted C_n-aralkylamino” refers to a radical having a single nitrogen atom as the point of attachment, further having at least one or two saturated carbon atoms attached to the nitrogen atom, further having a total of n carbon atoms, 0, 1, or more than one hydrogen atom, at least one additional heteroatom, that is, in addition to the nitrogen atom at the point of attachment, wherein at least one of the carbon atom incorporated into an aromatic ring, further wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a heteroatom-substituted C₇-C₁₀- aralkylamino has 7 to 10 carbon atoms. The term “heteroatom-substituted C_n-aralkylamino” includes groups, having the structure —NHR, in which R is a heteroatom-substituted Cn-aralkyl, as that term is defined above. The term “heteroatom-substituted aralkylamino” includes the term “heteroaralkylamino.” The term amido includes N-alkyl-amido, N-aryl-amido, N-aralkyl-amido, acylamino, alkylcarbonylamino, arylcarbonylamino, and ureido groups. The group, —NHCOCH3, is an example of a heteroatom-unsubstituted amido group. The term “heteroatom-unsubstituted Cn-amido” refers to a radical having a single nitrogen atom as the point of attachment, further having a carbonyl group attached via its carbon atom to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, 1 or more hydrogen atoms, a total of one oxygen atom, a total of one nitrogen atom, and no additional heteroatoms. For example, a heteroatom-unsubstituted C1-C10-amido has 1 to 10 carbon atoms. Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS The term “heteroatom-unsubstituted C_n-amido” includes groups, having the structure —NHR, in which R is a heteroatom-unsubstituted Cn-acyl, as that term is defined above. The term “heteroatom-substituted Cn-amido” refers to a radical having a single nitrogen atom as the point of attachment, further having a carbonyl group attached via its carbon atom to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, further having a total of n aromatic or nonaromatic carbon atoms, 0, 1, or more than one hydrogen atom, at least one additional heteroatom in addition to the oxygen of the carbonyl group and the nitrogen atom at the point of attachment, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a heteroatom-substituted C1-C10-amido has 1 to 10 carbon atoms. The term “heteroatom-substituted C_n-amido” includes groups, having the structure —NHR, in which R is a heteroatom-unsubstituted C_n-acyl, as that term is defined above. The group, —NHCO2CH3, is an example of a heteroatom-substituted amido group. In addition, atoms making up the compounds of the present invention are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³C and ¹⁴C. Similarly, it is contemplated that one or more carbon atom(s) of a compound of the present invention may be replaced by a silicon atom(s). Similarly, it is contemplated that one or more oxygen atom(s) of a compound of the present invention may be replaced by a sulfur or a selenium atom(s). Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to the atom. 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.” Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects. Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS 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. The term “effective,” as that term is used in the specification and/or claims, means adequate to accomplish a desired, expected, or intended result. The term “hydrate” when used as a modifier to a compound means that the compound has less than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) water molecules associated with each compound molecule, such as in solid forms of the compound. As used herein, the term “IC50” refers to an inhibitory dose which is 50% of the maximum response obtained. 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. As used herein, the term “patient” or “subject” refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human subjects are adults, juveniles, infants and fetuses. “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use. “Pharmaceutically acceptable salts” means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS 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). As used herein, “predominantly one enantiomer” means that a compound contains at least about 85% of one enantiomer, or more preferably at least about 90% of one enantiomer, or even more preferably at least about 95% of one enantiomer, or most preferably at least about 99% of one enantiomer. Similarly, the phrase “substantially free from other optical isomers” means that the composition contains at most about 15% of another enantiomer or diastereomer, more preferably at most about 10% of another enantiomer or diastereomer, even more preferably at most Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS about 5% of another enantiomer or diastereomer, and most preferably at most about 1% of another enantiomer or diastereomer. “Prevention” or “preventing” includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and/or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease. The term “saturated” when referring to an atom means that the atom is connected to other atoms only by means of single bonds. 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 minor images of each other, like left and right hands. “Diastereomers” are stereoisomers of a given compound that are not enantiomers. “Therapeutically effective amount” or “pharmaceutically effective amount” means that amount which, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease. “Treatment” or “treating” includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and/or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and/or symptomatology), and/or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease. Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS As used herein, the term “water soluble” means that the compound dissolves in water at least to the extent of 0.010 mole/liter or is classified as soluble according to literature precedence. Other abbreviations used herein are as follows: DMSO, dimethyl sulfoxide; NO, nitric oxide; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; NGF, nerve growth factor; IBMX, isobutylmethylxanthine; FBS, fetal bovine serum; GPDH, glycerol 3-phosphate dehydrogenase; RXR, retinoid X receptor; TGF-β, transforming growth factor-β; IFNγ or IFN-γ, interferon-γ; LPS, bacterial endotoxic lipopolysaccharide; TNFα or TNF-α, tumor necrosis factor- α; IL-1β, interleukin-1β; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MTBE, methyl- tert-butylether; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; TCA, trichloroacetic acid; HO-1, inducible heme oxygenase. The above definitions supersede any conflicting definition in any of the reference that is incorporated by reference herein. DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS Figure 1 – Novel synthesis protocol for synthesis of CDDO-EA. The CDDO-EA analog possesses modifications at C28. The arrows (1-5) indicate the synthesis steps that were modified to provide a reduced ratio of catalyst (HBr) equivalent per substrate equivalent, in providing for synthesis of Compound #6 (See Figure 6). Figures 2A-2B – High purity and correct mass of synthesized CDDO-EA (Figure 2A). HPLC chromatogram of synthesized CDDO-EA (Figure 2B). The experimental APCI-MS spectrum of synthesized CDDO-EA and expected spectrum of known CDDO-EA. Figure 3 – NMR – spectrum of crude mixture (before purification) of Compound 6. analysis of combined preparations of Compound #6 (the brominated compound, bardoxolone methyl (CDDO-Me) before purification. (one preparation using a reduced catalyst (HBr) amount (about less than 5% compared to literature reports) and the second preparation synthesized with an even lesser amount of catalyst). For comparison, the spectrum of the brominated product previously obtained was stacked. The spectra evidence that a preparation having a more Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS homogenous Compound #6 was obtained according the present chemical synthesis. Figure 4 –NMR spectrum of Compound #6: Top: after purification, bottom: before purification (Also, see Figure 3). Figure 5 – Chemical Synthesis of CDDO-EA. Synthesis of CDDO-Me from a brominated Compound #6 was provided using a very low amount of catalyst (less than about 5% or less than about 1% the required catalyst reported in the literature) (0.025 eq HBr). A unique ratio of catalyst and Br₂ (HBr (0.025 eq.) + Br₂ (2.4 eq)), is found in the present synthesis protocols to successfully provide the non-alpha brominated precursor Compound #6 . This Compound #6 is then further processed to intermediate Compound #7 (CDDO) via CuCN, KI/DMF. The intermediate product Compound #7 (CDDO-Me) is then further processed (LiI) to provide Compound #8 (CDDO). The Compound #8, (CDDO), is then further processed ((COCl)₂) to synthesize the intermediate Compound #9. The Compound #9 may then be further processed (EtNH2) to provide Compound #10 (CDDO-EA). Figure 6 – Chemical synthesis of CDDO-EA (alternative method – modified from that described by Fu et al. (2013). Chemical synthesis of CDDO-EA according to Fu et al., (2013) was unsuccessful. Changes in the amount of catalyst were required in order to avoid production of an over-brominated Compound #11, and to instead provide the properly brominated Compound #6. This was accomplished by modifying the Fu et al. to change the ratio of HBr (0.44 eq) + Br₂ (2.4 eq), to HBr (0.025 eq.) + Br2 (2.4 eq). The properly mono-brominated intermediate Compound #6 could then be processed to provide Compound #7 (CDDO-Me), as depicted in the Figure, and then Compound #7 was further processed to synthesize the appropriate Compound #8 (CDDO), using lithium iodide to transform the methyl ester to carboxylic acid. The appropriate Compound #8, (CDDO), was then further processed to synthesize the appropriate Compound #9. The Compound #9 was then further processed to synthesize Compound #10 (CDDO-EA). Figure 7 – The first batch of CDDO-EA (Batch #1) and the second batch of CDDO- EA (Batch #2) were tested for its biological property of anti-inflammatory activity. Anti- inflammatory activity was assessed using the mouse macrophage cell line RAW264.7. RAW264.7 Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS macrophages were pre-treated with 400 μM CDDO-EA for 1 hour then stimulated with 100 ng/ml of lipopolysaccharide (LPS) for 6 hr. Supernatants were collected, and an enzyme linked immunoassay (ELISA) was performed to detect the pro-inflammatory protein, monocyte chemotactic protein-1 (MCP-1). The macrophages were also treated with LPS alone or with CDDO-EA alone. A control (no treatment) group was also included in the study. The second batch CDDO-EA blocked the LPS-induced production of MCP-1 in RAW264.7 macrophages. This suppression of MCP-1 production by the second batch CDDO-EA is similar to that observed for the first batch of CDDO-EA. These findings show that the second batch of CDDO-EA has anti- inflammatory properties similar to the first batch of CDDO-EA, and that the synthesis procedure provides consistent, repeatable product that demonstrate predictable and consistent biological activity. DETAILED DESCRIPTION OF THE INVENTION The following examples present a description of various specific aspects of the intended invention, and are not presented to limit the intended invention in any way. In the following description, for purposes of explanation, specific numbers, materials and configurations are set forth in order to provide a thorough understanding of the invention. It will be apparent, however, to one having ordinary skill in the art that the invention may be practiced without these specific details. In some instances, well-known features may be omitted or simplified so as not to obscure the present invention. Furthermore, reference in the specification to phrases such as “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. The appearances of phrases such as “in one embodiment” in various places in the specification are not necessarily all referring to the same embodiment. Example 1 – Chemical Synthesis of Compound #6 from Oleanolic Acid In the present chemical synthesis strategy for Compound #6, the bromination reaction was run with both epoxide and ketone compounds using a much reduced amount of the acid catalyst (about 50 to 100 times less catalyst eq (HBr catalyst) to substrate equivalent), than Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS used in other synthesis methods for CDDO-Me (Fu et al., (2013)). In addition, while the prior methods required at least 24 hours for chemical synthesis of bardoxolone methyl (CDDO-Me), the presently disclosed chemical synthesis pathway provides for a much shorter synthesis time of about 2 hours to provide synthesis of Compound #6 (less than 2 hours). Chemical conversion from Oleanolic acid to Compound #6 may take place either through the use of substrates comprising both or either of an epoxide compound or a ketone compound. A mixture of the epoxide compound (Compound #4) and the ketone compound (Compound #5) was brominated to provide an intermediate brominated compound (Compound #6). Compound #6 was substantially free of α-carbon substitutions (bromine). The series of the following steps, to be performed in sequence, was created in the present example for successful preparation of Compound #6. Step 1 - Synthesis of methyl (4aS,6aS,6bR,8aR,10S,12aR,12bR,14bS)-10-hydroxy- 2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b- octadecahydropicene-4a(2H)-carboxylate (2): K2CO3 (30.0 g, 21.7 mmol, 3.0 eq) was added potion wise to a stirred solution of oleanolic acid (1) (33.0 g, 72.3 mmol, 1.0 eq) in dimethyl formamide (300 ml). The reaction mixture was cooled down to 0 ˚C. Iodomethane (11.3 g, 4.95 ml, 79.5 mmol, 1.1 eq) was added dropwise to the suspension mixture. After the completion of addition, the reaction was warmed up to room temperature and stirred overnight. After the completion of the reaction, dimethyl formamide was removed by distillation. The resulting solid was dissolved in 1 L of dichloromethane. The solution was washed with water (300 ml) four times and sat. NaCl aq. The organic layer was dried over Na2SO4, and the solvent was evaporated. 32.5 g of crude product 2 was obtained (96%) as a white solid, which was used for the next step without further purifications. This step is shown in the following Diagram 1: Diagram 1 Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS - 2,2,6a,6b,9,9,12a-heptamethyl-10-oxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b- hexadecahydropicene-4a(2H)-carboxylate (3): Ester 2 (29.0 g, 61.6 mmol, 1.0 eq) obtained above was dissolved in anhydrous dimethyl sulfoxide (700 ml) at r.t. Fluorobenzene (12.3 ml) and iodoxybenzoic acid (51.7 g, 184.8 mmol, 3.0 eq) which was freshly prepared by the literature procedure² were added to the solution. The resulting suspension was heated to 85˚ C under nitrogen and stirred for 16 hours. The reaction was cooled down and quenched with 20% sodium thiosulfate aq. (500 ml) and extracted with dichloromethane four times. The combined organic extracts were washed with sat.NaHCO3 aq. and sat. NaCl aq. And then dried over Na2SO4. The solvent was removed to give the crude product 3 as yellowish solid. Purification by column chromatography (hexane:ethyl acetate = 80:20) afforded 21.4 g of white foamy Compound #3 (75%). This Step 2 is shown in the following Diagram 2: Diagram 2 Step 3 - Synthesis of methyl (4aR,6aR,6bR,10aR,12aR,12bS,14aS)- 3,3,6b,10,10,12a,12b-heptamethyl-9-oxo-2,3,4,4a,6,6a,6b,9,10,10a,11,12,12a,12b,13,14- hexadecahydro-1H-piceno[12b,13-b]oxirene-14a(5aH)-carboxylate (4) + methyl Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS (4aS,6aR,6bR,8aR,12aR,12bR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo- 1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b-octadecahydropicene-4a(2H)-carboxylate (5): Substrates: Enone 3 (21.4 g, 45.8 mmol, 1.0 equiv) was dissolved in methylene chloride (100 ml) and solution was cooled down to 0 ˚C. m- Chloroperbenzoic acid (14.7 grams, 70% in water, 59.5 mmol, 1.3 eq) was added potion wise at 0 ˚C. After the completion of addition, the reaction was warmed up to room temperature and kept stirring for overnight. The reaction mixture was diluted with methylene chloride (300 ml), and the resulting mixture was washed with 20% aqueous sodium thiosulfate three times, 10% potassium carbonate three times, and sat. NaCl aq. The organics were dried over Na₂SO₄ and the solvent was evaporated to afford 21.7 g crude mixture of 4 and 5 as white solid (98%), which was used directly for the next step without further purifications. This Step 3 is shown in the following Diagram 3: Diagram 3 Step 4 - Synthesis of methyl (4aS,6aR,6bS,8aR,12aR,14bS)-11-bromo- 2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b- hexadecahydropicene-4a(2H)-carboxylate (6): The solution of 4 and 5 (4.00 g, 8.30 mmol, 1.0 eq) in acetic acid (18 ml) was added dropwise 47% HBr aq. (0.025 ml, 0.22 mmol, 0.026 eq) at room temperature. The reaction mixture was then heated to 35 ˚C, and Br2 (2.13 ml, 41.3 mmol, 5.0 eq) was added dropwise. The resulting reaction mixture was kept stirring for 1.5 h at the same temperature. Acetic acid was partially Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS removed under vacuum. The residue was then quenched with 20% aqueous sodium thiosulfate, and extracted with dichloromethane four times. The combined organic extracts were washed with saturated sodium bicarbonate twice, brine, and dried over Na2SO4. The solvent was evaporated, and column chromatography (hexanes: ethyl acetate= 80:20) gave 3.46 g (75%) of bromo enone 6 as yellow solid. This Step 4 is shown in the following Diagram 4: Diagram 4 The product at each step was purified and the structure was confirmed by NMR spectroscopy. In contrast to prior art methods, including those of Fu et al., (2013), the intermediate product Compound #6, was successfully obtained according to the present synthesis steps with the lower acid catalyst equivalent used (HBr). The present synthesis method avoids the production of an unsatisfactory over-bromination Compound #11 (See Figure 6). The successful production of Compound #6 was achieved by reducing the equivalent amount of catalyst (HBr) in the reaction. The catalyst equivalent described in the Fu et al. (HBr, 0.44 eq.) process was several fold greater (about 20-fold to 200-fold greater/catalyst equivalent) than the catalyst (HBr) equivalent employed in the presently disclosed process (HBr, 0.025 eq) . The reduction in the equivalent catalyst amount was critical to obtaining the desired and correctly brominated product Compound #6 in reacting the starting mixture of substrates (Compounds #4 and #5), having the appropriate bromine substitutions at the appropriate bromination sites of the compound, and eliminating product having α-bromination (See Figure 6). Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS The chemical synthesis method process used included the steps as illustrated in Figure 5, and as provided in the following description: 1. To the solution of Compounds #4 and #5 (4.00 g, 8.29 mmol, 1.0 eq) in acetic acid (18 ml), 47% HBr aq (0.025 ml, 0.22 mmol, 0.026 eq) was added dropwise at room temperature. 2. The reaction mixture was then heated to 35 ˚C, and Br2 (2.13 ml, 41.3 mmol, 5.0 eq) was added dropwise. 3. The resulting reaction mixture was kept stirring for 1.5 h. 4. After completion of the reaction, the acid was removed under a partial vacuum to provide a residue. 5. The residue was then quenched with 20% aqueous sodium thiosulfate, and extracted with methylene chloride four times. The organic extracts were then combined. 6. Combined organic extracts were washed with saturated sodium bicarbonate twice, brine, and dried over Na2SO4. Collect solvent. 7. The solvent was evaporated, and column chromatography (Hex:AcOEt= 80:20) of the material provided for obtaining Compound #6 as yellow solid. Example 2 - Novel Syntheses of CDDO-Me – Elimination/Reduction of Over Reacted Bromination Product Formation with Reduced eq. of Acid Catalyst (HBr) The present synthesis method provides a multi-step method (to be performed in sequence), for preparing a high purity preparation of Compound #7 (CDDO-Me). Beginning from the Step 6 Compound #6 from Example 1, the next step is to be performed in sequence to provide CDDO-Me (Compound #7). Reacting Compound #6 with CuCN, KI in DMF to provide Compound #7 (CDDO- Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS Me). Example 3 – Novel Synthesis of CDDO Transforming the methyl ester of CDDO-Me to a carboxylic acid (CDDO) by adding lithium iodide. The CDDO (Compound #8) produced according to this method uses lithium iodide. Beginning with the CDDO-Me compound prepared according to Example 2, the following steps in sequence will be performed to provide the CDDO Compound #8. Converting the CDDO-Me (Compound #7) to CDDO (Compound #8) with lithium iodide. The significant reduction in the equivalent acid catalyst (HBr) required in the present synthesis scheme, the greater degree of specificity of reaction products to provide the appropriately brominated Compound #6, the vastly shorted processing time (2 hours), among other things, provides a commercially-scalable technique for the commercial manufacture of high purity preparations comprising CDDO-Me (Compound #7). Consequently, these CDDO-Me preparations may be implemented into further synthesis steps to produce the CDDO (Compound #8). From Compound #8, CDDO, virtually any desired CDDO, CDDO analog, CDDO derivative, or any combination thereof may be synthesized. (e.g., CDDO-EA) having the desired and appropriately substituted, structure. A flow-chart of the chemical synthesis appears in Figure 5. Figures 3 and 4 provide the spectral analysis of the brominated product (#6) obtained according to the present synthesis techniques, employing less than 1% of the equivalent of the acidic catalyst (HBr) described for a similar process. Example 4 – Synthesis of CDDO-EA (10) from Oleanolic Acid (Compound #1) The present example provides a detailed description of one particular synthesis method having multiple sequential steps, for preparing a preparation of CDDO-EA of high purity, Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS from oleanolic acid. The intermediate Compound #6 is synthesized from the substrate of a mixture of Compounds #4 and #5 within about 2 hours or less (1.5 hours). In summary of the prior examples 1, 2, and 3, the CDDO-Me (Compound #7), having the desired C₂₈ methyl substituted structure, was reacted with lithium iodide to transform the methyl ester to carboxylic acid. This resulted in the formation of CDDO (Compound #8). The CDDO (Compound #8) was then reacted to form the Compound #9, and ultimately processed to synthesize the Compound #10, CDDO-EA. The complete synthesis steps for CDDO-EA from oleanolic acid are stated as follows: Step 1 - Synthesis of methyl (4aS,6aS,6bR,8aR,10S,12aR,12bR,14bS)-10-hydroxy- 2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b- octadecahydropicene-4a(2H)-carboxylate (2): K2CO3 (30.0 g, 21.7 mmol, 3.0 eq) was added potion wise to a stirred solution of oleanolic acid (1) (33.0 g, 72.3 mmol, 1.0 eq) in dimethyl formamide (300 ml). The reaction mixture was cooled down to 0 ˚C. Iodomethane (11.3 g, 4.95 ml, 79.5 mmol, 1.1 eq) was added dropwise to the suspension mixture. After the completion of addition, the reaction was warmed up to room temperature and stirred overnight. After the completion of the reaction, dimethyl formamide was removed by distillation. The resulting solid was dissolved in 1 L of dichloromethane. The solution was washed with water (300 ml) four times and sat. NaCl aq. The organic layer was dried over Na2SO4, and the solvent was evaporated. 32.5 g of crude product 2 was obtained (96%) as a white solid, which was used for the next step without further purifications. This step is shown in the following Diagram 1: Diagram 1 Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS - 2,2,6a,6b,9,9,12a-heptamethyl-10-oxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b- hexadecahydropicene-4a(2H)-carboxylate (3): Ester 2 (29.0 g, 61.6 mmol, 1.0 eq) obtained above was dissolved in anhydrous dimethyl sulfoxide (700 ml) at r.t. Fluorobenzene (12.3 ml) and iodoxybenzoic acid (51.7 g, 184.8 mmol, 3.0 eq) which was freshly prepared by the literature procedure² were added to the solution. The resulting suspension was heated up to 85 ˚C under nitrogen and stirred for 16 hours. The reaction was cooled down and quenched with 20% sodium thiosulfate aq. (500 ml) and extracted with dichloromethane four times. The combined organic extracts were washed with sat.NaHCO3 aq. and sat. NaCl aq. And then dried over Na2SO4. The solvent was removed to give the crude product 3 as yellowish solid. Purification by column chromatography (hexane:ethyl acetate = 80:20) afforded 21.4 g of white foamy Compound #3 (75%). This Step 2 is shown in the following Diagram 2: Diagram 2 Step 3 - Synthesis of methyl (4aR,6aR,6bR,10aR,12aR,12bS,14aS)- Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS 3,3,6b,10,10,12a,12b-heptamethyl-9-oxo-2,3,4,4a,6,6a,6b,9,10,10a,11,12,12a,12b,13,14- hexadecahydro-1H-piceno[12b,13-b]oxirene-14a(5aH)-carboxylate (4) + methyl (4aS,6aR,6bR,8aR,12aR,12bR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo- 1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b-octadecahydropicene-4a(2H)-carboxylate (5): Substrates Enone 3 (21.4 g, 45.8 mmol, 1.0 eq.) was dissolved in methylene chloride (100 ml) and solution was cooled down to 0 ˚C. m- Chloroperbenzoic acid (14.7 grams, 70% in water, 59.5 mmol, 1.3 eq) was added potion wise at 0 ˚C. After the completion of addition, the reaction was warmed up to room temperature and kept stirring for overnight. The reaction mixture was diluted with methylene chloride (300 ml), and the resulting mixture was washed with 20% aqueous sodium thiosulfate three times, 10% potassium carbonate three times, and sat. NaCl aq. The organics were dried over Na2SO4 and the solvent was evaporated to afford 21.7 g crude mixture of 4 and 5 as white solid (98%), which was used directly for the next step without further purifications. This Step 3 is shown in the following Diagram 3: Diagram 3 Step 4 – Synthesis of methyl (4aS,6aR,6bS,8aR,12aR,14bS)-11-bromo- 2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b- hexadecahydropicene-4a(2H)-carboxylate (6): To the solution of Compound #4 and Compound #5 (substrates) (4.00 g, 8.30 mmol, 1.0 eq) in acetic acid (18 ml), a 47% HBr aq. (0.025 ml, 0.22 mmol, 0.026 eq) was added dropwise at room temperature, to form a reaction mixture. The reaction mixture was then heated to 35˚C, Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS and Br₂ (2.13 ml, 41.3 mmol, 5.0 eq) was added dropwise. The resulting reaction mixture was kept stirring for 1.5 h at the same temperature. Acetic acid was partially removed under vacuum. The residue was then quenched with 20% aqueous sodium thiosulfate, and extracted with dichloromethane four times. The combined organic extracts were washed with saturated sodium bicarbonate twice, brine, and dried over Na2SO4. The solvent was evaporated, and column chromatography (hexanes: ethyl acetate= 80:20) gave 3.46 g (75%) of bromo enone 6 as a yellow solid. This Step 4 is shown in the following Diagram 4: Diagram 4 1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicene-4a(2H)-carboxylate(7): Bromo enone 6 (4.98 g mmol, 8.90 mmol 1.0 eq) is dissolved in anhydrous dimethyl formamide (50 ml) under nitrogen at room temperature. To the stirred solution, copper (I) cyanide (1.72 g, 9.79 mmol, 1.1 eq) and potassium iodide (566 mg, 1.78 mmol, 0.20 eq) were added, and the resulting reaction mixture was heated up to 120 ˚C and stirred for 24 h. The suspension was cooled to room temperature, quenched with water (200 ml), and diluted with ethyl acetate (500 ml). Formed cupper salts were removed by filtration before extraction. The organic phase was washed with saturated NaHCO3 twice and sat. NaCl aq., and dried over Na2SO4. After evaporated the solvent, and column chromatography (hexanes: ethylacetate =75:25) to give 3.82 g (85%) of bardoxolone methyl (7) as a yellowish solid. Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS This Step 5 is shown in the following Diagram 5. Diagram 5     Step 6 – Synthesis of bardoxolone (CDDO), (4aS,6aR,6bS,8aR,12aS,14bS)-11- cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b- hexadecahydropicene-4a(2H)-carboxylic acid (8)³. CDDO-Me (7) (3.82g, 7.55 mmol, 1 eq) and dry LiI (18.71 g, 140 mmol, 18.5 eq) in dry DMF (10 ml) was heated under reflux for 4 h. The solution is quenched with 5% HCl aq. The mixture was extracted with EtOAc three times. The organic extract was washed with water three times, sat. NaCl aq., and dried over Na₂SO₄. The solvent was evaporated. Purification was by column chromatography (dichloromethane only to dichloromethane: methanol = 90:10) to give 3.56 g (96%) of CDDO (8). This Step 6 is shown in the following Diagram 6. Diagram 6

Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS Step 7 – Synthesis of 4aS,6aR,6bS,8aR,12aS,14bS)-11-cyano-2,2,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicene- 4a(2H)-carbonyl chloride (9)⁴: A mixture of CDDO (8) (3.0 g, 6.1 mmol) and oxalyl chloride (8.73 g, 5.9 ml, 68.8 mmlol, 11.3 eq) in anhydrous dichloromethane (60 ml) was stirred at room temperature overnight. The solvent was evaporated, and the residue was co-evaporated with benzene three times. 3.66 g (99%) of crude Compound #9 was obtained. The Compound #9 was used for next step without further purification. This Step 7 is shown in the following Diagram 7: Diagram 7   Step 8 – Synthesis of CDDO-EA, (4aS,6aR,6bS,8aR,12aS,14bS)-11-cyano-N-ethyl- 2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b- hexadecahydropicene-4a(2H)-carboxamide (10). The solution of Compound #9 (3.36 g, 6.59 mmol, 1.0 eq) in benzene (60 ml) was added to a solution of ethylamine hydrochloride (1.18 g, 14.4 mmol, 2.2 eq) and NaHCO3 (3.0 g, 35.9 mmol, 5.5 eq) in water (60 ml). The mixture was stirred at room temperature overnight. The layers were separated, and the aqueous layer was extracted with benzene (60 ml). The combined organic layers were washed with sat. NaHCO3 aq, water, and sat. NaCl aq, and dried over Na2SO4. The solvent was evaporated. Purification was performed by column chromatography (dichloromethane only to dichloromethane: methanol = 90:10) to give 2.45 g (72%) of CDDO-EA (Compound #10). Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS This Step 8 is shown in the following Diagram 8: Diagram 8 Example 5 – Compound #6 The present example outlines some of the advantages of the present chemical synthesis methods. Previous methods for synthesis of a brominated product (Compound #6) included a relatively high equivalent amount of the catalyst (in this case, Br₂) (Fu et al., 2013, Organic Letters, 15 (7): 1622-1625, the substrates (Compounds #4 and #5, 0.44 HBr eq). In contrast, the present synthesis provides for complete reaction of substrate to the brominated compound with a much reduced amount of catalyst, HBr, of 0.025 eq. Thus, the required catalyst for the reaction as provided in the present synthesis technique is significantly reduced, by at least 50-fold, 100-fold, or even 200-fold. HBr: Br₂ = 1: 50 to 1:200, ratio of HBr to Br₂. The ratio of the catalyst to the ratio of the substrate (Compound 4+5) is described as: HBr = 0.5 – 3 mole % catalyst. Therefore HBr is provided at a 0.005 to 0.03 equivalent. This is a much lower catalyst amount than the reported eq. mole % catalyst for bromination reported in Fu et al. (2013), where the HBr mole % catalyst is 0.44 eq. Ratio of HBr (catalyst) eq to Br2 (reagent): Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS The present synthesis provides for a reaction of substrate materials 5 and 6 with about 0.025 eq HBr (catalyst) and about 2.4 eq Br2 (reagent). The synthesis reaction in Fu et al. provides for a reaction of substrate materials with about 0.44 eq HBr and about 2.4 eq Br2. The “ratio” of HBr to Br₂ that was described in Fu et al., requires much more catalyst (HBr) than the synthesis reaction of the present methods. Expressed as a “ratio” of HBr: Br2 (catalyst:reagent) “equivalents”, Fu provides for a reaction with about 1 equivalent HBr and about 5.5 equivalent Br₂. In contrast, the present synthesis provides for a ratio of about 1 equivalent HBr: 90.4 equivalent Br₂ (reagent). The present synthesis method may be described as requiring a ratio of about 1 equivalent HBr with about 50 equivalent Br₂, or about 1 equivalent HBr with about 150 (or 200) equivalent Br₂, for the reaction of substrate to produce Compound #6. The present process requires at least 50-fold less, or at least 100-fold less, or even 200 fold less acid catalyst (HBr) than the comparable synthesis reaction for Compound #6 described in Fu et al. (2013). In the present synthesis method, HBr is used as 0.5 – 3 mole % catalyst.” In other words, HBr is used at a 0.005 to 0.03 equivalent. Thus, the present synthesis for Compound #6 provides for a reaction that requires proportionately much less catalyst per substrate. In addition, upon recalculation of the Fu et al. prior synthesis method, the procedure recited an amount of reagent, Br2, of (5.8 ml, 0.05 mol, 2.4 eq). The accurate molecular weight of Br2 is 159.8, and the density is 3.10g/ml. 5.8 ml = 17.98 g = 0.113 mol. Therefore, while Fu et al. states a calculation of 0.05 mmol = 2.4 eq Br₂, this was an error in calculation, and was instead 5.4 eq. of reagent Br2. In contrast, the present reaction provides for use of reagent Br2 at an equivalent of 2.4 eq. Therefore, this further distinction may be made between the present chemical synthesis protocol and that of the prior art. The reaction to provide production of Compound #6 from the substrate is accomplished in the present synthesis in less than 2 hours. (about 1.5 hours). In contrast, the synthesis for bardoxolone methyl (CDDO-Me) in Fu et al. requires 24 hours. As the production of Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS the Compound #6 is a rate-limiting step in production of CDDO-Me, CDDO-EA and CDDO, it is significant that the present chemical synthesis techniques have reduced the overall time to product production by at least 20 hours, or about 10 to about 14-fold. Example 6 – Synthesis Procedure for CDDO-EA Batch #1 The present example details a use of the synthesis procedure in preparation of a first batch of CDDO-EA (“Batch #1). The present example demonstrates the utility of the herein described chemical synthesis technique for providing repeatable and consistent production of the desired CDDO product, including CDDO-EA, CDDO-Me and CDDO. The overall yield of CDDO-EA observed in the present Batch #1 scheme was about 31%. This was accomplished in the following 8-step procedure. Step 1: Synthesis of methyl (4aS,6aS,6bR,8aR,10S,12aR,12bR,14bS)-10- hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b- octadecahydropicene-4a(2H)-carboxylate (2): K₂CO₃ (30.0 g, 21.7 mmol, 3.0 eq) was added potion wise to a stirred solution of oleanolic acid (1) (33.0 g, 72.3 mmol, 1.0 eq) in dimethyl formamide (300 ml). The reaction mixture was cooled down to 0 ˚C. Iodomethane (11.3 g, 4.95 ml, 79.5 mmol, 1.1 eq) was added dropwise to the suspension mixture. After the completion of addition, the reaction was warmed up to room temperature and stirred overnight. After the completion of the reaction, dimethyl formamide was removed by distillation. The resulting solid was dissolved in 1 L of dichloromethane. The solution was washed with water (300 ml) four times and sat. NaCl aq. The Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS organic layer was dried over Na₂SO₄, and the solvent was evaporated. 32.5 g of crude product 2 was obtained (96%) as a white solid, which was used for the next step without further purifications. Step 2: Synthesis of methyl (4aS,6aS,6bR,8aR,12aR,12bR,14bS)- 2,2,6a,6b,9,9,12a-heptamethyl-10-oxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b- hexadecahydropicene-4a(2H)-carboxylate (3): Ester 2 (29.0 g, 61.6 mmol, 1.0 eq) obtained above was dissolved in anhydrous dimethyl sulfoxide (700 ml) at room temperature. Fluorobenzene (12.3 ml) and iodoxybenzoic acid (51.7 g, 184.8 mmol, 3.0 eq) which was freshly prepared by the literature procedure2 were added to the solution. The resulting suspension was heated up to 85 ˚C under nitrogen and stirred for 16 hours. The reaction was cooled down and quenched with 20% sodium thiosulfate aq. (500 ml) and extracted with dichloromethane four times. The combined organic extracts were washed with sat.NaHCO₃ aq. and sat. NaCl aq. And then dried over Na₂SO₄. The solvent was removed to give the crude product 3 as yellowish solid. Purification by column chromatography (hexanes: ethyl acetate = 80:20) afforded 21.4 g of white foamy Compound #3 (75%). Step 3: Synthesis of methyl (4aR,6aR,6bR,10aR,12aR,12bS,14aS)- 3,3,6b,10,10,12a,12b-heptamethyl-9-oxo-2,3,4,4a,6,6a,6b,9,10,10a,11,12,12a,12b,13,14- hexadecahydro-1H-piceno[12b,13-b]oxirene-14a(5aH)-carboxylate (4) + methyl (4aS,6aR,6bR,8aR,12aR,12bR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo- 1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b-octadecahydropicene-4a(2H)-carboxylate (5): Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS (100 ml) and the solution was cooled down to 0 ˚C. m- Chloroperbenzoic acid (14.7 grams, 70% in water, 59.5 mmol, 1.3 eq) was added potion wise at 0 ˚C. After the completion of this addition, the reaction was warmed up to room temperature and kept stirring for overnight. The reaction mixture was diluted with methylene chloride (300 ml), and the resulting mixture was washed with 20% aqueous sodium thiosulfate three times, 10% potassium carbonate three times, and sat. NaCl aq. The organics were dried over Na2SO4 and the solvent was evaporated to afford 21.7 g crude mixture of 4 and 5 as white solid (98%), which was used directly for the next step without further purifications. Step 4: Synthesis of methyl (4aS,6aR,6bS,8aR,12aR,14bS)-11-bromo- 2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b- hexadecahydropicene-4a(2H)-carboxylate (Compound #6): The solution of #4 and #5 (4.00 g, 8.30 mmol, 1.0 eq) in acetic acid (18 ml) was added dropwise 47% HBr aq. (0.025 ml, 0.22 mmol, 0.026 eq) at room temperature. The reaction mixture was then heated to 35 ˚C, and Br₂ (2.13 ml, 41.3 mmol, 5.0 eq) was added dropwise. The resulting reaction mixture was kept stirring for 1.5 h at the same temperature. Acetic acid was partially removed under vacuum. The residue was then quenched with 20% aqueous sodium Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS thiosulfate, and extracted with dichloromethane four times. The combined organic extracts were washed with saturated sodium bicarbonate twice, brine, and dried over Na2SO4. The solvent was evaporated, and column chromatography (hexanes: ethyl acetate= 80:20) gave 3.46 g (75%) of bromo enone 6 as a yellow solid. Step 5: Synthesis of bardoxolone methyl (CDDO-Me): methyl (4aS,6aR,6bS,8aR,12aS,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo- 1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicene-4a(2H)-carboxylate(7): 1.0 eq) is dissolved in anhydrous dimethyl formamide (50 ml) under nitrogen at room temperature. To the stirred solution, copper (I) cyanide (1.72 g, 9.79 mmol, 1.1 eq) and potassium iodide (566 mg, 1.78 mmol, 0.20 eq) were added, and the resulting reaction mixture was heated up to 120 ˚C and stirred for 24 h. The suspension was cooled to room temperature, quenched with water (200 ml), and diluted with ethyl acetate (500 ml). Formed copper salts were removed by filtration before extraction. The organic phase was washed with saturated NaHCO₃ twice and sat. NaCl aq., and dried over Na₂SO₄. After evaporated the solvent, and column chromatography (hexanes: ethylacetate =75:25) to give 3.82 g (85%) of bardoxolone methyl (7) as a yellowish solid. Step 6: Synthesis of bardoxolone (CDDO), (4aS,6aR,6bS,8aR,12aS,14bS)-11- cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b- hexadecahydropicene-4a(2H)-carboxylic acid (8)3: Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS CDDO-Me (7) (3.82g, 7.55 mmol, 1 eq) and dry LiI (18.71 g, 140 mmol, 18.5 eq) in dry DMF (10 ml) was heated under reflux for 4 h. The solution is quenched with 5% HCl aq. The mixture was extracted with EtOAc three times. The organic extract was washed with water three times, sat. NaCl aq., and dried over Na₂SO₄. The solvent was evaporated. Purification by column chromatography (dichloromethane only to dichloromethane: methanol = 90:10) to give 3.56 g (96%) of CDDO (8). Step 7: Synthesis of 4aS,6aR,6bS,8aR,12aS,14bS)-11-cyano-2,2,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicene- 4a(2H)-carbonyl chloride (9)4: A mixture of CDDO (8) (3.0 g, 6.1 mmol) and oxalyl chloride (8.73 g, 5.9 ml, 68.8 mmlol, 11.3 eq) in anhydrous dichloromethane (60 ml) was stirred at room temperature overnight. The solvent was evaporated, and the residue was co-evaporated with benzene three times. 3.66 g (99%) of crude 9 was obtained. This was used for next step without further purification. Step 8: Synthesis of CDDO-EA, (4aS,6aR,6bS,8aR,12aS,14bS)-11-cyano-N- ethyl-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b- hexadecahydropicene-4a(2H)-carboxamide (10): Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS eq) in benzene (60 ml) was added to the solution of ethylamine hydrochloride (1.18 g, 14.4 mmol, 2.2 eq) and NaHCO₃ (3.0 g, 35.9 mmol, 5.5 eq) in water (60 ml). The mixture was stirred at room temperature overnight. The layers were separated, and the aqueous layer was extracted with benzene (60 ml). The combined organic layers was washed with sat. NaHCO₃ aq, water, and sat. NaCl aq, and dried over Na₂SO₄. The solvent was evaporated. Purification by column chromatography (dichloromethane only to dichloromethane: methanol = 90:10) to give 2.45 g (72%) of CDDO-EA (10). The overall yield of CDDO-EA was about 31% employing the above described 8 steps. Example 7 – Synthesis Procedure for CDDO-EA Batch #2 The present example details the procedure used to synthesize a second batch of CDDO-EA (Batch #2). The overall yield of CDDO-EA from oleanolic acid was about 7%. This was accomplished in the following 8-step procedure. Step 1: Synthesis of methyl (4aS,6aS,6bR,8aR,10S,12aR,12bR,14bS)-10- hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b- octadecahydropicene-4a(2H)-carboxylate (Compound #2): Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS wise to a stirred solution of oleanolic acid (1) (21.0 g, 46.0 mmol, 1.0 eq) in dimethyl formamide (200 ml). The reaction mixture was cooled down to 0 ˚C. Iodomethane (7.78 g, 3.15 ml, 50.6 mmol, 1.1 eq) was added dropwise to the suspension mixture. After the completion of addition, the reaction was warmed up to room temperature and stirred overnight. After the completion of the reaction, dimethyl formamide was removed by distillation. The resulting solid was dissolved in 1 L of dichloromethane. The solution was washed with water (200 ml) four times and sat. NaCl aq. The organic layer was dried over Na2SO4, and the solvent was evaporated. 20.3 g of crude product 2 was obtained (94%) as a white solid, which was used for the next step without further purifications. Step 2: Synthesis of methyl (4aS,6aS,6bR,8aR,12aR,12bR,14bS)- 2,2,6a,6b,9,9,12a-heptamethyl-10-oxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14b- hexadecahydropicene-4a(2H)-carboxylate (Compound #3): Ester 2 (20.2 g, 42.9 mmol, 1.0 eq) obtained above was dissolved in anhydrous dimethyl sulfoxide (500 ml) at room temperature. Fluorobenzene (8.6 ml) and iodoxybenzoic acid (36.0 g, 128.7 mmol, 3.0 eq) which was freshly prepared as described in the literature, and added to the solution. The resulting suspension was heated up to 85 ˚C under nitrogen and stirred for 18 hours. The TLC and NMR showed the mixture is the ketone intermediate, and the repeated the Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS reaction with Fluorobenzene (8.6 ml) and iodoxybenzoic acid (36.0 g, 128.7 mmol, 3.0 eq) in 500 ml of DMSO. The second TLC was the comparison of the reaction mixture and the product from the prior synthesis. This shows the major product is the Compound #3. The reaction was cooled down and quenched with 20% sodium thiosulfate aq. (350 ml) and extracted with dichloromethane four times. The combined organic extracts were washed with sat.NaHCO3 aq. and sat. NaCl aq. And then dried over Na2SO4. The solvent was removed to give the crude product 3 as a yellowish solid. Purification by column chromatography (hexanes: ethyl acetate = 80:20) afforded 11.0 g of white foamy Compound #3 (55%). Step 3: Synthesis of methyl (4aR,6aR,6bR,10aR,12aR,12bS,14aS)- 3,3,6b,10,10,12a,12b-heptamethyl-9-oxo-2,3,4,4a,6,6a,6b,9,10,10a,11,12,12a,12b,13,14- hexadecahydro-1H-piceno[12b,13-b]oxirene-14a(5aH)-carboxylate (Compound #4) + methyl (4aS,6aR,6bR,8aR,12aR,12bR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo- 1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,12b,13,14,14a,14b-octadecahydropicene-4a(2H)-carboxylate (Compound #5): Enone 3 (10.9 g, 22.5 mmol, 1.0 equiv) was dissolved in methylene chloride (50 ml) and the solution was cooled down to 0 ˚C. m- Chloroperbenzoic acid (7.21 grams, 70% in water, 29.2 mmol, 1.3 eq) was added potion wise at 0 ˚C. After the completion of the addition, the reaction was warmed up to room temperature and kept stirring for overnight. The reaction mixture was diluted with methylene chloride (150 ml), and the resulting mixture was washed with 20% aqueous sodium thiosulfate three times, 10% potassium carbonate three times, and sat. NaCl aq. The organics were dried over Na₂SO₄ and the solvent was evaporated to afford 9.75 g crude mixture of Compound #4 (an epoxide CDDO compound) and Compound #5 (a ketone CDDO Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS compound) as a white solid (90%), which was used directly for the next step without further purifications. Step 4: Synthesis of methyl (4aS,6aR,6bS,8aR,12aR,14bS)-11-bromo- 2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b- hexadecahydropicene-4a(2H)-carboxylate (Compound #6): in acetic acid (30 ml) was added dropwise 47% HBr aq. (0.06 ml, 0.55 mmol, 0.025 eq) at room temperature. The reaction mixture was then heated to 35 ˚C, and Br₂ (5.17 ml, 0.1 mol, 5.0 eq) was added dropwise. The resulting reaction mixture was kept stirring for 1.5 h at the same temperature. Acetic acid was partially removed under vacuum. The residue was then quenched with 20% aqueous sodium thiosulfate, and extracted with dichloromethane four times. The combined organic extracts were washed with saturated sodium bicarbonate twice, brine, and dried over Na2SO4. The solvent was evaporated, and column chromatography (hexanes: ethyl acetate= 80:20) gave 5.13 g (46%) of bromo enone 6 as a yellow solid. Step 5: Synthesis of bardoxolone methyl (CDDO-Me): methyl (4aS,6aR,6bS,8aR,12aS,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo- 1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicene-4a(2H)-carboxylate (Compound #7): Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS eq) is dissolved in anhydrous dimethyl formamide (15 ml) under nitrogen at room temperature. To the stirred solution, copper (I) cyanide (193 mg, 2.16 mmol, 1.1 eq) and potassium iodide (65.4 mg, 0.394 mmol, 0.20 eq) were added, and the resulting reaction mixture was heated up to 120˚ C and stirred for 9 h. TLC after 9 h showed the starting material (#6) had almost disappeared, and Compound #7 was formed. Since it was observed that the longer-hour reaction time made the Compound #6 decompose, the reaction was stopped after 9 hours, even though unreacted starting material was left: This reaction may be time sensitive. However, 18-24 hours also worked, but 46 hours made the product (Compound #7) decompose. The suspension was cooled to room temperature, quenched with water (50 ml), and diluted with ethyl acetate (50 ml). Formed copper salts were removed by filtration before extraction. The organic phase was washed with saturated NaHCO₃ twice and sat. NaCl aq., and dried over Na2SO4. After evaporating the solvent, and column chromatography (hexanes: ethylacetate =75:25), 815 mg (82%) of bardoxolone methyl (7) as a yellowish solid was produced. Step 6: Synthesis of bardoxolone (CDDO), (4aS,6aR,6bS,8aR,12aS,14bS)-11- cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b- hexadecahydropicene-4a(2H)-carboxylic acid (Compound #8) 3:

Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS CDDO-Me (Compound #7) (800 mg, 1.58 mmol, 1 eq) and dry LiI (3.9 g, 29.3 mmol, 18.5 eq) in dry DMF (15 ml) was heated under reflux for 4 h. The solution was quenched with 5% HCl aq. The mixture was extracted with EtOAc three times. The organic extract was washed with water three times, sat. NaCl aq., and dried over Na₂SO₄. The solvent was evaporated. Purification by column chromatography (dichloromethane only to dichloromethane: methanol = 90:10) was performed to give 478 mg (62%) of CDDO (Compound #8). Step 7: Synthesis of 4aS,6aR,6bS,8aR,12aS,14bS)-11-cyano-2,2,6a,6b,9,9,12a- heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicene- 4a(2H)-carbonyl chloride (Compound #9) 4: (769 mg, 1.56 mmol, 1.0 eq) and oxalyl chloride (2.24 g, 1.51 ml, 17.7 mmol, 11.3 eq) in anhydrous dichloromethane (5 ml) was stirred at room temperature overnight. The solvent was evaporated, and the residue was co-evaporated with benzene three times. 786 mg (99%) of crude 9 was obtained. This was used for next step without further purification. Step 8: Synthesis of CDDO-EA, (4aS,6aR,6bS,8aR,12aS,14bS)-11-cyano-N-ethyl- 2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b- hexadecahydropicene-4a(2H)-carboxamide (Compound #10):

Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS The solution of 9 (786 mg, 1.54 mmol, 1.0 eq) in benzene (15 ml) was added to the solution of ethylamine hydrochloride (285 mg, 3.89 mmol, 2.2 eq) and NaHCO3 (690 mg, 8.47 mmol, 5.5 eq) in water (15 ml). The mixture was stirred at room temperature overnight. The layers were separated, and the aqueous layer was extracted with benzene (15 ml). The combined organic layers were washed with sat. NaHCO3 aq, water, and sat. NaCl aq, and dried over Na2SO4. The solvent was evaporated. Purification by column chromatography (dichloromethane only to dichloromethane: methanol = 90:10) produced 521 mg (65%) of CDDO-EA (Compound #10): To obtain pure compound, the repeated column chromatography was required. The Compound #10 purity was confirmed by HPLC and NMR ( > 99.5 %). The overall yield of the CDDO-Me was about 7 % with the above described 8 steps. Any embodiment discussed herein with respect to one aspect of the invention applies to other aspects of the invention as well. Unless specifically noted otherwise. Other objects, features and advantages of the present invention will become apparent from the following detailed description and any accompanying drawings. It should be understood, however, that the detailed description and any specific examples or drawings provided, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. The present invention also provides a product by process method for preparing CDDO, CDDO-Me, CDDO-EA, and other analogs and derivatives, that require and/or include the synthesis of the Compound #6 as an intermediate compound, as provided herein, as an intermediate synthesis step. Example 8 – Biological Activity – Anti-Inflammatory Action The Batch #1 and the Batch #2 CDDO-EA were both examined for their biological activity. A first batch (CDDO-EA Batch #1) and a second batch (CDDO-EA Batch #2) were compared for ability to act as an anti-inflammatory agent. The second batch of CDDO-EA, was tested for its biological property of anti-inflammatory activity. As with the first batch of CDDO- Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS EA, this was tested by using the mouse macrophage cell line RAW264.7. RAW264.7 macrophages were pre-treated with 400 μM CDDO-EA for 1 hour then stimulated with 100 ng/ml of lipopolysaccharide (LPS) for 6 hr. Supernatants were collected, and an enzyme linked immunoassay (ELISA) was performed to detect the pro-inflammatory protein, monocyte chemotactic protein-1 (MCP-1). The macrophages were also treated with LPS alone or with CDDO-EA alone. A control (no treatment) group was also included in the study. The second batch CDDO-EA blocked the LPS-induced production of MCP-1 in RAW264.7 macrophages. This suppression of MCP-1 production by the second batch CDDO-EA is similar to that observed for the first batch of CDDO-EA. These findings show that the second batch of CDDO-EA has anti-inflammatory properties similar to the first batch of CDDO-EA, and that the synthesis procedure provides consistent, repeatable product that demonstrate predictable and consistent biological activity. As shown in Figure 7, both batches of the CDDO-EA demonstrated significant anti-inflammatory activity.

Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS BIBLIOGRAPHY The following references are incorporated herein in their entirety. 1. Liangfeng Fu, Gordon W., and Gribble M., 2013, Org. Lett., 15, 1622. 2. Marco Frigerio, et al., 1999, J. Org. Chem., 64: 4537. 3. T. Honda, B. V. Rounds, L. Bore, H. J. Finlay, F. G. Favaloro, Jr., N. Suh, Y. Wang, M. B. Sporn, G. W. Gribble, 2000, J. Med. Chem.43, 4233. 4. Yang et al. (2013) 5. Marco Frigerio, Marco Santagostino, and Simona Sputore, 1999, J. Org. Chem., 64, 4537. 6. T. Honda, T. Janosik, Y. Honda, J. Han, K. T. Liby, C. R. Williams, R.D. Couch, A. C. 2000, J. Med. Chem., 43:4233. 7. Anderson, M. B. Sporn, G.W. Gribble, 2004, J. Med. Chem.47, 4923. 8. Yates et al. (2007), Mol Cancer Ther., 6 (1): 154-162. 9. Fu et al. (2013), Organic Letters, 15 (7), 1622-1625.

Claims

Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS CLAIMS What is claimed is: 1. A method for synthesizing a pharmacologically active preparation of a CDDO-Me from oleanolic acid comprising: reacting an amount of oleanolic acid with MeI in the presence of K2CO3 in DMF, and obtaining an intermediate Compound #2; reacting the Compound #2 with IBX in the presence of PhF in DMSO, to provide a Compound #3; reacting the Compound #3 in the presence of mCPBA in CH2Cl2, to provide a substrate mixture comprising Compound #4 and Compound #5; reacting the substrate mixture (about 1.0 eq) with Br2 (about 5 eq) and a catalyst HBr (about 0.025 eq), at about 35°C for about 1.5 to about 2 hours, to provide a Compound #6; and reacting the Compound #6 in the presence of CuCn, KI in DMF to provide a Compound #7 (CDDO-Me). 2. The method of claim 1 wherein the amount of HBr comprises about 0.025 ml, 0.22 mmol, the amount of the Compound #4 and #5 substrate mixture comprises about 4.00 grams to about 5 grams, 8.29 mmol to 10.36 mmol., and the amount of Br2 is about 2.13 ml, 41.3 mmol. 3. A method for synthesizing a Compound #6 from substrate synthesized from oleanolic acid, comprising: combining an amount of oleanolic acid and K2CO3 in DMF to form a mixture, cooling the mixture, adding an amount of iodomethane to the cooled mixture, warming and stirring the mixture, removing the DMF to form a solid, dissolving the solid in dichloromethane to provide a solution, washing the solution, drying the organic layer and evaporating the solvent from the solution to provide a Compound #2 having a structure: Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS iodoxybenzoic acid to form a suspension, heating and stirring the suspension, cooling and quenching the solution with sodium thiosulfate, and extracting the reaction solution, combining and washing the organic extracts and drying the combined extracts to provide a Compound #3 having a structure: dissolving an amount of Compound #3 in methyl chloride to provide a solution, and cooling the solution, adding chloroperbenzoic acid to the cooled solution, warming and stirring the solution, diluting the solution with methyl chloride to form a mixture, washing the mixture, drying the organic layer and evaporating the solvent to provide a substrate mixture comprising Compound #4 and Compound #5:

Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS preparing a solution comprising the substrate solution with an amount of a catalyst HBr at an equivalent of about 0.020 to about 2, to provide a reaction mixture, heating the reaction mixture and adding Br2 dropwise to provide a 5.0 eq Br2 in the reaction mixture, stirring the reaction mixture about 1-2 hours at room temperature, removing acetic acid from the reaction mixture to form a residue, extracting the residue, collecting and combining extracted organic extracts, washing and drying the combined organic extracts to provide a dried material comprising Compound #6, as depicted in the following structure: 4. The method of claim 3 wherein the amount of the HBr is about 0.025 ml of an about 50% HBr, 0.22 mmol., at an equivalent of about 0.026 eq. to the substrate solution comprising Compound #4 and Compound #5. 5. The method of claim 3 wherein the substrate solution of Compound #4 and Compound #5 comprises an about 0.8 eq to an about 1.0 eq., in an amount of about 4.0 to 5.0 grams, about 8 to 9 mmol. 6. The method of claim 3 wherein the amount of Compound #3 is about 20 grams to about 25 grams, about 46 mmol, at an eq of about 1.0. 7. A method for synthesizing a Compound #7 CDDO-Me from oleanolic acid, comprising: dissolving and stirring an amount of Compound #6 in DMF, and adding an amount of copper cyanide I and potassium iodide to provide a reaction mixture, and heating and stirring the reaction mixture; removing formed copper salts from the reaction mixture; collecting washing and drying an organic phase from the reaction mixture; and Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS isolating a Compound #7, according to the following:   8. The method of claim 7 wherein the amount of copper cyanide added is about 1 to 2 grams, about 9 mmol, at an about 1.1 eq. 9. The method of claim 7 wherein the amount of potassium iodide is about 550 to about 575 mg., about 2 mmol, at an about 0.20 eq. 10. The method of claim 7 wherein the amount of Compound #6 dissolved in DMF is about 5 grams (9 mmol), at an about 1.0 eq. 11. A composition comprising a Compound #6 prepared according to the method of claim 3. 12. A composition comprising a Compound #7 prepared according to the method of claim 7. 13. A chemical synthesis method for CDDO-Me Compound #7, comprising: obtaining a substrate mixture comprising Compound #4 and Compound #5 dissolved in AcOH at room temperature; adding a solution of HBr dropwise to the mixture with constant stirring over a period of about 90 minutes; removing the AcOH to provide a residual powder; adding an amount of sodium thiosulfate aqueous and DCM to the residual powder; extracting and collecting fractions from an extraction of the residual powder; purifying the collected fractions; and Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS collecting CDDO-Me. 14. The chemical synthesis method of claim 13 wherein the equivalent of catalyst (HBr) is about 0.025 eq. 15. The chemical synthesis method of claim 5 wherein the equivalent of HBr is about 0.025 eq and the equivalent of Br2 is about 2.4 eq. 16. The chemical synthesis method of claim 3 or 7 wherein the product is essentially free of compounds having more than one C₂₈ bromine substituted group. 17. The method of claim 3 wherein synthesis of Compound #6 is provided from a substrate mixture of Compound #4 and Compound #5. 18. A method of synthesis for CDDO-EA comprising the steps of, in order: subjecting an amount of oleanolic acid (#1) to MeI and K₂CO₃ in DMF, and obtaining an Compound #2; subjecting the Compound #2 to IBX and PhF in DMSO, to provide a Compound #3; reacting the Compound #3 with mCPBA and CH₂Cl₂, to provide substrate solution comprising Compound #4 and Compound #5; adding to an amount of the substrate solution about 47% HBr aq (0.026 eq) dropwise at room temperature to provide a mixture; heating the mixture and adding an amount of Br₂ (about 5.0 eq), and stirring for about 1.5 h. to about 2 hours to form a reaction mixture comprising Compound #6; removing acid from the mixture, and quenching a resulting residue with an aqueous sodium thiosulfate; extracting the quenched residue with methylene chloride to provide organic extracts, and combining and washing the combined organic extracts; drying the resulting material; evaporating the solvent and collecting a solution; purifying the solution and collecting a Compound #6 as a yellow solid; subjecting the Compound #6 in the presence of CuCN and KI in DMF to provide a Inventor: Shizue Mito Docket No.119526-000014 Title: CHEMICAL SYNTHESIS METHODS AND CDDO/CDDO-EA PREPARATIONS CDDO-Me (Compound #7); subjecting the compound CDDO-Me (#7) to lithium iodide to provide CDDO (compound #8); subjecting an amount of the CDDO (Compound #7) to (COCl)₂ to provide a Compound #9; and reacting an amount of the Compound #9 with EtNH2, and collecting CDDO-EA (Compound #10).