Methods for producing triterpenoid derivatives

Abstract

In some aspects, the present disclosure provides methods for preparing omastolone. Also provided herein are processes for the preparation of compounds of formula (III), wherein the variables are as defined herein.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480057279.9 (22) Application Date 2024.07.26 (30) Priority Data 63 / 516,483 2023.07.28 US (85) PCT International Application Entering National Phase Date 2026.03.06 (86) PCT International Application Application Data PCT / US2024 / 039909 2024.07.26 (87) PCT International Application Publication Data WO2025 / 029691 EN 2025.02.06 (71) Applicant Riata Pharmaceutical Holdings LLC Address Texas, USA (72) Inventors C.G. Bates G.D. Altman III (74) Patent Agency Qingdao Lianzhi Patent & Trademark Agency Co., Ltd. 37101 Patent Attorney Yan Wubin, Lü Dongxia (51) Int.Cl. C07J 63 / 00 (2006.01) (54) Invention Title Method for Preparing Triterpenoid Derivatives (57) Abstract In some aspects, this disclosure provides a method for preparing omasorone. This document also provides a method for preparing compounds having formula (III), wherein the variables are as defined herein. Claims 12 pages Description 89 pages Drawings 2 pages CN 121794280 A 2026.04.03 CN 1 21 79 42 80 A 1. A multi-step method for preparing omasorone from oleanolic acid, the method comprising using a compound of formula I as a reagent in one or more steps, wherein formula I is defined as: (I), where: R1, R1', and R1'' are each independently hydrogen, halo, amino, cyano, or carboxyl; or alkyl (C≤8), cycloalkyl (C≤8), alkenyl (C≤8), alkynyl (C≤8), aryl (C≤8), aralkyl (C≤8), heteroaryl (C≤8), heteroaryl (C≤8), alkoxy (C≤8), cycloalkoxy (C≤8), alkenyloxy (C≤8), alkynyloxy (C≤8), aryloxy (C≤8), arylalkoxy (C≤8), heteroaryloxy (C≤8), heteroarylalkoxy (C≤8), alkylamino (C≤8), dialkylamino (C≤8), amide (C≤8), or substituted forms of any of these groups. 2. The method of claim 1, wherein R1, R1', and R1'' are each propyl. 3. The method of claim 1 or claim 2, wherein the method comprises reacting oleanolic acid with an alkylating agent in a reaction mixture to form compound A, wherein compound A is defined as: (A). 4. The method of claim 3, wherein the reaction mixture further comprises potassium carbonate. 5. The method of claim 3 or claim 4.The reaction mixture further comprises 2-methyltetrahydrofuran. 6. The method according to any one of claims 3 to 5, wherein the reaction mixture further comprises tetrabutylammonium bromide. 7. The method according to any one of claims 3 to 6, wherein the alkylating agent is dimethyl sulfate. 8. The method according to any one of claims 3 to 7, wherein the reaction is carried out at a temperature of about 30°C. 9. The method according to any one of claims 3 to 8, wherein the reaction is carried out for about 1.0 hour. 10. The method according to any one of claims 3 to 9, wherein the method further comprises contacting the reaction mixture with triethylamine at a second temperature of about 50°C for about 3 hours for a second time period. 11. The method according to any one of claims 1 to 10, wherein the method further comprises reacting compound A: (A) (Claims 1 / 12 page 2 CN 121794280 A) with an oxidizing agent in the reaction mixture to form compound B, wherein compound B is defined as: (B). 12. The method according to claim 11, wherein the oxidizing agent comprises m-chloroperoxybenzoic acid. 13. The method according to claim 11 or claim 12, wherein the molar ratio of compound A to the oxidizing agent is about 4:5. 14. The method of any one of claims 11 to 13, wherein the reaction mixture comprises dichloromethane. 15. The method of any one of claims 11 to 14, wherein the reaction is carried out at a temperature of about 25°C. 16. The method of any one of claims 11 to 15, wherein the reaction is carried out for a period of about 15 hours. 17. The method of any one of claims 11 to 16, wherein the method further comprises contacting the reaction mixture with a sodium bicarbonate solution and separating the organic layer. 18. The method of claim 17, wherein the method further comprises contacting the separated organic layer with methanesulfonic acid. 19. The method of any one of claims 1 to 18, wherein the method further comprises reacting compound B: (B) with an oxidant in the reaction mixture to form compound C, wherein compound C is defined as: (C). 20. The method of claim 19, wherein the oxidant is perbrominated pyridine. 21. The method of claim 19 or claim 20, wherein the reaction mixture comprises compound B in a molar ratio of about 1:1 to about 1:2 to the oxidant. 22. The method of any one of claims 19 to 21, wherein the reaction mixture further comprises toluene. 23. The method according to any one of claims 19 to 22,The method further includes reacting compound B with the oxidant at a temperature of about 33°C. Claims 2 / 12, page 3, CN 121794280, A 24. The method according to any one of claims 19 to 23, wherein the method further includes a reaction period of about 2 hours during which compound B reacts with the oxidant. 25. The method according to any one of claims 1 to 24, wherein the method further comprises reacting compound C: (C) with an oxidant in the presence of a compound of formula I: (I) in a reaction mixture to form compound D, wherein compound D is defined as: (D), wherein: R1, R1' and R1'' are each independently hydrogen, halogenated, amino, cyano or carboxyl; or alkyl (C≤8), cycloalkyl (C≤8), alkenyl (C≤8), alkynyl (C≤8), aryl (C≤8), aralkyl (C≤8), heteroaryl (C≤8), heteroaryl (C≤8), alkoxy (C≤8), cycloalkoxy (C≤8), alkenyloxy (C≤8), alkynyloxy (C≤8), aryloxy (C≤8), arylalkoxy (C≤8), heteroaryloxy (C≤8), heteroarylalkoxy (C≤8), alkylamino (C≤8), dialkylamino (C≤8), amide (C≤8) or a substituted form of any of these groups. 26. The method of claim 25, wherein R1, R1', and R1'' are each propyl. 27. The method of claim 25 or claim 26, wherein the reaction mixture comprises compound C in a molar ratio of about 1:1 to about 1:2 with respect to the compound of formula I. 28. The method of any one of claims 25 to 27, wherein the reaction mixture further comprises diisopropylethylamine. 29. The method of claim 28, wherein the reaction mixture comprises compound C in a molar ratio of about 1:1 to about 1:2 with respect to the compound of formula I. 30. The method of any one of claims 25 to 29, wherein the oxidant is dimethyl sulfoxide. 31. The method of claim 30, wherein the reaction mixture comprises compound C in a molar ratio of about 1:5 to about 1:7 with respect to the compound of formula I. 33. The method of any one of claims 25 to 32, wherein the method comprises contacting compound C with a solution containing the compound of formula I. 34. The method of claim 33, wherein the concentration of the compound of formula I in the solution is about 50% by weight. 35. The method of any one of claims 25 to 34, wherein the solution comprises ethyl acetate. 36. The method of any one of claims 25 to 35,The reaction of compound C with dimethyl sulfoxide in the presence of the compound of formula I is carried out at a temperature of about 25°C. 37. The method according to any one of claims 25 to 36, wherein the reaction of compound C with dimethyl sulfoxide in the presence of the compound of formula I is carried out for a reaction period of about 3 hours. 38. A method for preparing a compound of formula III, the method comprising obtaining a compound of formula II: (II), and reacting the compound of formula II with an oxidizing agent in the presence of a compound of formula I: (I) in a reaction mixture to form a compound of formula III: (III), wherein: R1, R1', and R1'' are each independently hydrogen, halogenated, amino, cyano, or carboxyl; or alkyl (C≤8), cycloalkyl (C≤8), alkenyl (C≤8), alkynyl (C≤8), aryl (C≤8), aralkyl (C≤8), heteroaryl (C≤8), heteroarylalkyl (C≤8), alkoxy (C≤8), cycloalkoxy (C≤8), alkenyloxy (C≤8), alkynyloxy (C≤8), aryloxy (C≤8), arylalkoxy (C≤8), heteroaryloxy (C≤8), heteroarylalkoxy (C≤8), alkylamino (C≤8), dialkylamino (C≤8), amide (C≤8), or a substituted form of any of these groups; and R2 is: 39. The method of claim 38, wherein R1, R1', and R1'' are each propyl. 40. The method of claim 38 or claim 39, wherein R2 is a C1-C15-acyl or a substituted C1-C15-acyl group. 41. The method of claim 40, wherein R2 is a substituted C1-C15-acyl group. 42. The method of claim 41, wherein R2 is -CO2CH3. 43. The method of any one of claims 38 to 42, wherein the reaction mixture comprises a molar ratio of the compound of formula II to the compound of formula I of about 1:1 to about 1:2. 44. The method of any one of claims 38 to 43, wherein the reaction mixture further comprises diisopropylethylamine. 45. The method of claim 44, wherein the reaction mixture comprises a molar ratio of the compound of formula II to diisopropylethylamine of about 1:1 to about 1:2. 46. The method of any one of claims 38 to 45, wherein the reaction mixture further comprises dimethyl sulfoxide. 47. The method of claim 46, wherein the reaction mixture comprises a molar ratio of the compound of formula II to dimethyl sulfoxide of about 1:5 to about 1:7. 48. The method of any one of claims 38 to 47,The method further includes reacting the compound of formula II with the compound of formula I under an inert atmosphere. 49. The method of any one of claims 38 to 48, wherein reacting the compound of formula II with the compound of formula I further includes contacting the compound of formula II with a solution containing the compound of formula I. 50. The method of claim 49, wherein the concentration of the solution is about 50% by weight. 51. The method of any one of claims 38 to 50, wherein the solution further comprises ethyl acetate. 52. The method of any one of claims 38 to 51, wherein the method further includes reacting the compound of formula II with the compound of formula I at a temperature of about 25°C. 53. The method of any one of claims 38 to 52, wherein the method further includes a reaction time of about 3 hours for reacting the compound of formula II with the compound of formula I. 54. A method for preparing compound A, the method comprising obtaining oleanolic acid, and reacting oleanolic acid with an alkylating agent in a reaction mixture to form compound A: (A), wherein the reaction mixture comprises a solvent immiscible with water. 55. The method of claim 54, wherein the reaction mixture further comprises a base. 56. The method of claim 55, wherein the base is potassium carbonate. 57. The method of any one of claims 54 to 56, wherein the reaction mixture further comprises a phase transfer catalyst. 58. The method of claim 57, wherein the phase transfer catalyst is tetrabutylammonium bromide. 59. The method of any one of claims 54 to 58, wherein the alkylating agent is dimethyl sulfate. 60. The method of any one of claims 54 to 59, wherein the solvent comprises 2-methyltetrahydrofuran. Claims 5 / 12 Page 6 CN 121794280 A 61. The method of any one of claims 54 to 60, wherein the method further comprises an aqueous purification step. 62. The method of any one of claims 54 to 61, wherein the reaction is carried out at a temperature of about 0°C to about 100°C. 63. The method of claim 62, wherein the temperature is about 30°C. 64. The method of any one of claims 54 to 63, wherein the reaction is carried out for a reaction period of about 0.5 hours to about 3.0 hours. 65. The method of claim 64, wherein the reaction period is about 1.0 hour. 66. The method of any one of claims 54 to 65, wherein compound A is prepared with a purity greater than 90% by measurement using high-performance liquid chromatography. 67. The method of claim 66, wherein compound A is prepared with a purity greater than 95% by measurement using high-performance liquid chromatography. 68. The method of claim 67, wherein compound A is prepared with a purity greater than 95% by measurement using high-performance liquid chromatography.69. A method for preparing compound C, the method comprising obtaining compound B: (B), and reacting compound B with perbrominated pyridine in a reaction mixture to form compound C: (C). 70. The method of claim 69, wherein the molar ratio of compound B to perbrominated pyridine is about 1:1 to about 1:2. 71. The method of claim 69 or claim 70, wherein the reaction mixture comprises a solvent. 72. The method of claim 71, wherein the solvent is immiscible with water. 73. The method of claim 72, wherein the solvent comprises toluene. 74. The method of any one of claims 69 to 73, wherein the reaction is carried out over a reaction period of about 1 hour to about 4 hours. 75. The method of claim 74, wherein the reaction period is about 2 hours. 76. The method of any one of claims 69 to 75, wherein the reaction is carried out at a temperature of about 0°C to about 100°C. 77. The method of claim 76, wherein the temperature is about 33°C. 78. The method according to any one of claims 69 to 77, wherein compound C with a purity greater than 90% is prepared by high performance liquid chromatography (HPLC). 79. The method according to claim 78, wherein compound C with a purity greater than 95% is prepared by high performance liquid chromatography (HPLC). 80. The method according to claim 79, wherein compound C with a purity greater than 98% is prepared by high performance liquid chromatography (HPLC). 81. A method for preparing omasorone.The method comprises: (a) reacting with dimethyl sulfate and potassium carbonate in the presence of tetrabutylammonium bromide to form; (b) reacting with m-chloroperoxybenzoic acid to form; (c) reacting with pyridine perbromin to form; (d) reacting with diisopropylethylamine and dimethyl sulfoxide to form; (e) reacting with sodium methoxide to form; (f) reacting with hydroxylamine and hydrochloric acid to form; (g) reacting with sodium methoxide to form; (h) reacting with; and (i) reacting with pyridine to form; (j) reacting with diphenylphosphohydrin and triethylamine to form; (l) heating to form; (m) reacting with diphenylphosphohydrin and triethylamine to form; and (n) reacting with to form omasorone. Claims 12 / 12 pages 12 CN 121794280 A Method for preparing triterpenoid derivatives

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 516,483, filed July 28, 2023, the entire contents of which are hereby incorporated by reference. Background Art

[0002] I. Technical Field

[0003] The present invention generally relates to the field of chemistry, and particularly to organic chemistry and process chemistry. More specifically, it relates to methods for synthesizing triterpenoid derivatives.

[0004] II. Description of Related Technology

[0005] Omaveloxolone (N-[(4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,7,8,8a,14a,14b-decahydro-4a-yl]-2,2-difluoropropionamide; RTA 408; SKYCLARYS®) in amorphous form (Class 1) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of Friedrich's ataxia in adults and adolescents aged 16 years and older.FA). Omasoron and related triterpenoid analogues are known potent activators of nuclear factor E2-derived 2-related factor (Nrf2) and inhibitors of nuclear factor kappa-light-chain enhancer of activated B cells, inducing anti-inflammatory and antioxidant phenotypes. Nrf2 signaling promotes antioxidant mechanisms (Muthusamy et al., 2012), and Nrf2 activation can increase mitochondrial respiration (Holmström et al., 2013; Ludtmann et al., 2014).

[0006] In view of the therapeutic uses of omamasoron and related triterpenoid derivatives, there is a need for improved methods for synthesizing triterpenoid derivatives. Currently known methods for forming triterpenoid derivatives and their applications have been disclosed in, for example, the following publications: Fu and Gribble, 2013; Wong et al., 2016; Honda et al., 1997; Honda et al., 1998; Honda et al., 1999; Honda et al., 2000a; Honda et al., 2000b; Honda et al., 2002; Suh et al., 1998; Suh et al., 1999; Place et al., 2003; Liby et al., 2005; and U.S. Patents 7,915,402, 7,943,778, and 8,071. References 632, 8,124,799, 8,129,429, 8,338,618, 8,993,640, 9,102,681, 9,701,709, 9,512,094, 9,889,143, 10,093,614, and 10,556,858 are incorporated herein by reference. This document describes methods for the synthesis of omasorlon and related triterpenoid derivatives, including those that improve yield, purity, efficiency, safety, environmental considerations, and / or otherwise improve the industrial-scale preparation of omasorlon and related triterpenoid derivatives. Summary of the Invention

[0007] This document provides methods for the preparation of omasorlon and related compounds. In some aspects, this disclosure provides a multi-step method for preparing omasorone from oleanolic acid, the method comprising using a compound of formula I as a reagent in one or more steps, wherein formula I is defined as: (I)

[0008] (I) (Page 1 / 89 of Specification, CN 121794280 A)

[0009] Wherein:

[0010] R1, R1' and R1'' are each independently hydrogen, halo, amino, cyano or carboxyl; or

[0011] alkyl (C≤8), cycloalkyl (C≤8), alkenyl (C≤8), alkynyl (C≤8), aryl (C≤8), aralkyl (C≤8), heteroaryl (C≤8), heteroaryl (C≤8), alkoxy (C≤8), cycloalkoxy (C≤8), alkenyloxy (C≤8), alkynyloxy (C≤8), aryloxy (C≤8), arylalkoxy (C≤8), heteroaryloxy (C≤8), heteroarylalkoxy (C≤8), alkylamino (C≤8), dialkylamino (C≤8), amide (C≤8) or a substituted form of any of these groups.

[0012] In some embodiments, R1, R1' and R1'' are each propyl. In some aspects, the method includes reacting oleanolic acid with an alkylating agent in a reaction mixture to form compound A, wherein compound A is defined as:

[0013] (A).

[0014] In some embodiments, the reaction mixture further comprises potassium carbonate. In some embodiments, the reaction mixture further comprises 2-methyltetrahydrofuran. In some embodiments, the reaction mixture further comprises tetrabutylammonium bromide. In some embodiments, the alkylating agent is dimethyl sulfate. In some aspects, the reaction is carried out at a temperature of about 30°C. In some aspects, the reaction is carried out for about 1.0 hour. In some aspects, the method further includes contacting the reaction mixture with triethylamine at a second temperature of about 50°C for about 3 hours.

[0015] In some embodiments, the method further includes reacting compound A:

[0016] (A)

[0017] with an oxidizing agent in a reaction mixture to form compound B, wherein compound B is defined as:

[0018] (B).

[0019] In some embodiments, the oxidizing agent comprises m-chloroperoxybenzoic acid. In some embodiments, the molar ratio of compound A to the oxidant (page 2 / 89, CN 121794280 A) is about 4:5. In some aspects, the reaction mixture contains dichloromethane. In some embodiments, the reaction is carried out at a temperature of about 25°C. In some embodiments, the reaction is carried out for about 15 hours. In some embodiments, the method further includes contacting the reaction mixture with a sodium bicarbonate solution and separating the organic layer. In some embodiments, the method further includes contacting the separated organic layer with methanesulfonic acid.

[0020] In some aspects, the method further includes reacting compound B:

[0021] (B)

[0022] with the oxidant in the reaction mixture to form compound C, wherein compound C is defined as:

[0023] (C).

[0024] In some embodiments, the oxidant is perbrominated pyridine. In some embodiments,The reaction mixture contains compound B in a molar ratio of about 1:1.4 to the oxidant. In some embodiments, the reaction mixture further contains toluene. In some embodiments, the method further includes reacting compound B with the oxidant at a temperature of about 33°C. In some embodiments, the method further includes a reaction time of about 2 hours for reacting compound B with the oxidant.

[0025] In some aspects, the method further includes reacting compound C:

[0026] (C)

[0027] with the oxidant in the presence of a compound of formula I:

[0028] (I)

[0029] in the reaction mixture to form compound D, wherein compound D is defined as: Specification 3 / 89 page 16 CN 121794280 A

[0030] (D),

[0031] wherein:

[0032] R1, R1' and R1'' are each independently hydrogen, halogenated, amino, cyano or carboxyl; or

[0033] Alkyl (C≤8), cycloalkyl (C≤8), alkenyl (C≤8), alkynyl (C≤8), aryl (C≤8), aralkyl (C≤8), heteroaryl (C≤8), heteroaralkyl (C≤8), alkoxy (C≤8), cycloalkoxy (C≤8), alkenyloxy (C≤8), alkynyloxy (C≤8), aryloxy (C≤8), arylalkoxy (C≤8), heteroaryloxy (C≤8), heteroarylalkoxy (C≤8), alkylamino (C≤8), dialkylamino (C≤8), amide (C≤8), or substituted forms of any of these groups.

[0034] In some embodiments, R1, R1', and R1'' are each propyl. In some embodiments, the reaction mixture comprises compound C in a molar ratio of about 1:1.35 to compound I. In some embodiments, the reaction mixture further comprises diisopropylethylamine. In some embodiments, the reaction mixture contains compound C in a molar ratio of about 1:1.6 to diisopropylethylamine. In some embodiments, the oxidant is dimethyl sulfoxide. In some embodiments, the reaction mixture contains compound C in a molar ratio of about 1:5.5 to dimethyl sulfoxide. In some embodiments, the method further includes reacting compound C with the compound of formula I under an inert atmosphere. In some aspects, the method includes contacting compound C with a solution containing the compound of formula I. In some embodiments, the concentration of the compound of formula I in the solution is about 50% by weight. In some embodiments, the solution contains ethyl acetate. In some embodiments, the reaction of compound C with dimethyl sulfoxide in the presence of the compound of formula I is carried out at a temperature of about 25°C. In some embodiments, the reaction of compound C with dimethyl sulfoxide in the presence of the compound of formula I is carried out for a reaction time of about 3 hours.

[0035] In some aspects, this disclosure provides a method for preparing a compound of formula III.The method includes obtaining a compound of formula II:

[0036] (II),

[0037] and reacting the compound of formula II with an oxidant in the presence of a compound of formula I:

[0038] (I)

[0039] in a reaction mixture to produce a compound of formula III: Specification 4 / 89 page 17 CN 121794280 A

[0040] (III),

[0041] wherein:

[0042] R1, R1' and R1'' are each independently hydrogen, halo, amino, cyano or carboxyl; or

[0043] Alkyl (C≤8), cycloalkyl (C≤8), alkenyl (C≤8), alkynyl (C≤8), aryl (C≤8), aralkyl (C≤8), heteroaryl (C≤8), heteroaryl (C≤8), alkoxy (C≤8), cycloalkoxy (C≤8), alkenyloxy (C≤8), alkynyloxy (C≤8), aryloxy (C≤8), arylalkoxy (C≤8), heteroaryloxy (C≤8), heteroarylalkoxy (C≤8), alkylamino (C≤8), dialkylamino (C≤8), amide (C≤8), or substituted forms of any of these groups; and

[0044] R2 is a C1-C15-acyl or C1-C15-alkyl, wherein any of these groups is substituted or unsubstituted.

[0045] In some embodiments, R1, R1', and R1'' are each propyl. In some embodiments, R2 is a C1-C15-acyl or a substituted C1-C15-acyl. In some embodiments, R2 is a substituted C1-C15-acyl. In some embodiments, R2 is -CO2CH3. In some embodiments, the reaction mixture contains a molar ratio of the compound of formula II to the compound of formula I of about 1:1 to about 1:2. In some embodiments, the reaction mixture further contains diisopropylethylamine. In some embodiments, the reaction mixture contains a molar ratio of the compound of formula II to diisopropylethylamine of about 1:1 to about 1:2. In some embodiments, the reaction mixture further contains dimethyl sulfoxide. In some embodiments, the reaction mixture contains a molar ratio of the compound of formula II to dimethyl sulfoxide of about 1:6.8. In some embodiments, the method further includes reacting the compound of formula II with the compound of formula I under an inert atmosphere. In some aspects, reacting the compound of formula II with the compound of formula I further includes contacting the compound of formula II with a solution containing the compound of formula I. In some embodiments, the concentration of the solution is about 50% by weight. In some embodiments, the solution further contains ethyl acetate. In some embodiments, the method further includes reacting the compound of formula II with the compound of formula I at a temperature of about 25°C. In some embodiments, the method further includes a reaction time of about 3 hours for reacting the compound of formula II with the compound of formula I.

[0046] In some aspects,This disclosure provides a method for preparing compound A, the method comprising obtaining oleanolic acid and reacting oleanolic acid with an alkylating agent in a reaction mixture to form compound A:

[0047] (A),

[0048] wherein the reaction mixture comprises a solvent that is immiscible with water.

[0049] In some embodiments, the reaction mixture further comprises a base, such as potassium carbonate. In some embodiments, the reaction mixture further comprises a phase transfer catalyst, such as tetrabutylammonium bromide. In some embodiments, the alkylating agent is dimethyl sulfate. In some embodiments, the solvent comprises 2-methyltetrahydrofuran. In some aspects, the method further comprises an aqueous purification step. In some embodiments, the reaction is carried out at a temperature of about 0°C to about 100°C. In some embodiments, the temperature is about 30°C. In some embodiments, the reaction is carried out for a reaction time of about 0.5 hours to about 3.0 hours. In some embodiments, the reaction time is about 1.0 hour. In some embodiments, the purity of the prepared compound A is greater than 90% as measured by high performance liquid chromatography (HPLC). In some embodiments, the purity of the prepared compound A is greater than 95% as measured by HPLC. In some embodiments, the purity of the prepared compound A is greater than 98% as measured by HPLC.

[0050] In some aspects, this disclosure provides a method for preparing compound C, the method comprising obtaining compound B:

[0051] (B),

[0052] and reacting compound B with perbrominated pyridine in a reaction mixture to form compound C:

[0053] (C).

[0054] In some embodiments, the molar ratio of compound B to perbrominated pyridine is about 1:1.4. In some embodiments, the reaction mixture contains a solvent. In some embodiments, the solvent is immiscible with water. In some embodiments, the solvent contains toluene. In some embodiments, the reaction is carried out for a reaction time of about 1 hour to about 4 hours. In some embodiments, the reaction time is about 2 hours. In some embodiments, the reaction is carried out at a temperature of about 0°C to about 100°C. In some embodiments, the temperature is approximately 33°C. In some embodiments, the purity of the prepared compound C is greater than 90%, as measured by high-performance liquid chromatography (HPLC). In some embodiments, the purity of the prepared compound C is greater than 95%, as measured by HPLC. In some embodiments, the purity of the prepared compound C is greater than 98%, as measured by HPLC.

[0055] In some aspects, this disclosure provides a method for preparing omasorone.The method comprises:

[0056] (a) reacting

[0057]

[0058] with dimethyl sulfate and potassium carbonate in the presence of tetrabutylammonium bromide to form

[0059] (page 6 / 89 of specification, CN 121794280 A);

[0060] (b) reacting

[0061]

[0062] with m-chloroperoxybenzoic acid to form

[0063] ;

[0064] (c) reacting

[0065] ;

[0066] with perbromopyridine to form

[0067] ;

[0068] (d) reacting

[0069] (page 7 / 89 of specification, CN 121794280 A);

[0070] reacting with

[0071] ,

[0072] diisopropylethylamine and dimethyl sulfoxide to form

[0073] ;

[0074] (e) causing

[0075] ;

[0076] to react with sodium methoxide to form

[0077] ;

[0078] (f) causing

[0079] ;

[0080] to react with hydroxylamine and hydrochloric acid to form

[0081] ;

[0082] (g) causing

[0083] ;

[0084] to react with sodium methoxide to form

[0085] ;

[0086] (h) causing

[0087] ;

[0088] to react with

[0090]

[0091] ;

[0092] (i) causing

[0093] ;

[0094] Reaction with pyridine to form

[0095] ;

[0096] (j) causing

[0097] ;

[0098] reacting under conditions suitable for forming

[0099]

[0100] ;

[0101] (k) causing

[0102] (page 23, CN 121794280 A, specification 10 / 89);

[0103] reacting with diphenylphosphine azide and triethylamine to form

[0104] ;

[0105] (l) heating

[0106] ;

[0107] to form

[0108] ;

[0109] (m) causing

[0110] ;

[0111] reacting under conditions suitable for forming

[0112]

[0113] (page 24, CN 121794280 A, specification 11 / 89); and

[0114] (n)

[0115]

[0116] react with

[0117]

[0118] to form omasoron. Brief Description of the Drawings

[0119] The following drawings form part of this specification.And are included to further illustrate certain aspects of the invention. The invention can be better understood by referring to one or more of these figures and in conjunction with the detailed description of the specific embodiments given herein.

[0120] Figure 1 shows the synthesis of compound D ((4aS,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrocarboxylic acid-4a(2H)-formic acid) using oleanolic acid ((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-2,2,6a, The scheme of 6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecylhydrofuran-4a(2H)-methyl formate. Compound A ((4aS,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrofuran-4a(2H)-formate) was prepared from oleanolic acid using Me2SO4, K2CO3, TBABr, 2-MeTHF and water. Compound B ((4aS,6aR,6bR,8aR,10S,12aR,14aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14-oxoeicosyl-4a(2H)-formate) was prepared from compound A by sequentially using mCPBA, DCM and MsOH. Compound C ((4aS,6aR,6bS,8aR,10S,12aS,14aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14-oxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecylhydrofuran-4a(2H)-formate) was prepared from compound B using PyH*Br3 and PhMe. Compound D was prepared from compound C.Prepared using T3P, DMSO, DIPEA and EtOAc.

[0121] Figure 2 shows the scheme for synthesizing omasoron (N-[(4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,7,8,8a,14a,14b-decahydro-4a-yl]-2,2-difluoropropionamide) using compound D as the starting material. Compound E ((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-formyl-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecylhydrofuran-4a(2H)-methyl formate) was prepared from compound D using NaOMe, ethyl formate, EtOH and HCl. Compound F ((4aS,6aR,6bS,8aR,13aS,15aR,15bS)-2,2,6a,6b,9,9,13a-heptamethyl-15-oxo-1,3,4,5,6,6a,6b,7,8,8a,9,13,13a,15,15a,15b-hexadecylhydro[2,3-d]isoxazole-4a(2H)-methyl formate) was prepared from compound E using NH2OH:HCl, DCM, H2O and MeOH. Compound G ((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecylhydrofuran-4a(2H)-formate) was prepared from compound F using NaOMe, MeOH, DCM and HCl. Compound H (methyl(4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-bromo-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecylhydrofuran-4a(2H)-formate) is derived from compound G.Compound J ((4aS,6aR, 6bS,8aR,12aS,14aR,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-hexadecylhydrofuran-4a(2H)-formate) was prepared from compound H using pyridine, DMF, DCM, H2O, and EtOH. Compound K ((4aS,6aR,6bS,8aR,12aS,14aR,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-hexadecylhydrofuran-4a(2H)-formic acid) was prepared from compound J using LiBr and DMAc. Compound L ((4aS, 6aR, 6bS, 8aR, 12aS, 14aR, 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-hexadecylhydro-4a(2H)-acylazide) was prepared from compound K using DPPA, Et3N and toluene. Compound N ((4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-amino-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydro-2-carboxynitrile) is derived from compound M ((4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-isocyano-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9, 10,11,12,12a,12b,13,14b-octadecylhydrocarbamate-2-carboxynitrile), prepared using H3PO4, H2O, toluene, K2CO3, H2O, and EtOAc. Omasoron is prepared from compound N using 2,2-difluoropropionic acid, T3P, DIPEA, EtOAc, EtOAc / n-heptane, and acetone / IPA / H2O. Detailed Embodiments

[0122] In one aspect of this disclosure, a novel method for preparing triterpenoid derivatives such as omamasoron (RTA-408) is provided. In some embodiments,The method of the present invention can be used to prepare ursolic acid or oleanolic acid derivatives. In some embodiments, the triterpenoid derivative is an oleanolic acid derivative. In other embodiments, the method of the present invention can be used to prepare omasorone or related triterpenoid derivatives (see Schemes 1 and 2 below). In other embodiments, the method of the present invention can be used to prepare CDDO (RTA 401), which can then be further converted into omasorone as described in U.S. Patent 8,993,640, which is incorporated herein by reference in its entirety. In some embodiments, the method of the present invention can be used to prepare (4aS, 6aR, 6bS, 8aR, 12aS, 14aR, 14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,7,8,8a,14a,14b-decahydrofuran-4a-carboxylate (RTA 402) and / or N-[(4aS, 6aR, 6bS, 8aR, 12aS, 14aR, 14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,7,8, 8a,14a,14b-decahydro-4a-yl]-2,2-difluoropropionamide (Omasolone), as shown in schemes 1 and 2. In some embodiments, the method of the present invention improves the method for introducing the triterpenoid skeleton of bardoxolone and omasolone. The method of the present invention improves the synthesis of triterpenoid compounds that can be further derivatized into different triterpenoid derivatives.

[0123] Specification 14 / 89 page 27 CN 121794280 A

[0124]

[0125] In some aspects, the preparation of triterpenoid derivatives and intermediate compounds in the synthesis of triterpenoid derivatives according to the methods provided herein will increase the availability of triterpenoid derivatives, for example, for therapeutic use or for research related to drug development. Specification 15 / 89 page 28 CN 121794280 A In some embodiments, the methods described in the following sections, whether used in combination or alone, are advantageous for forming the target compounds described below, and particularly advantageous for forming the triterpenoid derivatives described below on an industrial scale. In some embodiments, the methods disclosed in this invention include improved methods for purifying intermediate compounds in the synthesis of triterpenoid derivatives or triterpenoid derivatives, particularly improved methods for purifying such compounds on an industrial scale. In some embodiments, the methods disclosed in this invention include improved methods for isolating intermediate compounds in the synthesis of triterpenoid derivatives or triterpenoid derivatives, particularly improved methods for isolating such compounds on an industrial scale.

[0126] As previously stated,The methods disclosed in this invention can be used to form triterpenoid derivatives. It has been demonstrated that the synthesis of triterpenoid derivatives, including oleanolic acid derivatives methylbardocoxone and omasolene, are inhibitors of cellular inflammatory processes, such as IFN-γ-induced inducible nitric oxide synthase (iNOS) and COX-2 in mouse macrophages. Studies have shown that compounds derived from oleanolic acid affect the function of multiple protein targets, thereby regulating the activity of several important cellular signaling pathways related to oxidative stress, cell cycle control, and inflammation. For example, the currently disclosed methods can be used to form methylbardocoxone or triterpenoid derivatives that are intermediates in the synthetic pathways of target compounds of methylbardocoxone or other triterpenoid derivatives. The efficacy of methylbardocoxone for the treatment and prevention of diabetic nephropathy and chronic kidney disease has been evaluated in phase II and phase III clinical trials. The currently disclosed methods can be used to form omasolidon or triterpenoid derivatives that are intermediates in the synthetic pathway of omasolidon or other triterpenoid derivative target compounds (see Scheme 1, Scheme 2, and U.S. Patent 8,993,640, which is incorporated herein by reference). The efficacy of omasolidon in treating Friedrich's ataxia has been evaluated in Phase I and Phase II clinical trials. This disclosure provides improved methods for forming these compounds, or for forming intermediates in the synthetic pathways of these compounds, and thus improves the pathways to obtaining these important therapeutic compounds. Currently known methods for forming triterpenoid derivatives and their applications have been disclosed in, for example, the following publications: Fu and Gribble, 2013; Wong et al., 2016; Honda et al., 1997; Honda et al., 1998; Honda et al., 1999; Honda et al., 2000a; Honda et al., 2000b; Honda et al., 2002; Suh et al., 1998; Suh et al., 1999; Place et al., 2003; Liby et al., 2005; and U.S. Patents 7,915,402, 7,943,778, and 8,071. References 632, 8,124,799, 8,129,429, 8,338,618, 8,993,640, 9,102,681, 9,701,709, 9,512,094, 9,889,143, 10,093,614, and 10,556,858 are incorporated herein by reference. The advantages of the methods disclosed herein compared to these references will be discussed in more detail below.

[0127] In some aspects, compared to previous methods,The methods provided herein may involve, for example, increasing the yield of compound D ((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecylhydrofuran-4a(2H)-formate) or compound IV, improving the purity of compound D or compound IV, and increasing the efficiency of preparing compound D or compound IV. The synthetic procedure for compound D or formula IV is simplified, the reaction conditions for manufacturing compound D or formula IV are milder, the safety of preparing compound D or formula IV is increased, the reaction time or manufacturing time of compound D or formula IV is shortened, the number of intermediates in the preparation of compound D or formula IV is reduced, the use or generation of undesirable byproducts in the preparation of compound D or formula IV is reduced, and / or the cost of preparing compound D or formula IV is reduced.

[0128] This disclosure provides alternative methods for preparing triterpenoid derivatives that may be superior to existing methods. The currently disclosed methods can reduce the cost or time of forming an acceptable combination of yield and purity of the target triterpenoid derivative, or can reduce the cost or time of purifying the target triterpenoid derivative, or can reduce the cost or time of isolating the target triterpenoid derivative. For example, compared to known methods, the currently disclosed methods can reduce the formation of unwanted byproducts during the formation, purification, or separation of the target triterpenoid compound, reduce the number of steps in the formation of the target triterpenoid compound, simplify the procurement of substances in the formation, purification, or separation of the target triterpenoid derivative, or reduce the cost of substances in the formation, purification, or separation of the target triterpenoid derivative. In some embodiments, the methods of the present invention are safer or require simpler reaction procedures compared to prior methods. The methods of the present invention may be advantageous on an industrial scale compared to known methods, for example, by including reactions carried out under mild reaction conditions, shortening manufacturing time or cycle time, or using compounds that are less expensive than those used in known methods. These examples of advantageous properties should not be construed as limiting the possible advantages of the methods disclosed in the present invention in any way.

[0129] In some embodiments, the currently disclosed methods produce higher yields of triterpenoid derivatives by mass or yield percentage compared to known methods. For example,The method presented herein improves the purity or yield of the chemical transformation of compound A ((4aS,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrofuran-4a(2H)-formate) to compound B ((4aS,6aR,6bR,8aR,10S,12aR,14aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14-oxoeicosylhydrofuran-4a(2H)-formate). See Figure 1. The method of the present invention also improves the purity or yield of several conversion reactions (e.g., the multi-step conversion of oleanolic acid to compound D ((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecylhydrofuran-4a(2H)-formate methyl ester) shown in Figure 1). In some embodiments, the synthetic pathway of the method of the present invention has the advantage of improved purification of compounds in downstream reactions. In some embodiments, the currently disclosed method produces fewer unwanted byproducts or impurities compared to known methods. In some embodiments of the method described below, impurities in the crude product are easier to identify than in corresponding known methods, which facilitates impurity removal. In some embodiments, the method of the present invention exhibits reduced yield loss compared to corresponding known methods. In some embodiments, the purity of the isolated triterpenoid derivatives is higher than that prepared according to corresponding known methods. In some embodiments, the method of the present invention is safer than corresponding known methods. In some embodiments, the method of the present invention for forming triterpenoid derivatives is not limited by reaction equipment requirements compared to corresponding known methods; a non-limiting example of reaction equipment requirements is reactor size. In some embodiments, the method of the present invention has favorable experimental conditions or allows greater flexibility in experimental parameters compared to known methods, while achieving the same or improved yield and / or purity of the target compound. Non-limiting examples of experimental parameters include reaction temperature, reaction vessel size, reaction time, reaction pressure, reaction solvent, stoichiometry of the reaction, or pH of the reaction. Further relevant details will be provided in subsequent sections and examples.

[0130] The currently disclosed method relates to the use of compounds superior to those used in known methods, including examples of various compound classes. Non-limiting examples of compound classes that can be used in the currently disclosed method are acids, bases, oxidizing agents, and reducing agents. In some embodiments,The present invention discloses embodiments using compounds that are safer, less costly, easier to handle, less toxic, or more environmentally friendly than those used in known methods. In some embodiments, the compounds used in the currently disclosed methods are easier to remove if the desired removal is desired; or, byproducts formed by the compounds used in the currently disclosed methods are easier to remove than those formed by compounds used in known methods.

[0131] In some embodiments, the currently disclosed methods allow for better processing or separation conditions than known methods. In some embodiments, the crude or purified target compounds formed according to the methods of the present invention have improved physical morphology. In some embodiments, the improved physical morphology contributes to improved separation of triterpenoids. In some embodiments, the triterpenoids formed or purified according to the current methods have improved filtration performance or improved filtration time. In some embodiments, the solvents used for processing or separating the target compounds according to the methods disclosed herein are superior to those used in known methods. In some embodiments, the methods of the present invention can reduce the amount of solvent required to separate or purify these compounds. In some embodiments, the solvents used for purifying or separating compounds synthesized according to the methods of the present invention may be less costly, less toxic, or more environmentally friendly than solvents used in previous methods. In some embodiments, either or both of the reaction solvents or processing solvents used in the method disclosed herein (pages 17 / 89, 30 CN 121794280 A) can be removed in a shorter time, with less energy, in a more environmentally friendly manner, or at a lower cost, compared to corresponding prior methods. In some embodiments, the method of the present invention discloses solvents used in the formation, purification, or separation steps of the preparation of triterpenoid compounds. In this way, the method of the present invention reduces the cost and complexity of the preparation of triterpenoid compounds.

[0132] Currently disclosed methods may include reagents, solvents, or steps that form unwanted water-soluble byproducts. Therefore, the method of the present invention allows for alternatives to obtain pure target compounds. These alternatives can provide benefits in any combination of the formation, purification, or separation of triterpenoid derivatives according to the method of the present invention, especially on an industrial scale, and non-limiting examples of such benefits may include reduced costs, reduced waste generation, shortened time required, improved energy efficiency, increased safety, or any combination of these benefits. See the “Examples” section below for further details.

[0133] In some aspects, this disclosure provides a multi-step method for preparing omasorone from oleanolic acid, the method comprising using a compound of formula I as a reagent in one or more steps, wherein formula I is defined as:

[0134] (I),

[0135] Wherein:

[0136] R1, R1' and R1'' are each independently hydrogen, halogenated, amino, cyano or carboxyl; or

[0137] alkyl (C≤8), cycloalkyl (C≤8), alkenyl (C≤8), alkynyl (C≤8), aryl (C≤8), aralkyl (C≤8), heteroaryl (C≤8), heteroaryl (C≤8), alkoxy (C≤8), cycloalkoxy (C≤8), alkenyloxy (C≤8), alkynyloxy (C≤8), aryloxy (C≤8), arylalkoxy (C≤8), heteroaryloxy (C≤8), heteroarylalkoxy (C≤8), alkylamino (C≤8), dialkylamino (C≤8), amide (C≤8) or a substituted form of any of these groups.

[0138] In some embodiments, the compound of formula I is used as a reagent in a two-step reaction. In some embodiments, R1, R1', and R1'' are each independently alkyl (C≤8) or substituted alkyl (C≤8). In some embodiments, R1, R1', and R1'' are each alkyl (C≤8), such as propyl.

[0139] In some embodiments, the method further includes reacting oleanolic acid with an alkylating agent in a reaction mixture under conditions suitable for forming compound A, wherein compound A is defined as:

[0140] (A).

[0141] In some embodiments, the reaction mixture further comprises a base, such as potassium carbonate. In some embodiments, the base is substantially free of sodium carbonate. In some embodiments, the reaction mixture further comprises a solvent, such as an organic solvent. In some embodiments, the organic solvent is substantially 2-methyltetrahydrofuran. In some embodiments, the organic solvent is substantially free of tetrahydrofuran.

[0142] In some embodiments, the reaction mixture further comprises a phase transfer catalyst, such as a quaternary ammonium salt. In some embodiments, the phase transfer catalyst is tetrabutylammonium bromide. In some embodiments, the alkylating agent is dimethyl sulfate. In some embodiments, the method further includes reacting oleanolic acid with an alkylating agent at a first temperature of about 10°C to about 40°C. In some embodiments, the first temperature is about 25°C to about 35°C. In some embodiments, the first temperature is about 30°C.

[0143] In some embodiments, the method further includes a first reaction time period of about 0.5 hours to about 2.0 hours. In some embodiments, the first reaction time period is about 0.75 hours to about 1.25 hours. In some embodiments, the first reaction time period is about 1.0 hour. In some embodiments, the method further includes contacting the reaction mixture with a quenching agent at a second temperature for a second time period. In some embodiments, the quenching agent is a base, such as a tertiary amine. In some embodiments,The quenching agent is triethylamine.

[0144] In some embodiments, the second temperature is about 40°C to about 60°C. In some embodiments, the second temperature is about 45°C to about 55°C. In some embodiments, the second temperature is about 50°C. In some embodiments, the second time period is about 2.0 hours to about 6.0 hours. In some embodiments, the second time period is about 2.0 hours to about 5.0 hours. In some embodiments, the second time period is about 3.0 hours. In some embodiments, the method produces at least about 1000 grams of compound A. In some embodiments, the method produces at least about 100 kilograms of compound A. In other embodiments, the method produces at least about 400 kilograms of compound A. In other embodiments, the method produces about 500 kilograms to about 1500 kilograms of compound A. In some embodiments, the method produces about 1000 kilograms of compound A.

[0145] In some embodiments, the reaction mixture further comprises a base, such as potassium carbonate. In some embodiments, the base is substantially free of sodium carbonate.

[0146] In some embodiments, the method further includes reacting compound A with an oxidant in a reaction mixture under conditions suitable for forming compound B:

[0147] (A)

[0148] wherein compound B is defined as:

[0149] (B).

[0150] In some embodiments, the oxidant comprises peroxybenzoic acid (C≤12), such as m-chloroperoxybenzoic acid. In some embodiments, the oxidant is substantially free of peracetic acid. In some embodiments, the molar ratio of compound A to the oxidant in the reaction mixture is about 2:1 to about 1:2. In some embodiments, the molar ratio is about 1:1 to about 2:3. In some embodiments, the molar ratio is about 4:5. In some embodiments, the reaction mixture also comprises a solvent, such as an organic solvent. In some embodiments, the organic solvent is dichloromethane.

[0151] In some embodiments, the method further includes reacting compound A with the oxidant at a temperature of about 10°C to about 40°C. In some embodiments, the temperature is about 20°C to about 30°C. In other embodiments, the temperature is about 25°C.

[0152] In some embodiments, the method further includes a reaction time period of about 10 hours to about 20 hours when compound A reacts with the oxidant. In some embodiments, the reaction time period is about 13 hours to about 17 hours. In some embodiments, the reaction time period is about 15 hours.

[0153] In some embodiments, the method further includes contacting the reaction mixture with a sodium bicarbonate solution and separating the organic layer. In some embodiments,The method further includes contacting the separated organic layer with an alkyl sulfonic acid (C≤8) such as methanesulfonic acid. In some embodiments, the method produces at least about 1000 grams of compound B. In some embodiments, the method produces at least about 100 kilograms of compound B. In other embodiments, the method produces about 325 kilograms to about 425 kilograms of compound B. In yet another embodiment, the method produces about 375 kilograms of compound B.

[0154] In some embodiments, the method further includes reacting compound B with an oxidant in a reaction mixture under conditions suitable for forming compound C:

[0155] (B)

[0156] wherein compound C is defined as:

[0157] (C).

[0158] In some embodiments, the oxidant is a perbrominate, such as pyridine perbrominate. In some embodiments, the molar ratio of compound B to the oxidant in the reaction mixture is about 2:1 to about 1:5. In some embodiments, the molar ratio is about 1:1 to about 1:2. In some embodiments, the reaction mixture also contains a solvent, such as an organic solvent. In some embodiments, the organic solvent is toluene. In some embodiments, the reaction mixture is substantially free of molecular bromine. In some embodiments, the reaction mixture is substantially free of acetonitrile.

[0159] In some embodiments, the method further includes reacting compound B with an oxidant at a temperature of about 20°C to about 40°C. In some embodiments, the temperature is about 28°C to about 38°C. In other embodiments, the temperature is about 33°C. In some embodiments, the method further includes a reaction period of about 1 hour to about 5 hours in which compound B reacts with the oxidant. In some embodiments, the reaction period is about 2 hours to about 4 hours. In some embodiments, the reaction period is about 2 hours. In some embodiments, the method produces at least about 1000 grams of compound C. In some embodiments, the method produces at least about 100 kilograms of compound C. In some embodiments, the method produces about 100 kilograms to about 500 kilograms of compound C. In other embodiments, the method produces about 300 kilograms to about 350 kilograms of compound C. In yet another embodiment, the method produces about 320 kilograms of compound C.

[0160] In some embodiments, the method further includes causing compound C: Specification 20 / 89 page 33 CN 121794280 A

[0161] (C)

[0162] to react with an oxidant in the presence of a compound of formula I:

[0163] (I)

[0164] in a reaction mixture to form compound D, wherein compound D is defined as:

[0165] (D),

[0166] Wherein:

[0167] R1, R1' and R1'' are each independently hydrogen, halo, amino, cyano or carboxyl; or alkyl (C≤8), cycloalkyl (C≤8), alkenyl (C≤8), alkynyl (C≤8), aryl (C≤8), aralkyl (C≤8), heteroaryl (C≤8), heteroaryl (C≤8), alkoxy (C≤8), cycloalkoxy (C≤8), alkenyloxy (C≤8), alkynyloxy (C≤8), aryloxy (C≤8), arylalkoxy (C≤8), heteroaryloxy (C≤8), heteroarylalkoxy (C≤8), alkylamino (C≤8), dialkylamino (C≤8), amide (C≤8), or a substituted form of any of these groups.

[0168] In some embodiments, R1, R1' and R1'' are each independently alkyl (C≤8) or substituted alkyl (C≤8). In some embodiments, R1, R1', and R1'' are each alkyl (C≤8), such as propyl. In some embodiments, the reaction mixture comprises a compound C in a molar ratio of about 2:1 to about 1:5 with respect to the compound of formula I. In some embodiments, the molar ratio is about 1:1 to about 1:2. In other embodiments, the molar ratio is about 1:1.6. In some embodiments, the molar ratio is about 1:1.35. In some embodiments, the reaction mixture further comprises a base. In some embodiments, the base is an amine, such as diisopropylethylamine.

[0169] In some aspects, the reaction mixture comprises a compound C in a molar ratio of about 2:1 to about 1:5 with respect to the base. In some aspects of these aspects, the molar ratio is about 1:1 to about 1:2. In some aspects, the reaction mixture further comprises an oxidizing agent, such as dimethyl sulfoxide. In some aspects, the reaction mixture comprises a molar ratio of compound C to an oxidizing agent, wherein the molar ratio is about 1:5 to about 1:10. In some aspects, the molar ratio is about 1:4 to 1:7. In other aspects, the molar ratio is about 1:6.8. In some aspects, the molar ratio is about 1:5.5. In some aspects, the method further includes reacting compound C with the compound of formula I under an inert atmosphere. In some aspects, the inert atmosphere is essentially nitrogen.

[0170] In some aspects, a solution containing the compound of formula I is used in the reaction between compound C and an oxidant (such as dimethyl sulfoxide). In some embodiments, the concentration of the compound of formula I in the solution is about 30% to about 70% by weight. In some embodiments, the concentration of the compound of formula I in the solution is about 40% to about 60% by weight. In other embodiments, as described on page 21 / 89 of CN 121794280 A, the concentration of the compound of formula I in the solution is about 50% by weight. In some embodiments, the solution contains an organic solvent, such as ethyl acetate.

[0171] In some embodiments,The reaction of compound C with the oxidant in the presence of the compound of formula I is carried out at a temperature of about -10°C to about 50°C. In some embodiments, the temperature is about -5°C to about 40°C. In other embodiments, the temperature is about 20°C to about 30°C. In still other embodiments, the temperature is about 25°C. In some embodiments, the reaction of compound C with the oxidant in the presence of the compound of formula I is carried out for a reaction period of about 0.5 hours to about 5 hours. In some embodiments, the reaction period is about 2 hours to about 4 hours. In other embodiments, the reaction period is about 3 hours. In some embodiments, the method produces at least about 1000 grams of compound D ((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecylhydrofuran-4a(2H)-formate). In some embodiments, the method produces at least about 100 kilograms of compound D. In other embodiments, the method produces at least about 250 kilograms to about 500 kilograms of compound D. In still other embodiments, the method produces about 410 kilograms of compound D.

[0172] In some embodiments, the reaction mixture substantially does not contain an iodine-containing oxidant, such as potassium 2-iodo-5-methylbenzenesulfonate, Dess-Martin periodide, or 2-iodooxybenzoic acid. In some embodiments, the reaction mixture substantially does not contain Oxone® (potassium peroxymonosulfate). In other embodiments, the reaction mixture substantially does not contain toluene. In some embodiments, the method does not include a hydrogenation step.

[0173] In some aspects, the method further includes reacting compound D:

[0174] (D)

[0175] with an acylating agent in the reaction mixture under conditions suitable for forming compound E, wherein compound E is defined as:

[0176] (E).

[0177] In some embodiments, the reaction mixture also contains a solvent, such as an organic solvent. In some embodiments, the solvent is substantially ethanol. In some embodiments, the acylating agent is ethyl formate. In some embodiments, the reaction mixture also contains a base. In some embodiments, the base is sodium methoxide. In some embodiments, the method produces at least about 500 grams of compound E. In some embodiments, the method produces at least about 1000 grams of compound E.

[0178] In some embodiments, the method further includes, under conditions suitable for the formation of compound F,Compound E: (E)

[0179] (Page 35, CN 121794280 A)

[0180] is reacted in a reaction mixture, wherein compound F is defined as:

[0181] (F).

[0182] In some embodiments, the reaction mixture further comprises hydroxylamine. In some aspects, the method produces at least about 500 grams of compound F. In some aspects, the method produces at least about 1000 grams of compound F. In other aspects, the method produces about 50 kg to about 500 kg of compound F. In yet another aspect, the method produces about 150 kg to about 300 kg of compound F. In yet another aspect, the method produces about 175 kg to about 275 kg of compound F. In yet another aspect, the method produces about 190 kg to about 235 kg of compound F.

[0183] In some embodiments, the method further includes reacting compound F:

[0184] (F)

[0185] in a reaction mixture under conditions suitable for forming compound G, wherein compound G is defined as:

[0186] (G).

[0187] In some embodiments, the reaction mixture further comprises sodium methoxide. In some embodiments, the method produces at least about 500 grams of compound G. In some embodiments, the method produces at least about 1000 grams of compound G.

[0188] In some embodiments, the method further includes reacting compound G:

[0189] (G)

[0190] with a compound having the following structure:

[0191]

[0192] in a reaction mixture under conditions suitable for forming compound H, wherein compound H is defined as:

[0193] (H).

[0194] In some embodiments, the reaction mixture further comprises a solvent. In some embodiments, the solvent is an organic solvent, such as N,N-dimethylformamide. In some embodiments, the method produces at least about 500 grams of compound H. In some embodiments, the method produces at least about 1000 grams of compound H.

[0195] In some embodiments, the method further includes causing compound H to react in a reaction mixture under conditions suitable for forming compound J:

[0196] (H)

[0197] wherein compound J is defined as:

[0198] (J).

[0199] In some embodiments, the reaction mixture further comprises a solvent. In some embodiments, the solvent is an organic solvent, such as N,N-dimethylformamide. In some embodiments, the reaction mixture further comprises a base, such as pyridine. In some embodiments, the reaction produces at least about 500 grams of compound J. In some embodiments, the reaction produces at least about 1000 grams of compound J. In other embodiments,The reaction produces about 100 kg to about 500 kg of compound J. In other embodiments, the reaction produces about 100 kg to about 300 kg of compound J. In still other embodiments, the reaction produces about 125 kg to about 250 kg of compound J. In still other embodiments, the reaction produces about 150 kg to about 190 kg of compound J.

[0200] In some embodiments, the method further includes reacting compound J in a reaction mixture under conditions suitable for forming compound K:

[0201] (J)

[0202] wherein compound K is defined as:

[0203] (K).

[0204] In some aspects, the reaction mixture further comprises a solvent. In some aspects, the solvent is an organic solvent, such as dimethylacetamide. In some aspects, the reaction mixture further comprises lithium bromide. In some aspects, the method produces at least about 500 g of compound K. In some aspects, the method produces at least about 1000 g of compound K. In other aspects, the method produces about 10 kg to about 200 kg of compound K. In still other aspects, the method produces about 50 kg to about 150 kg of compound K. In some aspects, the method produces about 85 kg to about 105 kg of compound K.

[0205] In some aspects, the method further includes reacting compound K in a reaction mixture under conditions suitable for forming compound L:

[0206] (K)

[0207] wherein compound L is defined as:

[0208] (L).

[0209] In some aspects, the reaction mixture further comprises a solvent. In some aspects, the solvent is an organic solvent, such as toluene. In some aspects, the reaction mixture further comprises an azide, such as diphenylphosphine azide. In some aspects, the reaction mixture further comprises triethylamine. In some aspects, the method produces at least about 500 g of compound L. On some pages 25 / 89 of the specification 38 CN 121794280 A, the method produces at least about 1000 g of compound L.

[0210] In some embodiments, the method further includes reacting compound L:

[0211] (L)

[0212] in a reaction mixture under conditions suitable for forming compound M, wherein compound M is defined as:

[0213] (M).

[0214] In some embodiments, the method includes heating compound L in a solvent. In some embodiments, a solution of compound L is heated at a temperature of about 50°C to about 100°C. In some embodiments, the solution is heated at about 80°C. In some embodiments, the solvent is an organic solvent, such as benzene. In some embodiments, the method produces at least about 500 grams of compound M. In some embodiments,The method produces at least about 1000 grams of compound M.

[0215] In some embodiments, the method further includes reacting compound M:

[0216] (M)

[0217] in a reaction mixture under conditions suitable for forming compound N, wherein compound N is defined as:

[0218] (N).

[0219] In some embodiments, the reaction mixture further comprises a solvent, such as an organic solvent. In some embodiments, the solvent is substantially toluene. In some embodiments, the reaction mixture further comprises an acid, such as phosphoric acid. In some embodiments, the method produces at least about 500 grams of compound N. In some embodiments, the method produces at least about 1000 grams of compound N. In other embodiments, the method produces about 25 kg to about 200 kg of compound N. In yet another embodiment, the method produces about 50 kg to about 150 kg of compound N. In yet another embodiment, the method produces about 95 kg to about 115 kg of compound N. Specification 26 / 89 pages 39 CN 121794280 A

[0220] In some embodiments, the method further includes, under conditions suitable for forming omasorone, reacting compound N:

[0221] (N)

[0222] with a compound having the following structure:

[0223]

[0224] in the presence of a coupling agent of formula I:

[0225] (I)

[0226] in a reaction mixture, wherein:

[0227] R1, R1' and R1'' are each independently hydrogen, halogenated, amino, cyano or carboxyl; or alkyl (C≤8), cycloalkyl (C≤8), Alkenyl (C≤8), alkynyl (C≤8), aryl (C≤8), aralkyl (C≤8), heteroaryl (C≤8), heteroaryl (C≤8), alkoxy (C≤8), cycloalkoxy (C≤8), alkenyloxy (C≤8), alkynyloxy (C≤8), aryloxy (C≤8), arylalkoxy (C≤8), heteroaryloxy (C≤8), heteroarylalkoxy (C≤8), alkylamino (C≤8), dialkylamino (C≤8), amide (C≤8), or substituted forms of any of these groups.

[0228] In some embodiments, R1, R1', and R1'' are each independently alkyl (C≤8) or substituted alkyl (C≤8). In some embodiments, R1, R1', and R1'' are each alkyl (C≤8), such as propyl. In some embodiments, the reaction mixture further comprises a solvent, such as an organic solvent. In some embodiments, the solvent is substantially ethyl acetate. In some embodiments, the reaction mixture comprises a compound N in a molar ratio of about 2:1 to about 1:5 to a coupling agent of formula I. In some embodiments, the molar ratio is about 1:1 to about 1:2. In other embodiments, the molar ratio is about 1:1.6. In some embodiments,The reaction mixture also contains a base, such as an amine. In some embodiments, the amine is diisopropylethylamine.

[0229] In some embodiments, the molar ratio of compound N to the base in the reaction mixture is about 2:1 to about 1:5. In some embodiments, the molar ratio is about 1:1 to about 1:2. In other embodiments, the molar ratio is about 1:1.6. In some embodiments, the method further includes reacting compound N with a coupling agent of formula I under an inert atmosphere. In some embodiments, the inert atmosphere is essentially nitrogen. In some embodiments, reacting compound N with the coupling agent of formula I further includes contacting compound N with a solution containing the coupling agent of formula I. In some embodiments, the method produces at least about 500 grams of omaxolone. In some embodiments, the method produces at least about 1000 grams of omaxolone. In other embodiments, the method produces about 50 kg to about 125 kg of omaxolone. In yet another embodiment, the method produces about 75 kg to about 95 kg of omaxolone.

[0230] In some aspects, this disclosure describes a method for preparing a compound of formula III, the method comprising obtaining a compound of formula II: (II),

[0232] or a salt thereof, and in a reaction mixture, reacting the compound of formula II with an oxidizing agent in the presence of a compound of formula I:

[0233] (I)

[0234] under conditions suitable for forming a compound of formula III:

[0235] (III)

[0236] or a salt thereof, wherein:

[0237] R1, R1' and R1'' are each independently hydrogen, halo, amino, cyano or carboxyl; or alkyl (C≤8), cycloalkyl (C≤8), Alkenyl (C≤8), alkynyl (C≤8), aryl (C≤8), aralkyl (C≤8), heteroaryl (C≤8), heteroaralkyl (C≤8), alkoxy (C≤8), cycloalkoxy (C≤8), alkenyloxy (C≤8), alkynyloxy (C≤8), aryloxy (C≤8), arylalkoxy (C≤8), heteroaryloxy (C≤8), heteroarylalkoxy (C≤8), alkylamino (C≤8), dialkylamino (C≤8), amide (C≤8), or a substituted form of any of these groups; and R2 is: C1-C15-acyl or C1-C15-alkyl, wherein any of these groups is substituted or unsubstituted.

[0238] In some embodiments, R1, R1', and R1'' are each independently alkyl (C≤8) or substituted alkyl (C≤8). In some embodiments, R1, R1', and R1'' are each alkyl (C≤8), such as propyl. In some embodiments, R2 is a C1-C15-acyl group or a substituted C1-C15-acyl group. In some embodiments,R2 is a substituted C1-C15-acyl group, such as -CO2CH3. In some embodiments, the reaction mixture contains a molar ratio of the compound of formula II to the compound of formula I of about 2:1 to about 1:5. In some embodiments, the molar ratio is about 1:1 to about 1:2. In other embodiments, the molar ratio is about 1:1.6. In some embodiments, the reaction mixture further contains a base. In some embodiments, the base is an amine, such as diisopropylethylamine.

[0239] In some embodiments, the reaction mixture contains a molar ratio of the compound of formula II to the base of about 2:1 to about 1:5. In some embodiments, the molar ratio is about 1:1 to about 1:2. In other embodiments, the molar ratio is about 1:1.6. In some embodiments, the molar ratio is about 1:1.4. In some embodiments, the molar ratio is about 1:1.35. In some embodiments, the reaction mixture further contains an oxidizing agent, such as dimethyl sulfoxide. In some aspects, the reaction mixture comprises a molar ratio of a compound of formula II to an oxidant, wherein the molar ratio is about 1:5 to about 1:10. In some embodiments, the molar ratio is about 1:5 to about 1:7. In other embodiments, the molar ratio is about 1:6.8. In some embodiments, the molar ratio is about 1:5.5. Specification 28 / 89 pages 41 CN 121794280 A

[0240] In some embodiments, the method further comprises reacting the compound of formula II with the compound of formula I under an inert atmosphere. In some embodiments, the inert atmosphere is essentially nitrogen. In some embodiments, a solution containing the compound of formula I is used in the reaction of the compound of formula II with the oxidant. In some embodiments, the concentration of the compound of formula I in the solution is about 30% to about 70% by weight. In some embodiments, the concentration of the compound of formula I in the solution is about 40% to about 60% by weight. In other embodiments, the concentration of the compound of formula I in the solution is about 50% by weight. In some embodiments, the solution comprises a solvent. In some embodiments, the solvent is an organic solvent, such as ethyl acetate.

[0241] In some embodiments, the method further includes reacting the compound of formula II with the compound of formula I at a temperature of about -10°C to about 50°C. In some embodiments, the temperature is about -5°C to about 40°C. In other embodiments, the temperature is about 20°C to about 30°C. In still other embodiments, the temperature is about 25°C.

[0242] In some embodiments, the method further includes a reaction time of about 0.5 hours to about 5 hours in which the compound of formula II reacts with the compound of formula I. In some embodiments, the reaction time is about 2 hours to about 4 hours. In other embodiments, the reaction time is about 3 hours. In some embodiments,The method produces at least about 500 grams of compound III. In some embodiments, the method produces at least about 1000 grams of compound III. In other embodiments, the method produces at least about 100 kilograms of compound III. In still other embodiments, the method produces about 100 kilograms to about 500 kilograms of compound III. In other embodiments, the method produces about 200 kilograms to about 400 kilograms of compound III. In some embodiments, the method produces about 300 kilograms of compound III.

[0243] In some embodiments, this disclosure describes a method for preparing omasorone, the method comprising, under conditions suitable for forming omasorone or a pharmaceutically acceptable salt thereof, reacting compound N:

[0244] (N),

[0245] or a salt thereof with 2,2-difluoropropionic acid and a coupling agent of formula I:

[0246] (I)

[0247] in a reaction mixture, wherein:

[0248] R1, R1' and R1'' are each independently hydrogen, halogenated, amino, cyano or carboxyl; or alkyl (C≤8), cycloalkyl (C≤8), Alkenyl (C≤8), alkynyl (C≤8), aryl (C≤8), aralkyl (C≤8), heteroaryl (C≤8), heteroaryl (C≤8), alkoxy (C≤8), cycloalkoxy (C≤8), alkenyloxy (C≤8), alkynyloxy (C≤8), aryloxy (C≤8), arylalkoxy (C≤8), heteroaryloxy (C≤8), heteroarylalkoxy (C≤8), alkylamino (C≤8), dialkylamino (C≤8), amide (C≤8), or substituted forms of any of these groups.

[0249] In some embodiments, R1, R1', and R1'' are each independently alkyl (C≤8) or substituted alkyl1 (C≤8). In some embodiments, R1, R1', and R1'' are each alkyl (C≤8), such as propyl.

[0250] In some embodiments, the reaction mixture further comprises a solvent. In some embodiments, the solvent is an organic solvent, such as ethyl acetate. In some embodiments, the reaction mixture contains compound N in a molar ratio of about 2:1 to about 1:5 with the coupling agent of formula I (see page 29 / 89, 42 CN 121794280 A). In some embodiments, the molar ratio is about 1:1 to about 1:2. In some embodiments, the molar ratio is about 1:1.6. In other embodiments, the reaction mixture further contains a base. In some embodiments, the base is an amine, such as diisopropylethylamine.

[0251] In some embodiments, the reaction mixture contains compound N in a molar ratio of about 2:1 to about 1:5 with the base. In some embodiments, the molar ratio is about 1:1 to about 1:2. In other embodiments, the molar ratio is about 1:1.6. In some embodiments,The method further includes reacting compound N with the coupling agent of formula I under an inert atmosphere. In some embodiments, the inert atmosphere is essentially nitrogen. In some embodiments, reacting compound N with the coupling agent of formula I further includes contacting compound N with a solution containing the coupling agent of formula I.

[0252] In some embodiments, the method further includes reacting compound N with the coupling agent of formula I under an inert atmosphere. In some embodiments, the method produces at least about 500 grams of omasulon. In some embodiments, the method produces at least about 1000 grams of omasulon. In other embodiments, the method produces about 50 kg to about 150 kg of omasulon. In still other embodiments, the method produces about 75 kg to about 95 kg of omasulon.

[0253] In some aspects, this disclosure provides a method for preparing omasorone, the method comprising

[0254] (a) reacting

[0255]

[0256] with dimethyl sulfate and potassium carbonate in the presence of tetrabutylammonium bromide to prepare

[0257] ;

[0258] (b) reacting

[0259]

[0260] with m-chloroperoxybenzoic acid to prepare

[0261] ;

[0262] (c) reacting

[0263] ;

[0264] with perbromopyridine to prepare

[0265] ;

[0266] (d) reacting

[0267] ;

[0268] with dimethyl sulfoxide in

[0269] ,

[0270] Reacted with diisopropylethylamine in the presence of the product specification, page 31 / 89, 44 CN 121794280 A

[0271] ;

[0272] (e) Reacted with sodium methoxide and diethyl formate to prepare

[0275] ;

[0276] (f) Reacted with hydroxylamine hydrochloride to prepare

[0279] ;

[0278] ;

[0280] (g) Reacted with sodium methoxide in the presence of the product specification, page 32 / 89, 45 CN 121794280 A

[0281] ;

[0282] ;

[0283] ;

[0284] (h) Reacted with

[0285] ;

[0286] ;

[0287] ;

[0288] to prepare

[0289]

[0290] (i) Make

[0291] ; Specification 33 / 89 page 46 CN 121794280 A

[0292] react with pyridine to prepare

[0293] ;

[0294] (j) Make

[0295] ;

[0296] react with lithium bromide to prepare

[0297] ;

[0298] (k) Make

[0299] ;

[0300] react with diphenylphosphine azide and triethylamine to prepare

[0301] ;

[0302] (l) Heat Specification 34 / 89 page 47 CN 121794280 A

[0303] ;

[0304] to prepare

[0305] ;

[0306] (m) Make

[0307] ;

[0308]

[0309] is prepared by reacting with phosphoric acid and potassium carbonate; and

[0310] (n) is prepared by reacting

[0311]

[0312] with

[0313] , , Specification 35 / 89 pages 48 CN 121794280 A

[0314] and

[0315]

[0316] to prepare omasorone.

[0317] The examples of advantageous properties listed above are for reference only and should not be construed as limiting the observed or anticipated benefits associated with the formation of the target compound or intermediate according to the methods disclosed herein. Any individual reaction disclosed in this application may exhibit any combination of the above benefits. As mentioned above, compounds formed using the methods disclosed herein may also have one or more other properties that are considered advantageous by those skilled in the art, optionally in combination with any of the properties listed in the foregoing paragraphs.

[0318] I. Formation of C3-oxotriterpenoid derivatives

[0319] On one hand, this disclosure provides a novel method for oxidizing C3-OH triterpenoid derivatives (carbon atom numbering shown in Figure 1) to C3-oxotriterpenoid derivatives (as a non-limiting example,See step 4 in Figure 1 (or the formation of compound D from compound C). In some embodiments, the currently disclosed method is an improvement, advantage, or superior to known methods. In some embodiments, the method disclosed herein is tolerant of other reactive functional groups present in the C3-OH triterpenoid derivative starting material. C3-OH triterpenoid derivatives can be prepared, for example, using the methods described in the following sections or the Examples section, or by other known methods.

[0320] In some embodiments, the currently disclosed methods for preparing C3-oxotriterpenoid derivatives (e.g., compound D in FIG. 1) involve using a compound of formula V:

[0321] (Formula V),

[0322] wherein R10, R10' and R10'' are each independently hydrogen, halogenated, amino, cyano or carboxyl; or alkyl (C≤8), alkenyl (C≤8), alkynyl (C≤8), aryl (C≤8), aralkyl (C≤8), heteroaryl1 (C≤8), heteroarylalkyl (C≤8), alkoxy (C≤8), alkenyloxy (C≤8), alkynyloxy (C≤8), aryloxy (C≤8), arylalkoxy (C≤8), heteroaryloxy (C≤8), heteroarylalkoxy (C≤8), alkylamino (C≤8), dialkylamino (C≤8), amide (C≤8), or a substituted form of any of these groups. The compound of formula V is combined with at least one reagent or compound known to those skilled in the art as an electrophilic target for the C3-OH group in the reactant triterpenoid derivative, wherein the subsequent deprotonation / elimination reaction provides the C3-oxotriterpenoid derivative product. In some embodiments, R10, R10', and R10'' are alkyl (C≤8), alkenyl (C≤8), or alkynyl (C≤8). In a preferred embodiment, R10, R10', and R10'' are alkyl (C≤8), such as propyl. Specification 36 / 89 pages 49 CN 121794280 A

[0323] In some embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) to the compound of formula V is about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, or any range thereof. In some embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) to the compound of formula V is between about 1:1 and 1:2. In a preferred embodiment, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in FIG. 1) to the compound of formula V is about 1:1.6.

[0324] As discussed above, in some embodiments of the methods disclosed herein for forming C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1),Compound V can be used in combination with at least one other reagent or compound. In some embodiments, the other reagent comprises an oxidizing agent. In a preferred embodiment, the oxidizing agent is an alkyl sulfoxide. In some embodiments, the oxidizing agent is dimethyl sulfoxide. In some embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in Figure 1) to the oxidizing agent is about 20:1, about 19:1, about 18:1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, or about 3:1. The molar ratios are approximately 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, or any range derived therefrom. In some embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in Figure 1) to the oxidant is between approximately 1:5 and approximately 1:10. In some preferred embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in Figure 1) to the oxidant is approximately 1:6.8. In some preferred embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in Figure 1) to the oxidant is approximately 1:5.5. In one embodiment, the advantage of the currently disclosed method for forming C3-oxotriterpenoid derivatives (e.g., compound C in FIG. 1) using a compound of formula V and an oxidant is that it suppresses the formation of unwanted byproducts, such as diene triterpenoid derivatives formed by methods known in the art. Thus, the method of the present invention has advantages in simplifying the complexity of purifying and isolating C3-oxotriterpenoid derivatives and reducing their cost. Further details regarding this advantage are provided below.

[0325] In some embodiments, the reaction mixture for forming C3-oxotriterpenoid derivatives (e.g., compound D in FIG. 1) according to the methods disclosed herein comprises a base. In some embodiments, the base is a weak nucleophile. In some embodiments, the base contains a nitrogen atom. In some embodiments, the base is an amine, such as triethylamine. In some embodiments, the base is diisopropylethylamine, also known as a Hunig base. In some embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in Figure 1) to the base is about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.Or any range from which it can be derived. In some embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in Figure 1) to the base is between about 2:1 and 1:5. In some preferred embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in Figure 1) to the base is about 1:1.6. In some preferred embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in Figure 1) to the base is about 1:1.4. In some preferred embodiments, the molar ratio of the C3-OH triterpenoid derivative (e.g., compound C in Figure 1) to the base is about 1:1.35.

[0326] The methods disclosed herein for preparing C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) are carried out in solvents determined by those skilled in the art. In some embodiments, the formation of the C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) is carried out in an organic solvent. In a preferred embodiment, the solvent is substantially ethyl acetate. In some embodiments, the solvents used to form C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) according to the methods disclosed herein are advantageous for the industrial production of C3-oxotriterpenoid derivatives. For example, the solvents used in the methods of the present invention are easier to remove during the purification or separation of C3-oxounsaturated triterpenoid derivatives (e.g., compound D in Figure 1), and according to the specification 37 / 89 pages 50 CN 121794280 A, the methods of the present invention use smaller volumes of solvents, are less expensive, are less toxic, or have another advantageous physical property as determined by those skilled in the art. In some embodiments, the solvents used in the methods discussed in this section are advantageous in that they are also used in other reactions described elsewhere in this application. In some embodiments, the solvent systems disclosed herein facilitate the formation of particles with improved physical morphology. For example, in some embodiments, the C3-oxounsaturated triterpenoid derivatives (e.g., compound D in Figure 1) formed or purified according to the methods of the present invention have improved physical morphology, such as uniform or consistent particle size, and therefore have improved filtration or drying efficiency.

[0327] In some embodiments, the method disclosed herein for forming a C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) involves dissolving a C3-OH triterpenoid derivative (e.g., compound C in Figure 1) in a solvent, followed by contacting the C3-OH triterpenoid derivative (e.g., compound C in Figure 1) with a compound of formula V and optionally at least one other reagent. In some embodiments, the compound of formula V, the C3-OH triterpenoid derivative (e.g., compound C in Figure 1), and any other reagent are directly combined and reacted. In some embodiments,The compound of formula V, a C3-OH triterpenoid derivative (e.g., compound C in Figure 1), and any other reagent are combined, the compound is dissolved in a solvent, and the reaction is carried out. In some embodiments, the method of the present invention discloses contacting a solution of a C3-OH triterpenoid derivative (e.g., compound C in Figure 1) with a solution of the compound of formula V and adding any other compound or reagent, either in pure form or in solution form, and carrying out the reaction. According to the method of the present invention, the solvent for the solution of compound V can be any aqueous or organic solvent that is advantageous to those skilled in the art. In some embodiments, the solvent for the solution of compound V disclosed herein is an organic solvent. In some embodiments, according to the method of the present invention, the solvent for the solution of compound V is ethyl acetate. In some embodiments, the concentration, by weight, of the solution of compound V contacted with the C3-OH triterpenoid derivative (e.g., compound C in Figure 1) according to the method of the present invention is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, or any range thereof. In some embodiments, the concentration of the solution of compound V contacted with the C3-OH triterpenoid derivative (e.g., compound C in Figure 1) according to the method of the present invention is between about 30% by weight and about 70% by weight. In some embodiments, the concentration of the solution of compound V contacted with the C3-OH triterpenoid derivative (e.g., compound C in Figure 1) according to the method of the present invention is between about 40% by weight and about 60% by weight. In some embodiments, the concentration of the solution of compound V contacted with the C3-OH triterpenoid derivative (e.g., compound C in Figure 1) according to the method of the present invention is about 50% by weight.

[0328] The methods disclosed herein for forming C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) can be carried out at any temperature, provided that it is determined by a person skilled in the art that such temperature provides an acceptable combination of yield and purity of the C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) within an acceptable time period. Depending on the specific circumstances, favorable temperatures may be higher or lower than those of the corresponding prior methods. Favorable temperatures may be closer to room temperature compared to the corresponding prior methods. For example, if less energy is required to maintain the reaction mixture at the reaction temperature, or if the cost of the energy supplied to maintain said temperature is lower, or if an acceptable combination of yield and purity of the target compound is formed in a shorter time compared to the corresponding prior methods.The reaction temperature may then be favorable. The formation of the C3-oxotriterpenoid derivatives disclosed in this invention can be achieved at temperatures ranging from approximately -10°C, approximately -9°C, approximately -8°C, approximately -7°C, approximately -6°C, approximately -5°C, approximately -4°C, approximately -3°C, approximately -2°C, approximately -1°C, approximately 0°C, approximately 1°C, approximately 2°C, approximately 3°C, approximately 4°C, approximately 5°C, approximately 6°C, approximately 7°C, approximately 8°C, approximately 9°C, approximately 10°C, approximately 11°C, approximately 12°C, approximately 13°C, approximately 14°C, approximately 15°C, approximately 16°C, approximately 17°C, approximately 18°C, approximately 19°C, approximately 20°C, approximately 21°C, approximately 22°C, approximately 23°C, approximately 24°C, approximately 25°C, approximately 26°C, approximately 27°C, approximately 28°C, approximately 29°C, approximately 30°C, approximately 31°C, approximately 32°C. The method is carried out at temperatures ranging from about 33°C, about 34°C, about 35°C, about 36°C, about 37°C, about 38°C, about 39°C, about 40°C, about 41°C, about 42°C, about 43°C, about 44°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, about 50°C, or any range derived therefrom. (Specification 38 / 89 pages, 51 CN 121794280 A) In some embodiments, the method of the present invention includes forming a C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) at a temperature between about -5°C and about 40°C. In some embodiments, the method of the present invention includes carrying out an oxidation reaction of the C3-OH triterpenoid derivative (e.g., step 4 in Figure 1) at a temperature between about -5°C and about 40°C. In some embodiments, the method of the present invention includes carrying out a reaction to form a C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) at a temperature between about 20°C and about 30°C. In some embodiments, the method of the present invention includes carrying out a reaction to form a C3-oxotriterpenoid derivative at about 25°C. In some embodiments, the method of the present invention includes carrying out a reaction to form a C3-oxotriterpenoid derivative (e.g., compound D in FIG1) at about room temperature.

[0329] As mentioned above, it has been determined by those skilled in the art that the method of the present invention for forming a C3-oxotriterpenoid derivative (e.g., compound D in FIG1) provides an acceptable combination of yield and purity of the C3-oxotriterpenoid derivative (e.g., compound D in FIG1) within an acceptable time period. In some embodiments, the time period required to obtain an acceptable combination of purity and yield according to the method disclosed herein is shorter than that of the corresponding prior methods, and therefore may be particularly attractive for the industrial production of C3-oxotriterpenoid derivatives (e.g., compound D in FIG1). In some embodiments, the method of the present invention is able to form a C3-oxotriterpenoid derivative (e.g., compound D in FIG1) with higher yield or increased purity within a time period comparable to that of the corresponding known methods. In some embodiments,The methods disclosed herein for forming C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) provide an acceptable combination of yield and purity of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) within a time period of about 0.5 hours, about 1 hour, 1.5 hours, about 2 hours, 2.5 hours, about 3 hours, 3.5 hours, about 4 hours, 4.5 hours, about 5 hours, 5.5 hours, about 6 hours, 6.5 hours, about 7 hours, 7.5 hours, about 8 hours, 8.5 hours, about 9 hours, 9.5 hours, about 10 hours, or any range derived therefrom. In some embodiments, the methods of the present invention provide an acceptable combination of yield and purity of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) within a time period of about 0.5 hours to about 5 hours. In some embodiments, the method of the present invention provides an acceptable combination of yield and purity of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) within a time period of about 2 hours to about 4 hours. In some embodiments, the method of the present invention provides an acceptable combination of yield and purity of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) within a time period of about 3 hours. In some embodiments, the method of the present invention includes an additional time period to provide an acceptable combination of yield and purity of C3-oxotriterpenoid derivative products (e.g., compound D in Figure 1), which is about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, or any range derived therefrom. In some embodiments, the additional time period is between about 2 hours and about 4 hours. In some embodiments, the additional time period is about 3 hours.

[0330] The method disclosed herein for forming C3-oxotriterpenoid derivatives (e.g., compound D in FIG. 1) can be carried out under atmosphere conditions favorable to practitioners. In some embodiments, the method disclosed herein includes steps performed at pressures below atmospheric pressure. In other embodiments, the method disclosed herein can be performed at atmospheric pressure. In some embodiments, the method disclosed herein can be performed at pressures above atmospheric pressure. In some embodiments, the method of the invention is carried out in a reaction vessel in communication with the atmosphere. In some embodiments, the method of the invention is carried out in a substantially inert atmosphere, such as under nitrogen or argon.

[0331] In some embodiments, the purity of the C3-oxotriterpenoid derivatives (e.g., compound D in FIG. 1) prepared according to the method disclosed herein is higher than that of C3-oxotriterpenoid derivatives prepared according to prior methods. In some embodiments,The C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) prepared by the method disclosed in this invention have fewer impurities than C3-oxotriterpenoid derivatives prepared by prior methods. Fewer impurities can be detected in any combination of crude reaction intermediates, purified reaction intermediates, crude C3-oxotriterpenoid derivatives, or purified or isolated C3-oxotriterpenoid derivatives (pages 39 / 89, CN 121794280, Class A). In some embodiments, the method of this invention produces purified and isolated C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) with about 0.1% or less impurities. Thus, the C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) provided by the method of this invention have fewer impurities than C3-oxotriterpenoid derivatives prepared by known methods. In some embodiments, the formation of unwanted dienone triterpenoid derivatives is suppressed.

[0332] This disclosure provides alternative methods for preparing C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) that are superior to existing methods. The methods disclosed in this invention can reduce the cost or time of forming an acceptable combination of yield and purity of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1), can reduce the cost or time of purifying C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1), or can reduce the cost or time of isolating C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1). For example, compared to known methods, the methods disclosed in this invention can reduce the formation of unwanted byproducts during the formation, purification, or isolation of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1), reduce the number of steps in the formation of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1), simplify the procurement of substances in the formation, purification, or isolation of the target triterpenoid derivative, or reduce the cost of substances in the formation, purification, or isolation of the target triterpenoid derivative. In one embodiment, the method of the present invention is safer or requires a simpler reaction procedure compared to prior methods, such as reducing the number of steps in preparing C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1), or obtaining an acceptable combination of yield and purity of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) without a hydrogenation step. The method of the present invention may be advantageous on an industrial scale compared to known methods, for example, by including reactions carried out under mild reaction conditions, or by using compounds that are less expensive than those used in known methods. These examples of advantageous properties should not be construed as limiting the potential advantages of the methods disclosed in this invention in any way.

[0333] In some embodiments, the method of the present invention for preparing C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) is advantageous in that…They do not require the use of compounds, reagents, solvents, or reaction conditions that are detrimental to practitioners, for example, as provided as exemplary examples at the beginning of this section. In some embodiments, the methods disclosed in this invention for forming C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) do not use iodine-containing oxidants. Non-limiting examples of iodine-containing oxidants or oxidizing agents are potassium 2-iodo-5-methylbenzenesulfonate, Dess-Martin periodide, or 2-iodooxybenzoic acid. In preferred embodiments, the reaction mixture for forming C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) is substantially free of potassium 2-iodooxy-5-methylbenzenesulfonate or any precursors thereof. In some embodiments, the methods of this invention for forming C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) do not use Oxone® (potassium peroxymonosulfate). In some embodiments, the method of the present invention for forming C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) does not use heterogeneous catalysts, such as palladium / activated carbon, as discussed below. In some embodiments, the method of the present invention uses a solvent for forming C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) that is substantially free of acetonitrile. In some embodiments, the method of the present invention uses a solvent for preparing C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) that is substantially free of toluene.

[0334] In some embodiments, the method of the present invention has the advantage that it is not carried out by reaction steps, reaction types or reaction categories, or reaction intermediates that are disadvantageous to practitioners, for example for the reasons provided at the beginning of this section as illustrative examples. In previously attempted methods, the formation of undesirable dienone triterpenoid derivatives requires a hydrogenation step to form other triterpenoid derivatives in an economically viable manner (see Figure 1). In some embodiments, the method provided herein forms fewer undesirable dienone triterpenoid derivatives and does not require a hydrogenation step. Thus, a two-step conversion according to known methods is completed in one step of the method according to the present invention. Therefore, at least for this reason, the methods of the invention described on pages 40 / 89 of this specification (CN 121794280 A) have the advantage of shortening the manufacturing cycle time. Furthermore, the hydrogenation reaction may utilize flammable reagents or may be carried out under high temperature or high pressure. Since the methods disclosed in this invention do not require a hydrogenation step, they have the advantage of improved safety compared to known methods. For the experimental considerations briefly described above, the hydrogenation reaction may need to be carried out in a specialized reaction vessel. Another advantage of the methods disclosed in this invention is that they do not require a hydrogenation step.They do not require specialized equipment for hydrogenation reactions. For at least this reason, the methods of the present invention are advantageous for the industrial-scale production of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1). In these ways, the methods of the present invention reduce the complexity and cost associated with forming C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) using known methods, and reduce other experimental and industrial limitations. In some embodiments, the methods of the present invention for forming C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) do not contain a dienone intermediate. Since the hydrogenation step according to known methods is carried out in toluene, the methods disclosed in the present invention also eliminate the cumbersome solvent exchange step. Therefore, in some embodiments, the methods disclosed herein for forming C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) do not include the cumbersome solvent exchange step. As described in Example 1, the solvent is exchanged from ethyl acetate to methanol. Although solvent exchange is still required, exchanging from ethyl acetate to methanol is much easier operationally than exchanging from toluene to methanol. In some embodiments, the purification and separation of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) is performed by co-evaporation between the solvent used in the C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) and at least one other solvent (e.g., methanol). This allows for a simplified reaction solvent system, which is particularly advantageous for the industrial production of C3-oxotriterpenoid derivatives.

[0335] As mentioned above, the method of the present invention can be used for the industrial-scale production of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1). In some embodiments, the method of the present invention produces or forms at least 50 grams of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1). In some embodiments, the method of the present invention produces or forms about 100 grams, about 250 grams, about 500 grams, about 750 grams, or about 1000 grams, or any range of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) from which they can be derived. In some embodiments, the method of the present invention produces or forms at least about 2 kg, about 5 kg, about 10 kg, about 20 kg, about 30 kg, about 40 kg, about 50 kg, about 60 kg, about 70 kg, about 80 kg, about 90 kg, or about 100 kg, or any range of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) from which they can be derived. In some embodiments,The method of the present invention can produce or form batches of about 100 kg, about 120 kg, about 140 kg, about 160 kg, about 180 kg, about 200 kg, about 220 kg, about 240 kg, about 260 kg, about 280 kg, about 300 kg, about 320 kg, about 340 kg, about 360 kg, about 380 kg, or about 400 kg, about 420 kg, about 440 kg, about 460 kg, about 480 kg, about 500 kg, or any range thereof. In some embodiments, the method of the present invention prepares or forms batches of about 325 g of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1). In some embodiments, the method of the present invention can be used to prepare or form batches of more than 500 kg of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1).

[0336] In some embodiments, the C3-oxotriterpenoid derivatives (e.g., compound D in FIG. 1) isolated by the method disclosed according to the present invention have improved purity compared to corresponding known methods. In some embodiments, the purity of the C3-oxotriterpenoid derivatives (e.g., compound D in FIG. 1) isolated by the method disclosed according to the present invention is about 94%, about 94.5%, about 95%, about 95.5%, about 96%, about 96.5%, about 97%, about 97.5%, about 98%, about 98.5%, about 99%, about 99.5%, or any range derived therefrom. In some embodiments, the purity of the C3-oxotriterpenoid derivatives (e.g., compound D in FIG. 1) isolated by the method disclosed according to the present invention is greater than 90%. In some embodiments, the purity of the C3-oxotriterpenoid derivatives (e.g., compound D in FIG. 1) isolated by the method disclosed according to the present invention is about 94% to about 97%. In some embodiments, the purity of the C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) isolated by the method disclosed according to the invention is about 96.5% to about 99.5%. In some embodiments, the purity is at least about 98%. In some embodiments, as described on pages 41 / 89 of CN 121794280 A, the purity is about 99%.

[0337] In some embodiments, the yield of the C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) isolated by the method disclosed according to the invention is improved compared to corresponding known methods, the yield being calculated from C3-oxotriterpenoid derivatives formed from C3-hydroxytriterpenoid derivatives (which may also correspond to C9-C11 unsaturated triterpenoid derivatives described in the following sections). In some embodiments,The yield of a C3-hydroxytriterpenoid derivative (e.g., compound C in Figure 1) reacting to form a C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or any range thereof. In some embodiments, the yield of a C3-hydroxytriterpenoid derivative (e.g., compound C in Figure 1) reacting to form a C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) is greater than 67%. In some embodiments, the yield of a C3-hydroxytriterpenoid derivative (e.g., compound C in Figure 1) reacting to form a C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) is from about 85% to about 95%. In some embodiments, the reaction of a C3-hydroxytriterpenoid derivative (e.g., compound D in Figure 1) to form a C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) yields about 85% to about 92%. In some embodiments, the yield is about 87%.

[0338] In some embodiments, according to the method disclosed in the invention, the reaction to form a C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) has an improved yield compared to corresponding known methods, calculated from the multi-step transformation of oleanolic acid (corresponding to the starting material described below for forming a C17-ester triterpenoid derivative (e.g., compound A in Figure 1)) to a C3-oxotriterpenoid derivative (e.g., compound D in Figure 1). In some embodiments, the yield of the multi-step reaction forming a C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, or any range derived therefrom. In some embodiments, the yield of the reaction forming a C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) is greater than 35%. In some embodiments, the yield of the reaction forming a C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) is from about 45% to about 55%. In some embodiments, the yield of the reaction from a C3-hydroxytriterpenoid derivative (e.g., compound C in Figure 1) to a C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) is from about 47% to about 60%. In some embodiments, the yield is about 56%.

[0339] II. Formation of C9-C11 unsaturated triterpenoid derivatives

[0340] One advantage of some of the methods provided herein is that they do not involve the protection of hydroxyl groups and subsequent deprotection.This eliminates many steps, making the process more efficient. This document provides a novel method for introducing double bonds between atoms 9 and 11 of triterpenoid derivatives (see compound C in Figure 1 as a non-limiting example). The starting material for the reactions discussed in this section is referred to herein as a C9-C11 saturated triterpenoid derivative, and in some embodiments, it is a C12-oxotriterpenoid derivative as described in the following sections. Triterpenoid derivatives having C9-C11 double bonds prepared according to the methods disclosed in this section are referred to herein as C9-C11 unsaturated triterpenoid derivatives. In some embodiments, the methods disclosed in this invention are improvements upon or advantages over prior methods. In some embodiments, the methods disclosed herein allow for other reactive functional groups present in the C9-C11 saturated triterpenoid derivative starting material. C9-C11 saturated triterpenoid derivatives can be prepared using the methods described below and in the Examples section. Any methods disclosed in this invention can be further modified and optimized using organic chemistry principles and techniques applied by those skilled in the art. These principles and techniques are taught, for example, in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (2007), which is incorporated herein by reference.

[0341] The method disclosed in this invention for converting a C9-C11 saturated triterpenoid derivative (e.g., compound B in Figure 1) into a C9-C11 unsaturated triterpenoid derivative (e.g., compound C in Figure 1) involves the use of an oxidizing agent. In some embodiments, 42 / 89 pages of 55 CN 121794280 A, the oxidizing agent used to form the C9-C11 unsaturated triterpenoid derivative (e.g., compound C in Figure 1) provides advantages for the industrial-scale formation of the C9-C11 unsaturated triterpenoid derivative (e.g., compound C in Figure 1) compared to corresponding known methods. For example, the oxidizing agent may be less expensive, more readily available, safer to use, or may be easier to remove in subsequent stages compared to the reagents used in corresponding known methods. According to the present invention, the oxidant used to form C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) has the advantage of being more readily available on an industrial or commercial scale than the oxidants used in previous methods. In some embodiments, the oxidant used to form C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) advantageously controls impurity formation, for example, reduces impurity formation. In some embodiments, the method of the present invention has the advantage of removing reagents from the process stream, which are hydrobromic acid, hydrobromic acid solution, sodium methoxide, or molecular bromine. In some embodiments,The oxidizing agent for forming C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) is at least as strong as bromine. In some embodiments, the oxidizing agent is used as a source of bromine. In some embodiments, the oxidizing agent has the advantage of being easier to handle or providing greater stoichiometric control for bromine addition compared to corresponding known methods for forming C9-C11 unsaturated triterpenoid derivatives. In some embodiments, the oxidizing agent is perbrominated pyridine. In some embodiments, the oxidizing agent is substantially free of molecular bromine. In some embodiments, the molar ratio of the C9-C11 saturated triterpenoid derivative (e.g., compound B in Figure 1) to the oxidant is about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, or any range derived therefrom. In a preferred embodiment, the molar ratio of the C9-C11 saturated triterpenoid derivative (e.g., compound B in Figure 1) to the oxidant is between about 2:1 and 1:1, or more preferably, between about 1.15:1 and about 1.01:1. In some embodiments, the molar ratio of the C9-C11 saturated triterpenoid derivative to the oxidant is about 1:1.09.

[0342] The methods disclosed herein for preparing C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) are carried out in solvents determined by those skilled in the art. In some embodiments, the method according to the invention uses one or more solvents advantageous over corresponding known methods in the preparation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1), particularly in the industrial-scale preparation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1), because they can include those mentioned at the beginning of this section. In some embodiments, the formation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) is carried out in an organic solvent. In some embodiments, the organic solvent is an organic solvent that is immiscible with water. The water-immiscible solvents used in the method for forming C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) disclosed in this invention help improve the separation or purification of the target compound. More specifically, using water-immiscible solvents facilitates aqueous purification steps, thereby more effectively removing water-soluble byproducts and impurities, and is superior to previous methods that often utilized water-miscible solvents. In a preferred embodiment, the solvent used for C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) comprises toluene. Toluene forms an azeotrope with water, thereby providing a further improvement over known methods.Because water can be removed more efficiently during the separation of the target C9-C11 unsaturated triterpenoid derivative (e.g., compound C in Figure 1). Furthermore, as disclosed in this invention, using toluene as a solvent to form the C9-C11 unsaturated triterpenoid derivative (e.g., compound C in Figure 1) will prevent or reduce the formation of impurities (such as imides) observed in corresponding known methods. Therefore, according to the method of the invention, the solvent used to form the C9-C11 unsaturated triterpenoid derivative (e.g., compound C in Figure 1) also has the advantage of being substantially free of compounds, including solvents, that may form undesirable byproducts. In some embodiments, the solvent for the C9-C11 unsaturated triterpenoid derivative (e.g., compound C in Figure 1) is substantially free of acetonitrile. In some embodiments, the solvent system disclosed herein facilitates the formation of particles with improved physical morphology. For example, in some embodiments, the C9-C11 unsaturated triterpenoid derivative (e.g., compound C in Figure 1) formed according to the method of the invention has improved physical morphology, such as uniform or consistent particle size, and therefore improved filtration or drying efficiency. Specification 43 / 89 pages 56 CN 121794280 A

[0343] In some embodiments, the method of the present invention for preparing C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) has the advantage that it does not require the use of compounds, reagents, solvents or reaction conditions that are unfavorable to practitioners, for example, as provided at the beginning of this section as exemplary examples. The method of the present invention for preparing C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) has the advantage that the additional reagents or steps required to remove such impurities in known methods are unnecessary in the method disclosed in the present invention and are eliminated. As mentioned above, the oxidant in the method of the present invention for forming C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) has the advantage that it prevents or reduces the formation of imine ester impurities. Therefore, in some embodiments, the method of the present invention for preparing C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) does not involve treating any crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) with an alkoxide (e.g., sodium methoxide), whereas current methods use alkoxides to remove such impurities. Thus, the method of the present invention simplifies the preparation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) and is attractive, especially on a commercial or industrial scale. In some embodiments, the method of the present invention does not require the protection or deprotection of functional groups present in the starting molecule, which may be necessary according to methods known in the art. In this way, the method disclosed in the present invention has fewer steps and is therefore simpler than similar prior methods.Shorter manufacturing time, or greater efficiency.

[0344] It should be recognized that adding an additional step to a method for purifying or separating C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG1) may be advantageous for a variety of reasons, such as increasing the purity of the separated compound. To this end, in some embodiments, the method of the present invention includes washing the crude C9-C11 unsaturated triterpenoid derivative (e.g., compound C in FIG1) with water, for example with an aqueous solution of sodium hydroxide. Such washing can efficiently or in an improved manner remove impurities, such as acid adducts of the crude C9-C11 unsaturated triterpenoid derivative (e.g., compound C in FIG1). The method of the present invention for purifying or separating C9-C11 unsaturated triterpenoid derivatives may include washing with an aqueous solution of NaCl. In some embodiments, washing the crude C9-C11 unsaturated triterpenoid derivative (e.g., compound C in FIG1) with an aqueous solution of about 2.5% NaOH or about 15% NaCl will remove impurities and unwanted byproducts of the reaction that form the C9-C11 unsaturated triterpenoid derivative. Therefore, embodiments of the method of the present invention, including such washing, are associated with improved purity of the isolated C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1). In some embodiments, the method of the present invention includes washing the crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) with water using an aqueous solution of about 2.5% NaOH, followed by washing with an aqueous solution of about 15% NaCl. In this way, the purity of the crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) is improved due to the improved removal of impurities and unwanted byproducts by the method of the present invention.

[0345] In some embodiments, the method of the present invention for purifying and separating C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) involves crystallizing the crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1). In some embodiments, the method of the present invention has the advantage of reduced process time, reduced manufacturing cycle time, or reduced waste generation. In some embodiments, the solvent used for crystallizing the C9-C11 unsaturated triterpenoid derivatives disclosed in this invention (e.g., compound C in Figure 1) is at least one organic solvent. In a preferred embodiment, the solvent is toluene and n-heptane. In this way, the method of the present invention provides C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) with higher yield and higher purity than corresponding known methods. Higher purity is particularly advantageous considering the commercial or industrial production of other triterpenoid derivatives described in this application; the isolated C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) contain fewer impurities.This results in fewer impurities in the reaction starting with C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) (see, for example, the previous section). The method of the present invention improves the purification procedure of known methods for preparing C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1). For example, the method disclosed in this invention for preparing C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) does not include recrystallization of the crude C9-C11 unsaturated triterpenoid derivative (e.g., compound C in Figure 1) in a mixture of methanol and water, nor does it optionally include a second recrystallization in a mixture of methanol, tetrahydrofuran, and water. The method of the present invention for preparing C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) includes purification by the above crystallization using toluene / n-heptane, optionally followed by recrystallization or reforming in toluene / n-heptane. Compared to known methods, the methods described herein (see also the Examples section) reduce the content of impurities, such as nonpolar impurities like 15-OH triterpenoids, in samples of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1). In some embodiments, the method of the present invention reduces the impurity content below the detection limit. Therefore, the method disclosed in this invention provides an improvement in removing nonpolar impurities from crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) compared to known methods. Thus, the purification of crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) according to the method of the present invention is an improvement over known methods because the purification method disclosed in this invention uses the same solvent as that used in the reaction that forms the C9-C11 unsaturated triterpenoid derivative (e.g., compound C in Figure 1). Therefore, the method of the present invention simplifies the overall preparation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) without unacceptable loss of yield or purity of the purified or isolated C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1).

[0346] In some embodiments, the method for forming C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) is carried out by dissolving a C9-C11 saturated triterpenoid derivative (e.g., compound B in Figure 1) in a solvent and contacting the C9-C11 saturated triterpenoid derivative (e.g., compound B in Figure 1) with an oxidant and optionally at least one other reagent. In some embodiments, the method of the present invention includes combining an oxidant with a C9-C11 saturated triterpenoid derivative (e.g., compound B in Figure 1) and any other reagent, and reacting. In some embodiments,The method of the present invention comprises combining a pure oxidizing agent with a C9-C11 saturated triterpenoid derivative (e.g., compound B in Figure 1) and any other reagent, dissolving the combined compound in a solvent, and reacting the mixture. In some embodiments, the method of the present invention comprises contacting a solution of a C9-C11 saturated triterpenoid derivative (e.g., compound B in Figure 1) with a solution of the oxidizing agent, optionally adding other reagents, either pure or in solution form, to form a reaction mixture, and reacting the mixture. In some embodiments, the solvents used to form C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) according to the methods disclosed herein are advantageous for the industrial production of C9-C11 unsaturated triterpenoid derivatives. For example, the solvents used in the methods of the present invention are easier to remove during the purification or separation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1), use smaller volumes of solvents according to the methods of the present invention, are less expensive, are less toxic, or have another advantageous physical property as determined by those skilled in the art. In some embodiments, the solvents used in the methods discussed in this section are advantageous because they are also used in other reactions described elsewhere in this application.

[0347] The method disclosed herein for forming the C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) can be carried out at any temperature, provided that a person skilled in the art determines that the temperature provides an acceptable combination of yield and purity of the C9-C11 unsaturated triterpenoid derivative product (e.g., compound C in FIG. 1) within an acceptable time period. Depending on the specific circumstances, advantageous temperatures may be higher or lower than the corresponding prior methods. Advantageous temperatures may be closer to room temperature compared to the corresponding prior methods. For example, a reaction temperature may be advantageous if less energy is required to maintain the reaction mixture at the reaction temperature compared to the corresponding prior methods, or if the cost of the energy supplied to maintain the temperature is lower, or if an acceptable combination of yield and purity of the target compound is formed in a shorter time. In some embodiments,The reaction temperature used to form C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) is favorable for industrial-scale formation of the target C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1). The reaction can be carried out at approximately -10°C, approximately -9°C, approximately -8°C, approximately -7°C, approximately -6°C, approximately -5°C, approximately -4°C, approximately -3°C, approximately -2°C, approximately -1°C, approximately 0°C, approximately 1°C, approximately 2°C, approximately 3°C, approximately 4°C, approximately 5°C, approximately 6°C, approximately 7°C, approximately 8°C, approximately 9°C, approximately 10°C, approximately 11°C, approximately 12°C, approximately 13°C, approximately 14°C, approximately 15°C, approximately 16°C, approximately 17°C, approximately 18°C, approximately 19°C, approximately 20°C, approximately 21°C, approximately 22°C, approximately 23°C, approximately 24°C, approximately 25°C, approximately 26°C, approximately 27°C, approximately 28°C, approximately 29°C, approximately 30°C, approximately 31°C, approximately 32°C, approximately 33°C. The reaction may be carried out at approximately 34°C, approximately 35°C, approximately 36°C, approximately 37°C, approximately 38°C, approximately 39°C, approximately 40°C, approximately 41°C, approximately 42°C, approximately 43°C, approximately 44°C, approximately 45°C, approximately 46°C, approximately 47°C, approximately 48°C, approximately 49°C, approximately 50°C, or any range derived therefrom. In some embodiments, the method of the present invention includes carrying out a reaction to form a C9-C11 unsaturated triterpenoid derivative product (e.g., compound C in Figure 1) at a temperature between approximately 28°C and approximately 38°C. In some embodiments, the method of the present invention includes a reaction to form a C9-C11 unsaturated triterpenoid derivative product (e.g., compound C in Figure 1) at approximately 33°C.

[0348] As mentioned above, those skilled in the art have determined that the methods disclosed herein for forming C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) provide an acceptable combination of yield and purity of C9-C11 unsaturated triterpenoid derivative products (e.g., compound C in Figure 1) within an acceptable time period. In some embodiments, the time period required to achieve an acceptable combination of purity and yield according to the methods disclosed herein is shorter than the time period of methods known in the art for producing the corresponding compounds, and may therefore be advantageous for the industrial production of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1). In some embodiments, the methods of the present invention are capable of forming C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) with higher yields or increased purity within a time period comparable to that of corresponding known methods. In some embodiments,The methods disclosed herein for forming C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) provide an acceptable combination of yield and purity of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) within a time period of about 0.5 hours, about 1 hour, 1.5 hours, about 2 hours, 2.5 hours, about 3 hours, 3.5 hours, about 4 hours, 4.5 hours, about 5 hours, 5.5 hours, about 6 hours, 6.5 hours, about 7 hours, 7.5 hours, about 8 hours, 8.5 hours, about 9 hours, 9.5 hours, about 10 hours, or any range derived therefrom. In some embodiments, the methods of the present invention provide an acceptable combination of yield and purity of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) within a time period of about 0.5 hours to about 5 hours. In some embodiments, the method of the present invention provides an acceptable combination of yield and purity of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) over a time period of about 2 hours to about 4 hours. In some embodiments, the method of the present invention provides an acceptable combination of yield and purity of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) over a time period of about 2 hours. In some embodiments, the method of the present invention includes an additional time period to provide an acceptable combination of yield and purity of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1), which is about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, or any range derived therefrom. In some embodiments, the additional time period is between about 0.5 hours and about 3 hours. In some embodiments, the additional time period is about 1 hour.

[0349] The method disclosed herein for forming C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) is carried out under atmosphere conditions favorable to the worker. The method disclosed herein may include steps carried out at pressures reduced relative to atmospheric pressure. In some embodiments, the method disclosed herein may be carried out at atmospheric pressure. In some embodiments, the method disclosed herein may be carried out at pressures above atmospheric pressure. In some embodiments, the method of the invention is carried out in a reaction vessel in communication with the atmosphere. In some embodiments, the method of the invention is carried out in a substantially inert atmosphere, such as under nitrogen or argon.

[0350] In some embodiments, the method described in this section has the advantage of improving the purification of crude products or the separation of pure products compared to known methods. In some embodiments,The method of the present invention for preparing C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) involves a purification step of intermediate structures. In some embodiments, the crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) formed according to the method of the present invention contain fewer impurities than the corresponding crude products formed according to known methods. In some embodiments, the method of the present invention removes more of the impurities present in the crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) by percentage or by mass. In some embodiments, the impurities (also referred to as impurity profiles) present in the crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) formed according to the method of the present invention can be removed more easily, less costly, faster, or with less starting material compared to the corresponding purification of crude C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) according to known methods. In some embodiments, the method of the present invention has the advantage of reducing the amount of impurities entering subsequent reactions, for example, due to less impurity formation or due to higher impurity removal efficiency during purification processes described elsewhere in this section, thereby reducing the complexity of subsequent purification steps.

[0351] In some embodiments, the method disclosed in this invention for forming C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) has higher yields or provides C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) with higher purity compared to corresponding known methods. In one embodiment, the C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in FIG. 1) formed, purified, or isolated according to the method disclosed in this invention have yields of about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or any range thereof. In some embodiments, the method of the present invention provides a C9-C11 unsaturated triterpenoid derivative (e.g., compound C in Figure 1) in about 62% to about 82% yield. In some embodiments, the method of the present invention provides a C12-oxotriterpenoid derivative in greater than about 75% yield. In some embodiments, the method of the present invention provides a C9-C11 unsaturated triterpenoid derivative (e.g., compound C in Figure 1) in about 80% to about 90% yield. In some embodiments,The method of this invention provides C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) in approximately 85% yield. The purity of the crude or purified C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) can be characterized by assays such as HPLC. Samples of crude or purified C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) may contain the target compound as well as organic or inorganic impurities, water, or residual solvents. Higher assay results correspond to higher purity, and therefore, in some embodiments, higher assay results can quantify the degree of improvement of the method disclosed in this invention relative to methods known in the art. In other embodiments, although the method disclosed in this invention provides C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) with lower assay results based on any variables described elsewhere in this section, it may still be an improvement over prior methods. In some embodiments, C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) formed, purified, or isolated according to the method disclosed in this invention have improved assay results compared to corresponding known methods. In some embodiments, the determination results of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) formed, purified, or isolated according to the methods disclosed in the present invention are about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or any range thereof. In some embodiments, the determination results of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) formed, purified, or isolated according to the methods disclosed in the present invention are about 90% to about 99%. In some embodiments, the determination results of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) formed, purified, or isolated according to the methods disclosed in the present invention are about 94% to about 99%. In a preferred embodiment, the determination result is about 98%. In some embodiments, the C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) isolated by the method disclosed according to the present invention have improved purity compared to corresponding known methods. In some embodiments, the purity of the C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) isolated by the method disclosed according to the present invention is at least about 95%. In some embodiments,The purity of the C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) isolated by the method disclosed in this invention is about 94%, about 94.5%, about 95%, about 95.5%, about 96%, about 96.5%, about 97%, about 97.5%, about 98%, about 98.5%, about 99%, about 99.5%, or any range derived therefrom. In some embodiments, the purity of the C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) isolated by the method disclosed in this invention is greater than about 90%. In some embodiments, the purity of the C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) isolated by the method disclosed in this invention is from about 94% to about 97%. In some embodiments, the purity of the C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1) isolated by the method disclosed in this invention is from about 96.5% to about 99.5%. In some embodiments, the purity is at least about 98%, for example, 99%. In some embodiments, the purity is about 98%.

[0352] III. Formation of C12-oxotriterpenoid derivatives (C12)

[0353] In some embodiments, this disclosure provides a novel method for preparing compounds having an oxo group on atom 12 of a triterpenoid derivative (see step 2 in FIG. 1 or the preparation of compound B from compound A as a non-limiting example). Thus, the method of the present invention discloses the formation, purification, and isolation of C12-oxotriterpenoid derivatives (e.g., compound B in FIG. 1). The methods discussed in this section relate to the conversion of C12-C13 unsaturated triterpenoid derivatives (e.g., compound A in FIG. 1) into C12-oxotriterpenoid derivatives (e.g., compound B in FIG. 1). In some embodiments, the method disclosed in this invention for preparing C12-oxotriterpenoid derivatives (e.g., compound B in FIG. 1) is an improvement, advantage, or benefit over previous methods. In some embodiments, the methods disclosed herein allow for the presence of other reactive functional groups in the starting material of C12-C13 unsaturated triterpenoid derivatives (e.g., compound A in Figure 1). C12-C13 unsaturated triterpenoid derivatives (e.g., compound A in Figure 1) can be prepared using the methods described below and in the Examples section.

[0354] In some embodiments, the methods disclosed herein for preparing C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) have the advantage that they do not require the use of compounds, reagents, solvents, or reaction conditions that are unfavorable to practitioners to form, purify, or isolate C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1), for example, for reasons provided at the beginning of this section as exemplary examples. In some embodiments,The advantage of the method disclosed in this invention for preparing C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) is that they do not involve certain unfavorable reaction steps, intermediates, or pathways. In some embodiments, the method of this invention does not require the protection or deprotection of functional groups present in the starting molecule, which may be necessary according to methods known in the art. Thus, the method disclosed in this invention has fewer steps and is therefore simpler, faster, or more efficient than similar prior methods.

[0355] The method disclosed in this invention for forming C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) involves the use of an oxidizing agent. In some embodiments, the oxidizing agent is a peracid (also known as a peroxyacid). In some embodiments, the oxidizing agent is an organic peracid, such as a peroxycarboxylic acid. In a preferred embodiment, the oxidizing agent is m-chloroperoxybenzoic acid. In some embodiments, the method of this invention for forming C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) involves the use of a sulfonic acid. In some embodiments, the sulfonic acid is an alkyl sulfonic acid, alkenyl sulfonic acid, cycloalkyl sulfonic acid, heterocycloalkyl sulfonic acid, alkyldiyl-heterocycloalkyl sulfonic acid, alkyldiyl-aryl sulfonic acid, or aryl sulfonic acid. Non-limiting examples of sulfonic acids that can be used in the methods of the present invention for forming C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) include methanesulfonic acid, ethanesulfonic acid, 1-propanesulfonic acid, 1-octanesulfonic acid, cyclohexanesulfonic acid, 2-tris(methylbenzene)sulfonic acid, benzenesulfonic acid, dodecylbenzenesulfonic acid, or camphorsulfonic acid. In some embodiments, the sulfonic acid is a substituted form of the groups listed above, such as trifluoromethanesulfonic acid, aminomethanesulfonic acid, PFOS, 4-hydroxybenzenesulfonic acid, or 3-hydroxypropane-1-sulfonic acid. In some embodiments, the sulfonic acid is a salt or hydrate of any of the above groups or compounds. As described above, in some embodiments, the advantage of the compounds (including oxidants) used in the preparation of the C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) disclosed in this invention is that they do not contain the compounds used in the corresponding known methods. For example, in some embodiments, the reaction mixture used to form the C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) is substantially free of peracetic acid. The absence of peracetic acid in the reaction mixture reduces the amount of undesirable acetylation byproducts and thus improves the purification and separation of the C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) compared to the corresponding known methods, as will be discussed further below. At least due to the embodiments outlined above, the method of this invention improves upon the corresponding known methods in terms of the yield and purity of the separated C12-oxotriterpenoid derivatives.

[0356] In some embodiments,The molar ratio of the C12-C13 unsaturated triterpenoid derivative (e.g., compound A in Figure 1) to the oxidant is about 5:1, about 4.5:1, about 3:1, about 3.5:1, about 3:1, about 2.5:1, about 2:1, about 1.5:1, about 1:1, about 1:2, about 1:2.5, about 1:3, about 1:3.5, about 1:4, about 1:4.5, about 1:5, or any range derived therefrom. In some embodiments, the molar ratio of the C12-C13 unsaturated triterpenoid derivative (e.g., compound A in Figure 1) to the oxidant is between about 3:1 and about 1:1. In some embodiments, the molar ratio of the C12-C13 unsaturated triterpenoid derivative (e.g., compound A in Figure 1) to the oxidant is about 2.3:1.

[0357] The methods disclosed herein for preparing C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) are carried out in solvents determined by those skilled in the art. As mentioned above, in some embodiments, the solvents used in the preparation of the C12-oxotriterpenoid derivatives disclosed herein (e.g., compound B in Figure 1) have the advantage that they do not contain the solvents used in the corresponding known methods. For example, in some embodiments, the solvents used to form the C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) are substantially free of acetic acid. The absence of acetic acid in the reaction mixture reduces the amount of undesirable acetylation byproducts and thus improves the purification and separation of the C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) compared to the corresponding known methods, as will be discussed further below. In some embodiments, the formation of the C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) is carried out in an organic solvent. In some embodiments, the solvent used to form the C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) comprises dichloromethane. In some embodiments, the solvent used to form C12-oxotriterpenoid derivatives (e.g., compound B in FIG. 1) comprises toluene. In a preferred embodiment, one or more solvents used to purify or separate C12-oxotriterpenoid derivatives (e.g., compound B in FIG. 1) comprise toluene. In some embodiments, one or more solvents used to purify or separate C12-oxotriterpenoid derivatives (e.g., compound B in FIG. 1) comprise water or methanol. In some embodiments, the solvent systems disclosed herein facilitate the formation of particles with improved physical morphology. For example, in some embodiments, the C12-oxotriterpenoid derivatives (e.g., compound B in FIG. 1) formed or purified according to the method of the invention have improved physical morphology, such as uniform or consistent particle size, and thus have improved filtration or drying efficiency.

[0358] In some embodiments,A method for forming C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) is performed by dissolving a C12-C13 unsaturated triterpenoid derivative (e.g., compound A in Figure 1) in a solvent and contacting the C12-oxotriterpenoid derivative with an oxidizing agent and optionally at least one other reagent. In some embodiments, the method of the present invention includes combining a pure oxidizing agent with a C12-C13 unsaturated triterpenoid derivative (e.g., compound A in Figure 1) and any other reagent, and reacting the resulting compound. In some embodiments, the method of the present invention includes combining a pure oxidizing agent with a C12-C13 unsaturated triterpenoid derivative (e.g., compound A in Figure 1) and any other reagent, dissolving the combined compound in a solvent, and reacting the resulting compound. In some embodiments, the method of the present invention includes contacting a solution of a C12-C13 unsaturated triterpenoid derivative (e.g., compound A in Figure 1) with an oxidizing agent solution, optionally adding other reagents, either pure or in solution form, to form a reaction mixture, and reacting the resulting compound. In some embodiments, the solvents used to form C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) according to the methods disclosed herein are advantageous for the industrial production of C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1). For example, the solvents used in the methods of the present invention are easier to remove during the purification or separation of C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1), have a smaller volume of solvents used in the methods of the present invention (pages 49 / 89, 62 CN 121794280 A), are less expensive, have lower toxicity, or have another advantageous physical property as determined by those skilled in the art. In some embodiments, the solvents used in the methods discussed in this section are advantageous because they are also used in other reactions described elsewhere in this application.

[0359] The methods disclosed herein for forming C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) can be carried out at any temperature, provided that a person skilled in the art determines that the temperature provides an acceptable combination of yield and purity of the C12-oxotriterpenoid derivative product (e.g., compound B in Figure 1) within an acceptable time period. Depending on the specific circumstances, favorable temperatures may be higher or lower than the corresponding prior methods. Favorable temperatures may be closer to room temperature compared to the corresponding prior methods. For example, if less energy is required to maintain the reaction mixture at the reaction temperature compared to the corresponding prior methods, or if the cost of the energy supplied to maintain the temperature is lower, or if an acceptable combination of yield and purity of the target compound is formed in a shorter time,The reaction temperature may then be favorable. The formation of the C12-oxotriterpenoid derivatives disclosed in this invention (e.g., compound B in Figure 1) can be achieved at temperatures ranging from approximately -10°C, approximately -9°C, approximately -8°C, approximately -7°C, approximately -6°C, approximately -5°C, approximately -4°C, approximately -3°C, approximately -2°C, approximately -1°C, approximately 0°C, approximately 1°C, approximately 2°C, approximately 3°C, approximately 4°C, approximately 5°C, approximately 6°C, approximately 7°C, approximately 8°C, approximately 9°C, approximately 10°C, approximately 11°C, approximately 12°C, approximately 13°C, approximately 14°C, approximately 15°C, approximately 16°C, approximately 17°C, approximately 18°C, approximately 19°C, approximately 20°C, approximately 21°C, approximately 22°C, approximately 23°C, approximately 24°C, approximately 25°C, approximately 26°C, approximately 27°C, approximately 28°C, approximately 29°C. The reaction may be carried out at temperatures ranging from approximately 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, or any range derived thereof. In some embodiments, the method of the present invention includes carrying out the reaction to form a C12-oxotriterpenoid derivative (e.g., compound B in Figure 1) at a temperature between approximately -5°C and approximately 40°C. In some embodiments, the method of the present invention includes carrying out the reaction to form a C12-oxotriterpenoid derivative (e.g., compound B in Figure 1) at a temperature between approximately 20°C and approximately 30°C. In some embodiments, the method of the present invention includes carrying out the reaction to form a C12-oxotriterpenoid derivative (e.g., compound B in Figure 1) at approximately 25°C. In some embodiments, the method of the present invention includes carrying out a reaction to form a C12-oxotriterpenoid derivative (e.g., compound B in Figure 1) at approximately room temperature.

[0360] As mentioned above, it has been determined by those skilled in the art that the method of the present invention for forming a C12-oxotriterpenoid derivative (e.g., compound B in Figure 1) provides an acceptable combination of yield and purity of the C12-oxotriterpenoid derivative (e.g., compound B in Figure 1) within an acceptable time period. In some embodiments, the time period required to obtain an acceptable combination of purity and yield according to the method disclosed herein is shorter than that of corresponding prior methods, and therefore may be particularly attractive for the industrial production of C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1). In some embodiments, the method of the present invention is capable of forming a C12-oxotriterpenoid derivative (e.g., compound B in Figure 1) with higher yield or increased purity within a time period comparable to that of corresponding known methods. In some embodiments,The method disclosed herein for forming C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) takes approximately 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, 12 hours, 12.5 hours, 13 hours, 13.5 hours, 14 hours, 14.5 hours, 15 hours, 15.5 hours, 16 hours, 16.5 hours, 17 hours, 17.5 hours, 18 hours, 18.5 hours, 19 hours, 19.5 hours, 20 hours, 21 hours, 21.5 hours, 22 hours, 22.5 hours, and 23 hours. The method provides C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) in acceptable combinations of yield and purity within a timeframe of approximately 23.5 hours, approximately 24 hours, approximately 24.5 hours, approximately 25 hours, or any range derived therefrom. In some embodiments, the method of the present invention provides an acceptable combination of yield and purity of C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) within a timeframe of approximately 10 hours to approximately 20 hours. In some embodiments, the method of the present invention provides an acceptable combination of yield and purity of C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) within a timeframe of approximately 13 hours to approximately 17 hours. In some embodiments, the method of the present invention provides an acceptable combination of yield and purity of C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) within approximately 15 hours. In some embodiments, the method of the present invention includes an additional time period to provide an acceptable combination of yield and purity of C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1), the time period being about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, or any range derived therefrom. In some embodiments, the additional time period is between about 1 hour and about 3 hours. In some embodiments, the additional time period is about 2 hours.

[0361] The method disclosed herein for forming C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) can be carried out under atmosphere conditions favorable to practitioners. In some embodiments, the method disclosed herein includes steps performed at pressures below atmospheric pressure. In other embodiments, the method disclosed herein can be performed at atmospheric pressure. In some embodiments, the method disclosed herein can be performed at pressures increased relative to atmospheric pressure. In some embodiments,The method of the present invention is carried out in a reaction vessel open to the atmosphere. In some embodiments, the method of the present invention is carried out in a substantially inert atmosphere, such as under nitrogen or argon.

[0362] In some embodiments, the method described herein for preparing C12-oxotriterpenoid derivatives (e.g., compound B in FIG. 1) has the advantage of improved purification of crude products or separation of pure products compared to known methods. These improvements may relate to the details above. In some embodiments, the method of the present invention for preparing C12-oxotriterpenoid derivatives (e.g., compound B in FIG. 1) includes a purification step that increases the supply of C12-oxotriterpenoid derivatives (e.g., compound B in FIG. 1). The purification step may, for example, purify the reaction intermediate before proceeding to the next reaction. The purification step may, for example, remove unreacted oxidants or other unwanted byproducts. In some embodiments, according to the method of the present invention, the purification step of the reaction intermediate includes a washing step, such as washing with water. In some embodiments, washing with water includes using an aqueous solution of sodium bicarbonate. In some embodiments, the purification and separation of C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) according to the method of the present invention includes a crystallization step. In some embodiments, the solvent for the crystallization step comprises an organic solvent and water, such as an alcohol and water. In a preferred embodiment, the method disclosed in the present invention for preparing C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) includes a crystallization step, wherein the crystallization solvent is isopropanol and water. In some embodiments, the solvent for the crystallization step comprises a mixture of organic compounds, such as toluene and heptane. In some embodiments, an improvement in the preparation of C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) is that the purification step used in corresponding known methods can be omitted. In some embodiments, the method of the present invention for purifying and separating C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) does not include a water precipitation step. In these ways, compared with known methods, the method of the present invention reduces the time required to purify C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) and improves the purity of the separated C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1).

[0363] In some embodiments, the C12-oxotriterpenoid derivatives (e.g., compound B in FIG. 1) formed according to the method of the present invention have fewer impurities than the corresponding crude products formed according to known methods. In some embodiments, the method disclosed in the present invention for forming C12-oxotriterpenoid derivatives (e.g., compound B in FIG. 1) produces fewer unwanted byproducts than the corresponding known methods. In some embodiments, the method disclosed in the present invention has the advantage of forming fewer unwanted byproducts during the reaction.For example, acetylated C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1). This reduces the need for remedial monitoring of acetylated C12-oxotriterpenoid derivatives in subsequent reactions starting with C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1). In this way, the method disclosed in this invention is associated with reduced industrial production costs or complexity of C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1). In some embodiments, the method of this invention removes a significant amount of impurities present in the crude C12-oxotriterpenoid derivative (e.g., compound B in Figure 1) by percentage or mass. In some embodiments, impurities present in the crude C12-oxotriterpenoid derivative (e.g., compound B in Figure 1) formed according to the method of this invention can be removed more easily, less costly, faster, or with less feedstock compared to corresponding purification of the crude C12-oxotriterpenoid derivative (e.g., compound B in Figure 1) according to known methods. For any of the reasons provided above, in some embodiments, the method disclosed in this invention for forming C12-oxotriterpenoid derivatives (e.g., compound B in FIG1) has higher purity compared to known methods.

[0364] In some embodiments, the method disclosed in this invention for forming C12-oxotriterpenoid derivatives (e.g., compound B in FIG1) has higher yields or provides C12-oxotriterpenoid derivatives (e.g., compound B in FIG1) with higher purity compared to corresponding known methods. In some embodiments, the C12-oxotriterpenoid derivatives (e.g., compound B in FIG1) formed, purified, or isolated according to the method disclosed in this invention have yields of about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or any range thereof. In some embodiments, the method of the present invention provides a C12-oxotriterpenoid derivative (e.g., compound B in Figure 1) in a yield greater than about 81%. In some embodiments, the method of the present invention provides a C12-oxotriterpenoid derivative (e.g., compound B in Figure 1) in a yield of about 70% to about 80%. In some embodiments, the method of the present invention provides a C12-oxotriterpenoid derivative (e.g., compound B in Figure 1) in a yield of about 74%. In some embodiments,The C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) formed, purified, or isolated by the methods disclosed in this invention yield improved assay results compared to corresponding known methods. The purity of the crude or purified C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) can be characterized by assays such as HPLC. Samples containing crude or purified C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) may also contain, for example, organic or inorganic impurities, water, or residual solvents. Higher assay results correspond to higher purity, and therefore, in some embodiments, higher assay results can quantify the degree of improvement of the methods disclosed in this invention relative to methods known in the art. In other embodiments, although the methods disclosed in this invention may provide C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) with lower assay results based on any variables described elsewhere in this section, improvements may still be possible compared to prior methods. In some embodiments, the C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) formed, purified, or isolated by the methods disclosed in this invention yield improved assay results compared to corresponding known methods. In some embodiments, the C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) formed, purified, or isolated according to the methods disclosed in the present invention are determined to be about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or any range thereof. In some embodiments, the C12-oxotriterpenoid derivatives formed, purified, or isolated according to the methods disclosed in the present invention are determined to be about 97% to about 99%. In a preferred embodiment, the determination result is about 98%. In some embodiments, the C12-oxotriterpenoid derivatives isolated according to the methods disclosed in the present invention (e.g., compound B in Figure 1) have improved purity compared to corresponding known methods. In some embodiments, the purity of the C12-oxotriterpenoid derivative (e.g., compound B in Figure 1) isolated by the method disclosed according to the invention is about 85%, about 85.5%, about 86%, about 86.5%, about 87%, about 87.5%, about 88%, about 88.5%, about 89%, about 89.5%, about 90%, about 90.5%, about 91%, about 91.5%, about 92%, about 92.5%, about 93%, about 93.5%, about 94%, about 94.5%, about 95%, about 95.5%, about 96%, about 96.5%, about 97%, about 97.5%, about 98%, about 98.5%, about 99%, about 99.5%, or any range thereof. In some embodiments,The purity is greater than about 90%. In some embodiments, the purity of the C12-oxotriterpenoid derivative (e.g., compound B in FIG. 1) isolated by the method disclosed according to the invention is about 89% to about 95%. In some embodiments, the purity is at least about 95%, for example 96%. In some embodiments, the purity is about 95%. Specification 52 / 89 pages 65 CN 121794280 A

[0365] IV. Formation of C17 ester triterpenoid derivatives (C17-C(O)OR)

[0366] This disclosure provides a new method for converting C17-carboxylic acid triterpenoid derivatives (e.g., oleanolic acid) into C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1). In some embodiments, the method disclosed herein is an improvement or advantage over a prior method, the details of which will be described below. In some embodiments, the method disclosed herein allows for other reactive functional groups present in the C17-carboxylic acid triterpenoid derivative starting material. In some embodiments of the methods disclosed herein, the C17-carboxylic acid triterpenoid derivatives used as starting materials can be isolated or prepared by prior methods.

[0367] It should be recognized that adding additional steps to methods for purifying or isolating C17-carboxylic acid triterpenoid derivatives may be advantageous for several reasons, such as increased purity of the isolated compound or compounds formed by subsequent reactions of the isolated C17-carboxylic acid triterpenoid derivative. For example, as mentioned above, known methods for forming C12-oxotriterpenoid derivatives (e.g., compound B in Figure 1) may not involve the isolation of C17-ester triterpenoid derivatives (e.g., compound A in Figure 1). However, the methods disclosed herein are advantageous over these prior methods because the isolation of the C17-ester intermediate is associated with improved impurities (i.e., fewer impurities or improved impurity distribution) in subsequent downstream reactions compared to known methods.

[0368] The methods disclosed herein for preparing C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) are carried out in solvents determined by those skilled in the art. As mentioned above, in some embodiments, the solvents used in the preparation of the C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) disclosed in this invention have the advantage that they do not contain the solvents used in corresponding known methods. In some embodiments, the formation of the C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) is carried out in an organic solvent. In some embodiments, the organic solvent is an immiscible organic solvent. The immiscible solvents in some embodiments of the method for forming C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) disclosed in this invention help improve the separation or purification of the target compound. More specifically, the use of immiscible solvents facilitates aqueous purification steps, thereby more effectively removing water-soluble byproducts and impurities.This is therefore superior to previous methods that often utilize water-miscible solvents. In some embodiments, the solvents disclosed in this invention facilitate better removal of unwanted inorganic byproducts from crude C17 ester triterpenoid derivative compositions (e.g., compound A in Figure 1). In some embodiments, crude C17 ester triterpenoid derivatives (e.g., compound A in Figure 1) formed according to the current method exhibit higher purification efficiency than C17 ester triterpenoid derivatives formed according to known methods. In a preferred embodiment, the solvent used in the formation of the C17 ester triterpenoid derivatives (e.g., compound A in Figure 1) comprises 2-methyltetrahydrofuran. In some embodiments, the solvent systems disclosed herein facilitate the formation of particles with improved physical morphology. For example, in some embodiments, C17 ester triterpenoid derivatives (e.g., compound A in Figure 1) formed or purified according to the method of this invention have improved physical morphology, such as uniform or consistent particle size, and therefore have improved filtration or drying efficiency.

[0369] The method disclosed in this invention for converting C17-carboxylic acid triterpenoid derivatives (e.g., oleanolic acid) into C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) involves the use of a base. In some embodiments, the base used to form C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) offers advantages for industrial-scale formation of C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) compared to corresponding known methods. For example, the base may be less expensive, more readily available, safer to use, or easier to remove in subsequent stages compared to the reagents used in corresponding known methods. According to the invention, the base used to form C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) has the benefit of being more readily available on an industrial or commercial scale than the bases used in previous methods. In some embodiments, the base used in the formation of C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) disclosed in this invention advantageously controls impurity formation, e.g., reduces impurity formation. In some embodiments, the base of the method disclosed in this invention has higher solubility in the reaction solvent compared to the method of this invention. Therefore, in some embodiments, the reaction concentration of the method provided in this disclosure is higher, thereby improving the efficiency and output of the manufacturing process and shortening the manufacturing time. In some embodiments, the base according to the method herein comprises potassium carbonate. In some embodiments, the base does not contain sodium carbonate or is substantially free of sodium carbonate.

[0370] In some embodiments,The molar ratio of the C17-carboxylic acid triterpenoid derivative (e.g., oleanolic acid) to the base is about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, or any range derived therefrom. In a preferred embodiment, the molar ratio of the C17-carboxylic acid triterpenoid derivative (e.g., oleanolic acid) to the base is between about 1:1 and 1:2, or more preferably, between about 1:1.40 and about 1:1.60. In some embodiments, the molar ratio of the C17-carboxylic acid triterpenoid derivative (e.g., oleanolic acid) to the base is about 1:1.50.

[0371] The method disclosed herein for converting C17-carboxylic acid triterpenoid derivatives (e.g., oleanolic acid) into C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) involves the use of a quenching agent. For example, the quenching agent may react with excess or residual unreacted reagent to prevent the formation of impurities, promote the removal of unreacted starting materials, or prevent the reagent from undergoing undesirable reactions in subsequent reactions. In some embodiments, the quenching agent provided by the method disclosed herein is superior to quenching agents used in prior methods. In some embodiments, the quenching agent of the method disclosed herein is more efficient than known quenching agents. In some embodiments, the use of the quenching agent disclosed herein is associated with improvement in impurities in subsequent reaction mixtures or product isolates (i.e., reduced impurity content or improved impurity distribution). In some embodiments, the use of the quenching agent disclosed herein is associated with lower levels of methylating agents, such as dimethyl sulfate or derivatives thereof. In some embodiments, the quenching agent comprises a base. In some embodiments, the quenching agent comprises an amine, such as a tertiary amine. In some embodiments, the quenching agent comprises triethylamine. In some embodiments, the quenching agent is substantially free of acetic acid.

[0372] In some embodiments, the quenching agent used to form C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) provides advantages for the industrial-scale formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) compared to corresponding known methods. For example, the quenching agent may be less expensive, more readily available, safer to use, or may be easier to remove in subsequent stages compared to the reagents used in corresponding known methods. According to the invention, the quenching agent used to form C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) may have the benefit of being more readily available on an industrial or commercial scale than the quenching agents used in previous methods. In some embodiments, the quenching agent used in the formation of C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) disclosed in this invention advantageously controls the formation of impurities.For example, reducing the formation of impurities.

[0373] In some embodiments, the molar ratio of the C17-carboxylic acid triterpenoid derivative (e.g., oleanolic acid) to the quenching agent is about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, or any range derived therefrom. In a preferred embodiment, the molar ratio of the C17-carboxylic acid triterpenoid derivative (e.g., oleanolic acid) to the quenching agent is between about 4:1 and 1:1, or more preferably, between about 3:1 and about 2:1. In some embodiments, the molar ratio of the C17-carboxylic acid triterpenoid derivative (e.g., oleanolic acid) to the quenching agent is about 2.85:1.

[0374] The methods disclosed herein for forming C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) can be carried out at any temperature, provided that a person skilled in the art determines that the temperature provides an acceptable combination of yield and purity of the C17-ester triterpenoid derivative (e.g., compound A in Figure 1) within an acceptable time period. Depending on the specific circumstances, favorable temperatures may be higher or lower than the corresponding prior methods. Favorable temperatures may be closer to room temperature compared to the corresponding prior methods. For example, a reaction temperature may be advantageous if less energy is required to maintain the reaction mixture at the reaction temperature compared to the corresponding prior methods, or if the cost of the energy supplied to maintain the temperature is lower, or if an acceptable combination of yield and purity of the target compound is formed in a shorter time. The C17-ester triterpenoid derivatives disclosed in this invention (e.g., compound A in Figure 1) can be formed at temperatures ranging from about -10°C, about -9°C, about -8°C, about -7°C, about -6°C, about -5°C, about -4°C, about -3°C, about -2°C, about -1°C, about 0°C, about 1°C, about 2°C, about 3°C, about 4°C, about 5°C, about 6°C, about 7°C, about 8°C, about 9°C, about 10°C, about 11°C, about 12°C, about 13°C, about 14°C, about 15°C, about 16°C, about 17°C, about 18°C, about 19°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, about 30°C, about 31°C. The temperature may be maintained at approximately 32°C, approximately 33°C, approximately 34°C, approximately 35°C, approximately 36°C, approximately 37°C, approximately 38°C, approximately 39°C, approximately 40°C, approximately 41°C, approximately 42°C, approximately 43°C, approximately 44°C, approximately 45°C, approximately 46°C, approximately 47°C, approximately 48°C, approximately 49°C, approximately 50°C, or any range derived therefrom. In some embodiments,The method of the present invention includes carrying out a reaction to form a C17-ester triterpenoid derivative (e.g., compound A in Figure 1) at a temperature between about 15°C and about 50°C. In some embodiments, the method of the present invention includes carrying out a reaction to form a C17-ester triterpenoid derivative (e.g., compound A in Figure 1) at a temperature between about 20°C and about 40°C. In some embodiments, the method of the present invention includes carrying out a reaction to form a C17-ester triterpenoid derivative (e.g., compound A in Figure 1) at about 30°C. In some embodiments, the method of the present invention includes carrying out a reaction to form a C17-ester triterpenoid derivative (e.g., compound A in Figure 1) at about room temperature.

[0375] As mentioned above, it has been determined by those skilled in the art that the method of the present invention for forming a C17-ester triterpenoid derivative (e.g., compound A in Figure 1) provides an acceptable combination of yield and purity of the C17-ester triterpenoid derivative (e.g., compound A in Figure 1) within an acceptable time period. In some embodiments, the time required to obtain an acceptable combination of purity and yield according to the methods disclosed herein is shorter than that of corresponding prior methods, and therefore may be particularly attractive for the industrial production of C17-ester triterpenoid derivatives (e.g., compound A in Figure 1). In some embodiments, the method of the present invention is capable of forming C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) in a time period comparable to that of corresponding known methods, with higher yields or increased purity. In some embodiments, the methods disclosed herein for forming C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) provide C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) in acceptable yields and purities within a range of about 0.25 hours, about 0.5 hours, about 0.75 hours, about 1 hour, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2 hours, about 2.25 hours, about 2.5 hours, about 2.75 hours, about 3 hours, about 3.25 hours, about 3.5 hours, about 3.75 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, or any range from which they are derived. In some embodiments, the method of the present invention provides an acceptable combination of yield and purity of C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) within a time period between about 0.5 hours and about 3 hours. In some embodiments, the method of the present invention provides an acceptable combination of yield and purity of C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) within a time period between about 0.75 hours and about 2 hours. In some embodiments,The method of the present invention provides an acceptable combination of yield and purity of C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) within about 1 hour.

[0376] In some embodiments, the method disclosed in this invention for forming C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) has a higher yield or provides C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) with higher purity compared to corresponding known methods. In some embodiments, the C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) formed, purified, or isolated by the method disclosed in this invention have yields of about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or any range thereof. In some embodiments, the method of the present invention provides C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) with yields of about 60% to about 98%. In some embodiments, the method of the present invention provides C17-ester triterpenoid derivatives in yield greater than about 85%. In some embodiments, the method of the present invention provides C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) in yield of about 85% to about 95%. In some embodiments, the method of the present invention provides C17-ester triterpenoid derivatives in yield of about 87%.

[0377] The purity of the crude or purified C17-ester triterpenoid derivative (e.g., compound A in Figure 1) can be characterized by assays such as HPLC. The crude or purified C17-ester triterpenoid derivative (e.g., compound A in Figure 1) sample may contain the target compound as well as organic or inorganic impurities, water, or residual solvent. Higher assay results correspond to higher purity, and therefore in some embodiments, higher assay results can quantify the degree of improvement of the method disclosed in the present invention relative to methods known in the art. In other embodiments, although the methods disclosed herein may yield C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) with lower assay results based on any variables described elsewhere in this section, they may still be improvements over prior methods. In some embodiments, C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) formed, purified, or isolated according to the methods disclosed herein have improved assay results compared to corresponding known methods. In some embodiments,The determination results of C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) formed, purified, or isolated according to the methods disclosed in this invention are about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or any range thereof. In some embodiments, the determination results of C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) formed, purified, or isolated according to the methods disclosed in this invention are about 90% to about 99%. In some embodiments, the determination results of C17-ester triterpenoid derivatives (e.g., compound A in Figure 1) formed, purified, or isolated according to the methods disclosed in this invention are about 94% to about 99%. In a preferred embodiment, the determination result is about 98%.

[0378] In some embodiments, the C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) isolated by the method disclosed according to the present invention have improved purity compared to corresponding known methods. In some embodiments, the purity of the C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) isolated by the method disclosed according to the present invention is at least about 95%. In some embodiments, the purity of the C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) isolated by the method disclosed according to the present invention is about 94%, about 94.5%, about 95%, about 95.5%, about 96%, about 96.5%, about 97%, about 97.5%, about 98%, about 98.5%, about 99%, about 99.5%, or any range thereof. In some embodiments, the purity of the C17-ester triterpenoid derivatives (e.g., compound A in FIG. 1) isolated by the method disclosed according to the present invention is greater than 90%. In some embodiments, the purity of the C17-ester triterpenoid derivative (e.g., compound A in Figure 1) isolated by the method disclosed according to the present invention is about 94% to about 97%. In some embodiments, the purity of the C17-ester triterpenoid derivative (e.g., compound A in Figure 1) isolated by the method disclosed according to the present invention is about 96.5% to about 99.5%. In some embodiments, the purity is at least about 98%, for example 99%. In some embodiments, the purity is about 98%.

[0379] In some embodiments, the synthetic steps provided herein can be used to improve yield, improve purity, improve efficiency, improve safety, improve environmental considerations and / or can otherwise improve the industrial-scale preparation of triterpenoid derivatives. In some embodiments, the methods disclosed herein can be used to improve prior synthetic methods. For example,The methods disclosed herein can provide improvements to the methods in the following literature: Fu and Gribble, 2013; Wong et al., 2016; Honda et al., 1997; Honda et al., 1998; Honda et al., 1999; Honda et al., 2000a; Honda et al., 2000b; Honda et al., 2002; Suh et al., 1998; Suh et al., 1999; Place et al., 2003; Liby et al., 2005; and U.S. Patents 7,915,402, 7,943,778, 8,071,632, 8,124,799, 8,129,429, 8,338,618, 8,993,640, and 9,102. References 681, 9,701,709, 9,512,094, 9,889,143, 10,093,614 and 10,556,858 are incorporated herein by reference.

[0380] In some aspects, the methods disclosed in this invention for forming C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) are advantageous for industrial applications because they do not use iodine-containing oxidants, such as potassium benzenesulfonate, Dess-Martin periodoalkane, or 2-iodooxybenzoic acid. In contrast, several previous synthetic methods describe the use of iodine-containing reagents, particularly 2-iodooxybenzoic acid (IBX) (Fu and Gribble, 2013; Honda et al., 2000a). See Schemes 3 and 4 below, which outline the synthesis of (4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,7,8,8a,14a,14b-decahydrofuran-4a-carboxylic acid ester (RTA 402) using IBX as a starting material to form C3-oxotriterpenoids. However, the use of IBX in industrial applications is limited due to serious safety concerns, namely its violent decomposition under shock and / or heating (Satam et al., 2010). Furthermore, IBX has been reported to be shock-sensitive and explosive when heated above 200°C; therefore, storing and distributing large quantities of IBX for industrial applications is both risky and impractical (Devadas et al., 2020).

[0381] In some respects,The method of the present invention for forming C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) does not use Oxone® (potassium peroxymonosulfate). Oxone® (potassium peroxymonosulfate) is widely used as an oxidant in the preparation of IBX (Nair, 2020; Frigerio, 1999); however, this method is not suitable for large-scale production. Oxone® (potassium peroxymonosulfate) has several problems, including its inherent instability leading to safety hazards and low oxidizing power (Amano et al., 2006).

[0382] In other respects, the method of the present invention can be used for the industrial-scale production or formation of C3-oxotriterpenoid derivatives (e.g., compound D in Figure 1) because they do not require a hydrogenation step. Several previous methods (Fu and Gribble, Honda et al., 2000a; Wong et al., 2016) describe dienone intermediates (see schemes 3, 4 and 5); however, the hydrogenation reactions in these syntheses all require specialized reaction vessels. Since the method disclosed in this invention does not require specialized equipment for this step, it reduces the complexity and cost associated with forming C3-oxotriterpenoid derivatives using known methods, and reduces other experimental and industrial limitations.

[0383] Furthermore, since the hydrogenation step of the methods described according to embodiments 3, 4, and 5 is carried out in toluene, the method disclosed in this invention also eliminates the cumbersome solvent exchange step. In some embodiments, the purification and separation of the C3-oxotriterpenoid derivative (e.g., compound D in Figure 1) is performed by co-evaporation between the solvent used in the C3-oxotriterpenoid derivative and at least one other solvent (e.g., methanol). Therefore, in some embodiments, the method disclosed herein for forming C3-oxotriterpenoid derivatives does not involve the cumbersome solvent exchange step. The methods of this invention allow for simplified reaction solvent systems, which are particularly advantageous for the industrial production of C3-oxotriterpenoid derivatives.

[0384] In some embodiments, the methods provided herein do not involve the protection of hydroxyl groups and subsequent deprotection, making the process more efficient. Therefore, the method of the present invention simplifies the preparation of C9-C11 unsaturated triterpenoid derivatives (e.g., compound C in Figure 1), especially on a commercial or industrial scale. In contrast, several methods known in the art require protection or deprotection of functional groups present in the starting molecule (Honda et al., 1998; Wong et al., 2016; Honda et al., 2000). See, for example, embodiments 5-7. Therefore, the method disclosed in this invention has fewer steps and a shorter manufacturing time compared to the prior methods shown in embodiments 3-7 below.Or more efficient.

[0385] Solution 3. Specification 57 / 89 pages 70 CN 121794280 A

[0386]

[0387] Solution 4. Specification 58 / 89 pages 71 CN 121794280 A

[0388]

[0389] Solution 5. Specification 59 / 89 pages 72 CN 121794280 A

[0390]

[0391] Solution 6. Specification 60 / 89 pages 73 CN 121794280 A

[0392]

[0393] Solution 7. Specification 61 / 89 pages 74 CN 121794280 A

[0394]

[0395] V. Definition

[0396] When used in the context of chemical groups: "hydrogen" means -H; "hydroxyl" means -OH; "oxo" means =O; "carbonyl" means -C(=O)-; "carboxyl" means -C(=O)OH (also written as -COOH or -CO2H); "halogen" independently means -F, -Cl, -Br or -I; "amino" means -NH2; "hydroxyamino" means -NHOH; "nitro" means -NO2; "imino" means =NH; "cyano" means -CN; "isocyanate" means -N=C=O; "azide" means -N3; ​​"phosphate" in terms of monovalent means - (See manual 62 / 89, page 75, CN 121794280 A) OP(O)(OH)2 or its deprotonated form; in the case of divalent, "phosphate" means -OP(O)(OH)O- or its deprotonated form; "mercapto" means -SH; and "thio-" means =S; "thiocarbonyl" means -C(=S)-; "sulfonyl" means -S(O)2-; and "sulfinyl" means -S(O)-.

[0397] In the case of chemical formulas, the symbol "-" means a single bond, "=" means a double bond, and "≡" means a triple bond. The symbol " " indicates an optional bond, if present, either a single or double bond. The symbol " " indicates a single or double bond. Thus, the formula covers, for example, , , , and. And it should be understood that no single ring atom forms part of more than one double bond. Furthermore, it should be noted that the covalent bond symbol "-" does not indicate any preferred stereochemistry when connecting one or two stereo atoms. Rather, it encompasses all stereoisomers and their mixtures. The symbol “ ” when drawn vertically through the bond (e.g., for methyl) indicates the attachment point of the group. It should be noted that for larger groups, attachment points are usually identified only in this way to help the reader clearly identify them. The symbol “ ” signifies a single bond, where the group attached to the thick end of the wedge symbol “extends out of the page.” The symbol “ ” signifies a single bond.The group attached to the thick end of the wedge symbol is “Enter Page”. The symbol “ " signifies a single bond, where the geometry surrounding the double bond (e.g., E or Z) is undefined. Thus, it signifies both options and their combinations. Any undetermined valence on an atom in the structure shown in this application implicitly represents a hydrogen atom bonded to that atom. The thick dot on the carbon atom indicates that the hydrogen bonded to that carbon is facing outwards from the plane of the paper.

[0398] For chemical groups and compound categories, the number of carbon atoms in the group or category is expressed as follows: “Cn” or “C=n” defines the exact number (n) of carbon atoms in the group / category. “C≤n” defines the maximum number (n) of carbon atoms that can exist in the group / category, and the minimum number is as small as possible for the group / category in question. For example, it should be understood that the minimum number of carbon atoms in the groups “alkyl (C≤8)”, “alkadiyl (C≤8)”, “heteroaryl (C≤8)”, and “acyl (C≤8)” is one; the minimum number of carbon atoms in the groups “alkenyl (C≤8)”, “alkynyl (C≤8)”, and “heterocyclic alkyl (C≤8)” is two; the minimum number of carbon atoms in the group “cycloalkyl (C≤8)” is three; and the minimum number of carbon atoms in the groups “aryl (C≤8)” and “aryldiyl (C≤8)” is six. “Cn-n'” defines the minimum number (n) and maximum number (n') of carbon atoms in the group. Therefore, “alkyl (C2-10)” refers to those alkyl groups having 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical group or class they modify, and may or may not be enclosed in parentheses without indicating any change in meaning. Therefore, the terms “C1-4-alkyl,” “C1-4-alkyl,” “C1-4-alkyl,” “alkyl (C1-4),” and “alkyl (C≤4)” are all synonymous. Unless otherwise specified below, each carbon atom is counted to determine whether a group or compound meets the specified number of carbon atoms. For example, the group dihexylamino is an example of a dialkylamino (C12) group; however, it is not an example of a dialkylamino (C6) group. Similarly, phenethyl is an example of an aralkyl (C=8) group. When any chemical group or compound class defined herein is modified by the term “substituted,” any carbon atoms in the portion substituting hydrogen atoms are not counted. Thus, methoxyhexyl, with a total of seven carbon atoms, is an example of a substituted alkyl (C1-6). Unless otherwise specified, any chemical group or compound class listed in the claims set without a carbon atom limit has a carbon atom limit of twelve or less.

[0399] Unless otherwise stated below, the term "saturated" when used to modify a compound or chemical group means that the compound or chemical group has neither carbon-carbon double bonds nor carbon-carbon triple bonds. When the term is used to modify an atom, it means that the atom does not belong to any double or triple bond. In the case of substitution of saturated groups,One or more carbon-oxygen double bonds or carbon-nitrogen double bonds may be present. And when such bonds are present, carbon-carbon double bonds that may be present as part of a ketone-enol tautomerism or an imine / enamine tautomerism are not excluded. When the term "saturated" is used in a solution of a modified substance, it means that the substance can no longer dissolve in the solution. Specification 63 / 89 pages 76 CN 121794280 A

[0400] The term "aliphatic" means that the modified compound or chemical group is an acyclic or cyclic but non-aromatic compound or group. In an aliphatic compound / group, carbon atoms may be linked together in the form of straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds / groups may be saturated, i.e., linked by a single carbon-carbon bond (alkane / alkyl), or unsaturated, with one or more carbon-carbon double bonds (alkene / alkenyl) or with one or more triple bonds (alkynyl / alkynyl).

[0401] The term “aromatic” means that a compound or chemical group modified in this way has a planar unsaturated atomic ring and 4n + 2 electrons in a fully conjugated cyclic π system. An aromatic compound or chemical group can be described as a single resonance structure; however, the description of one resonance structure is also used to refer to any other resonance structure. For example:

[0402] is also used to refer to.

[0403] Aromatic compounds can also be depicted using circles to represent the delocalization of electrons in a fully conjugated cyclic π system, two non-limiting examples of which are shown below:

[0404] and.

[0405] The term “alkyl” refers to a monovalent saturated aliphatic group having a straight-chain or branched acyclic structure with one carbon atom as a attachment point and no atoms other than carbon and hydrogen. The groups -CH3 (Me), -CH2CH3 (Et), -CH2CH2CH3 (n-Pr or propyl), -CH(CH3)2 (i-Pr, iPr or isopropyl), -CH2CH2CH2CH3 (n-Bu), -CH(CH3)CH2CH3 (sec-butyl), -CH2CH(CH3)2 (isobutyl), -C(CH3)3 (tert-butyl, tert-butyl, t-Bu or tBu), and -CH2C(CH3)3 (neopentyl) are non-limiting examples of alkyl groups. The term "alkanediyl" refers to a divalent saturated aliphatic group having a straight-chain or branched acyclic structure with one or two saturated carbon atoms as attachment points, without carbon-carbon double or triple bonds, and without atoms other than carbon and hydrogen. The groups -CH2- (methylene), -CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2CH2- are non-limiting examples of alkanediyl groups. The term "alkylene" refers to a divalent group =CRR', where R and R' are independently hydrogen or alkyl. Non-limiting examples of alkylene include =CH2, =CH(CH2CH3), and =C(CH3)2. "Alkane" refers to a class of compounds having the formula H-R, where R is an alkyl group.As defined above, this term

[0406] The term “cycloalkyl” refers to a monovalent saturated aliphatic group having one carbon atom as a connecting point (the carbon atom forming part of one or more non-aromatic ring structures), no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused, bridged, or spirocyclic. Non-limiting examples include: -CH(CH2)2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). As used herein, this term does not exclude the presence of one or more alkyl groups attached to a carbon atom of a non-aromatic ring structure (if the carbon number limitation allows). The term “cycloalkyldiyl” refers to a divalent saturated aliphatic group having two carbon atoms as connecting points, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples of cycloalkyldiyl groups. “Cycloalkanes” refers to a class of compounds having the formula H-R, where R is a cycloalkyl group, as defined above.

[0407] The term "alkenyl" refers to a monovalent unsaturated aliphatic group having a straight-chain or branched acyclic structure with one carbon atom as a bond, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bond, and no atoms other than carbon and hydrogen. Non-limiting examples include: -CH=CH2 (vinyl), -CH=CHCH3, -CH=CHCH2CH3, -CH2CH=CH2 (allyl), -CH2CH=CHCH3, and -CH=CHCH=CH2. The term "alkenyl" refers to a divalent unsaturated aliphatic group having a straight-chain or branched acyclic structure with two carbon atoms as bond, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bond, and no atoms other than carbon and hydrogen. The groups -CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2-, and -CH2CH=CHCH2- are examples of alkenadiyl groups, as described in the non-limiting specification 64 / 89, page 77, CN 121794280 A. It should be noted that although alkenadiyl groups are aliphatic, once connected at both ends, this does not preclude the group from forming part of an aromatic structure. The terms "alkene" and "olefin" are synonymous and refer to a class of compounds having the formula H-R, where R is an alkenyl group, as defined above. Similarly, the terms "terminal olefin" and "α-olefin" are synonymous and refer to an olefin having only one carbon-carbon double bond, where the bond is part of a vinyl group at the end of the molecule.

[0408] The term "alkynyl" refers to a monovalent unsaturated aliphatic group having a straight-chain or branched acyclic structure with one carbon atom as an attachment point, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. As used herein,The term alkynyl does not exclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups -C≡CH, -C≡CCH3, and -CH2C≡CCH3 are non-limiting examples of alkynyl groups. "Alkyne" refers to a class of compounds having the formula H-R, where R is an alkynyl group.

[0409] The term "aryl" refers to a monovalent unsaturated aromatic group having an aromatic carbon atom as a attachment point, said carbon atom forming part of one or more aromatic ring structures, each ring structure having six ring atoms, all of which are carbon, and wherein the composition of the group contains no atoms other than carbon and hydrogen. If more than one ring is present, the rings can be fused or unfused. Unfused rings are connected by covalent bonds. As used herein, the term aryl does not exclude the presence of one or more alkyl groups attached to the first aromatic ring or any other aromatic ring present (if the carbon number limitation allows). Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C6H4CH2CH3 (ethylphenyl), naphthyl, and monovalent groups derived from biphenyl (e.g., 4-phenylphenyl). The term "aryl dimethyl" refers to a divalent aromatic group having two aromatic carbon atoms as attachment sites, said carbon atoms forming part of one or more six-membered aromatic ring structures, each ring structure having six ring atoms, all of which are carbon, and wherein the composition of the divalent group has no atoms other than carbon and hydrogen. As used herein, the term aryl dimethyl does not exclude the presence of one or more alkyl groups attached to a first aromatic ring or any other aromatic ring present (if the carbon number limit allows). If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected by covalent bonds. Non-limiting examples of aryl dimethyl include:

[0410] , , , and .

[0411] "Aromatic hydrocarbon" refers to a class of compounds having the formula H-R, where R is an aryl group, as defined above for the term. Benzene and toluene are non-limiting examples of aromatic hydrocarbons.

[0412] The term "aralkyl" refers to a monovalent group - alkyldiyl-aryl, wherein the terms alkyldiyl and aryl are used in a manner consistent with the definitions provided above. Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.

[0413] The term "heteroaryl" refers to a monovalent aromatic group having an aromatic carbon atom or nitrogen atom as an attachment point, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures, each aromatic ring structure having three to eight ring atoms, wherein at least one of the ring atoms of the aromatic ring structure is nitrogen, oxygen or sulfur, and wherein the composition of the heteroaryl group has no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings are fused; however,The term heteroaryl does not exclude the presence of one or more alkyl or aryl groups attached to one or more ring atoms (if the carbon number restriction allows). Non-limiting examples of heteroaryl include benzoxazolyl, benzimidazolyl, furanyl, imidazolyl (Im), indolyl, indazole, isoxazolyl, methylpyridinyl, oxazolyl, oxadiazolyl, phenylpyridinyl, pyridinyl (pyridyl / pyridinyl), pyrroleyl, pyrimidinyl, pyrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thiophene, and triazolyl. The term "N-heteroaryl" refers to a heteroaryl having a nitrogen atom as a connecting point. "Heteroary hydrocarbon" refers to a class of compounds having the formula H-R, where R is a heteroaryl. Pyridine and quinoline are non-limiting examples of heteroary hydrocarbons. Specification page 65 / 89 78 CN 121794280 A

[0414] The term "heterocyclic alkyl" refers to a monovalent non-aromatic group having a carbon or nitrogen atom as a attachment point, said carbon or nitrogen atom forming part of one or more non-aromatic ring structures, each non-aromatic ring structure having three to eight ring atoms, wherein at least one of the ring atoms of the non-aromatic ring structure is nitrogen, oxygen or sulfur, and wherein the composition of the heterocyclic alkyl group has no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings may be fused, bridged or spirocyclic. As used herein, the term does not exclude the presence of one or more alkyl groups attached to one or more ring atoms (if the carbon number limit allows). Moreover, the term does not exclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocyclic alkyl groups include aziridinyl, aziridine, pyrrolidine, piperidinyl, piperazine, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, tetrahydropyridinyl, pyranyl, oxadicyclopropane, and oxadicyclobutane. The term “N-heterocyclic alkyl” refers to a heterocyclic alkyl group having a nitrogen atom as a connecting point. N-pyrrolidine is an example of such a group.

[0415] The term “acyl” refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, or aryl, as defined above for those terms. The groups -CHO, -C(O)CH3 (acetyl, Ac), -C(O)CH2CH3, -C(O)CH(CH3)2, -C(O)CH(CH2)2, -C(O)C6H5, and -C(O)C6H4CH3 are non-limiting examples of acyl groups. "Thioacyl" is defined in a similar manner, except that the oxygen atom of the group -C(O)R has been replaced by a sulfur atom, -C(S)R. The term "aldehyde" corresponds to an alkyl group attached to a -CHO group, as defined above.

[0416] The term "alkoxy" refers to the group -OR, where R is an alkyl group.As defined above, this term is not limited to the following: -OCH3 (methoxy), -OCH2CH3 (ethoxy), -OCH2CH2CH3, -OCH(CH3)2 (isopropoxy), or -OC(CH3)3 (tert-butoxy). When used without the modifier "substituted," the terms "cycloalkoxy," "alkenoxy," "alkynoxy," "aryloxy," "araneoxy," "heteroaryloxy," "heterocycloalkoxy," "heteroarylalkoxy," "alkylsiloxy," and "acyloxy" refer to groups defined as -OR, where R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, heteroarylalkyl, alkylsilyl, and acyl, respectively. The terms "alkathioyl" and "acylthioyl" refer to the group -SR, where R is alkyl and acyl, respectively. The term "alkylsulfonyl" refers to the -SO2R group, where R is alkyl. The term "alcohol" corresponds to an alkane as defined above, wherein at least one hydrogen atom has been replaced by a hydroxyl group. The term “ether” corresponds to an alkane as defined above, wherein at least one of the hydrogen atoms has been replaced by an alkoxy group.

[0417] The term “alkylamino” refers to the group -NHR, wherein R is an alkyl group as defined above. Non-limiting examples include -NHCH3 and -NHCH2CH3. The term “dialkylamino” refers to the group -NRR', wherein R and R' can be the same or different alkyl groups. Non-limiting examples of dialkylamino include -N(CH3)2 and -N(CH3)(CH2CH3). When used without the modifier “substituted”, the term “acylamino” (acylamino) refers to the group -NHR, wherein R is an acyl group as defined above. A non-limiting example of an acylamino is -NHC(O)CH3.

[0418] The term “heteroarylalkyl” refers to the monovalent group -alkyldiyl-heteroaryl, wherein the terms alkyldiyl and heteroaryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: pyridylmethyl and 2-quinolinyl-ethyl.

[0419] When a chemical group is used with the modifier “substituted”, one or more hydrogen atoms are independently substituted by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CO2CH2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH or -S(O)2NH2. For example,The following groups are non-limiting examples of substituted alkyl groups: -CH2OH, -CH2Cl, -CF3, -CH2CN, -CH2C(O)OH, -CH2C(O)OCH3, -CH2C(O)NH2, -CH2C(O)CH3, -CH2OCH3, -CH2OC(O)CH3, -CH2NH2, -CH2N(CH3)2, and -CH2CH2Cl. The term "haloalkyl" is a subset of substituted alkyl groups in which hydrogen substitution is limited to halogroups (i.e., -F, -Cl, -Br, or -I), and therefore no atoms other than carbon, hydrogen, and halogen are present. The group -CH2Cl is a non-limiting example of a haloalkyl group. The term "fluoroalkyl" is a subset of substituted alkyl groups in which hydrogen substitution is limited to fluorine, and therefore no atoms other than carbon, hydrogen, and fluorine are present. The groups -CH2F, -CF3, and -CH2CF3 are non-limiting examples of fluoroalkyl groups. Non-limiting examples of substituted aralkyl groups are (3-chlorophenyl)-methyl and 2-chloro-2-phenyl-ethyl-1-yl. The groups -C(O)CH2CF3, -CO2H (carboxyl), -CO2CH3 (methylcarboxyl), -CO2CH2CH3, -C(O)NH2 (carbamoyl), and -CON(CH3)2 are non-limiting examples of substituted acyl groups. The groups -NHC(O)OCH3 and -NHC(O)NHCH3 are non-limiting examples of substituted amide groups.

[0420] An "isomer" of the first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but those atoms have different three-dimensional configurations.

[0421] The term "salt" as used herein is not particularly limited. The salts of the compounds of this invention refer to salts commonly used in the field of organic chemistry. Salts of compounds containing a carboxyl group can be (but are not limited to) basic addition salts of a carboxyl group, for example. Salts of compounds containing an amino group or a basic heterocyclic group can be (but are not limited to) acid addition salts of that amino group or basic heterocyclic group. Examples of basic addition salts include: alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; ammonium salts; and organic amine salts, such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, and N,N'-diphenylmethylethylenediamine salts. Examples of acid addition salts include: inorganic acid salts, such as hydrochlorides, sulfates, nitrates, phosphates, and perchlorates; organic acid salts, such as acetates, formates, maleates, fumarates, tartrates, citrates, ascorbic acid salts, and trifluoroacetates; and sulfonates, such as methanesulfonates, hydroxyethanesulfonates, benzenesulfonates, and p-toluenesulfonates. According to the definition of the present invention,As used herein, “salt” can be a pharmaceutically acceptable salt. “Pharmaceutically acceptable salt” means a salt of the compound disclosed herein that has the desired pharmacological activity. Such salts include acid addition salts formed with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; and organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-en-1 carboxylic acid), 4-methylbicyclo[2.2.2]octyl-2-en-1 carboxylic acid, acetic acid, aliphatic monocarboxylic acids and dicarboxylic acids, aliphatic sulfuric acid, aromatic sulfuric acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, etc. Glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthylcarboxylic acid, lactic acid, lauryl sulfate, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tert-butylacetic acid, trimethylacetic acid, etc. Pharmaceutically acceptable salts also include base addition salts that can be formed when the present acidic protons can react 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-methylglucosamine, etc. It should be understood that the specific anion or cation forming part of any salt of the present invention is not critical, as long as the salt as a whole is pharmacologically acceptable. The Handbook of Pharmaceutical Salts: Properties, and Use (edited by PH Stahl and CG Wermuth, Verlag Helvetica Chimica Acta, 2002) provides further examples of pharmaceutically acceptable salts and their preparation and use. In some embodiments, the salts of the compounds of the present invention have the advantage of having useful pharmacological, physical, or chemical properties compared to compounds known in the art, whether for the indications described herein or for other indications. In some embodiments, the compounds and formulations provided herein are present in salt or non-salt forms. Regarding salt forms, in some embodiments, the specific anion or cation forming part of any salt form of the compounds provided herein is not critical.

[0422] 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 in which those atoms have different configurations in three dimensions. An “enantiomer” is a stereoisomer of a given compound that is a mirror image of each other.Like the left and right hands. "Diabeta-isomers" are stereoisomers of a given compound that are not enantiomers. A chiral molecule contains a chiral center, also called a stereocenter or steric center, which is any point, but not necessarily an atom, in a molecule bearing a group such that the interchange of any two groups results in a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus, or sulfur atom, although other atoms can also be stereocenters in both organic and inorganic compounds. A molecule can have multiple stereocenters, thus giving it many stereoisomers. In compounds where stereoisomerism originates from a tetrahedral stereocenter (e.g., tetrahedral carbon), it is assumed that the total number of possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry often have fewer stereoisomers than the maximum possible number. A 50:50 mixture of enantiomers is called a racemic mixture. Alternatively, the mixture of enantiomers may be enantiomerically enriched, such that the presence of one enantiomer is greater than 50%. Typically, enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. Considering any stereocenter or chiral axis whose stereochemistry is not yet well-defined, the stereocenter or chiral axis may exist in its R form, S form, or as a mixture of R and S forms, including racemic and non-racemic mixtures. As used herein, the phrase “substantially free of other stereoisomers” means that the composition contains ≤15%, more preferably ≤10%, even more preferably ≤5%, or most preferably ≤1% of other stereoisomers.

[0423] As used herein, “substantially free of” for a specified component means that any specified component is not intentionally formulated into the composition and / or exists only as a contaminant or in trace amounts. The total amount of the specified component resulting from any unintentional contamination of the composition is therefore well below 0.05%, preferably below 0.01%. Most preferably, the composition is one in which no amount of the specified component can be detected by standard analytical methods.

[0424] As used herein, “substantially free of” means that the total amount of the specified component is ≤15%, preferably ≤10%, more preferably ≤5%.

[0425] As used herein, “an” may mean one or more. In the claims and / or description, the word “a” or “an” when used in conjunction with the term “comprising” may mean “an”, but is consistent with the meanings of “one or more,” “at least one,” and “one or more.”

[0426] The term “or” is used in the claims to mean “and / or” unless explicitly stated that it refers only to an alternative or that the alternatives are mutually exclusive, although this disclosure supports only the definition of alternatives and “and / or.” As used herein,“Another” may mean at least a second or more.

[0427] The terms “comprises,” “have,” and “include” are open-ended linking verbs. Any form or tense of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes,” and “including,” is also open-ended. For example, any method that “comprises,” “has,” or “includes” one or more steps is not limited to having only those one or more steps and also includes other steps not listed.

[0428] As used herein, the term “water-immiscible solvent” means any non-aqueous or hydrophobic solvent that, when mixed with water, separates from the solution into two distinct phases. Liquids that are immiscible with water are generally nonpolar. Non-limiting examples of liquids that are immiscible with water include terpenoids, 2-methyltetrahydrofuran, sesquiterpenoids, butanone, butyl acetate, heptane, hexane, toluene, dichloromethane, cyclohexane, petroleum ether (60-80), petroleum ether (80-100), petroleum ether (100-120), dibutyl ether, dipentyl ether, hexadecane, tetrachloroethylene, 1,1,1-trichloroethane, or other liquids known in the art that are immiscible with water.

[0429] Other abbreviations used herein are as follows: DMSO, dimethyl sulfoxide; DMF, dimethylformamide; MeOH, methanol; EtOH, ethanol; EtOAc, ethyl acetate; THF, tetrahydrofuran; NaOMe, sodium methoxide; Me2SO4, dimethyl sulfate; K2CO3, potassium carbonate; TBABr, tetrabutylammonium bromide; 2-MeTHF, 2-methyltetrahydrofuran; mCPBA, m-chloroperoxybenzoic acid; DCM, dichloromethane; MsOH, methanesulfonic acid; PhMe, toluene; T3P, propylphosphonic anhydride; DIPEA, diisopropylethylamine; LiBr, lithium bromide; NaCl, sodium chloride; DMAc, N,N-dimethylacetamide; DPPA, diphenylphosphine azide; NaOH, sodium hydroxide; H3PO4. Phosphoric acid; IPA, isopropanol; IBX, 2-iodobenzoic acid; NaHCO3, sodium bicarbonate; KF, key process control; ID, identification method; Instruction manual, pages 68 / 89, 81 CN 121794280 A; IR, infrared spectroscopy; HPLC, high performance liquid chromatography; TEA or Et3N, triethylamine; LCMS, liquid chromatography-mass spectrometry; ppm, parts per million; ICP-MS, inductively coupled plasma mass spectrometry; GCMS, gas chromatography-mass spectrometry; GC, gas chromatography; MW, molecular weight; PyHBr3 or PyH*Br3, pyridine tribromide; IM1-9, impurity compounds 1-9; LC, liquid chromatography; RRT, relative retention time; DMSDimethyl sulfate.

[0430] TEA, triethylamine; NO, nitric oxide; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; IFNγ or IFN-γ, interferon-γ; FA, Friedrich ataxia; Nrf2, nuclear factor E2-related factor 2.

[0431] Throughout this application, the term “about” is used to indicate values ​​including inherent variations in the error of the device, inherent variations in the method used to determine the value, variations present among study subjects, or values ​​within 10% of a specified value.

[0432] Table 1. Intermediate compounds

[0433] Specification 69 / 89 pages 82 CN 121794280 A

[0434]

[0435] In the event of any conflicting definitions in any references incorporated herein by reference, the above definitions shall prevail. However, the fact that certain terms are defined should not be construed as indicating that any undefined term is indeterminate. In fact, all terms used are considered to explicitly describe the invention, enabling those skilled in the art to understand the scope of the invention and practice it.

[0436] VI. Embodiments

[0437] The following embodiments are included to illustrate preferred embodiments of the invention. It should be understood by those skilled in the art that the techniques disclosed in the following embodiments represent techniques that the inventors have found to work well in the practice of the invention and can therefore be considered as preferred modes of practice. However, it should be understood by those skilled in the art that, according to this disclosure, many changes can be made to the specific embodiments disclosed without departing from the spirit and scope of the invention, and similar or analogous results can still be obtained.

[0438] Example 1 – Formation of C3-oxotriterpenoid Derivatives

[0439] Preparation of Product D from C:

[0440]

[0441] Table 2: Preparation of Product D from C Specification 71 / 89 pages 84 CN 121794280 A

[0442]

[0443] Ethyl acetate (EtOAc; 6.6-7.6X), C (0.99-1.01X) and dimethyl sulfoxide (DMSO; 0.84-0.94X) were loaded into a reactor and the contents were adjusted to -5°C. A solution of propylphosphonic anhydride (T3P) (50% w / w in ethyl acetate, 1.72-1.84X) was loaded into the reactor and the temperature was maintained at -5–5°C. Then, the reaction mixture was stirred at -5°C for 2.0 hours. Diisopropylethylamine (DIPEA; 0.41–0.45X) was added to the reactor, and the temperature was maintained at -5°C. Ethyl acetate (EtOAc; 0.10–0.20X) was added to the reactor, and the temperature was maintained at -5–5°C. The temperature of the contents was then adjusted to 20–30°C.Maintain the temperature at 20–30°C for at least 2.0 hours until the reaction is confirmed to be complete. Then, add purified water (4.75–5.25X) to the reactor and maintain the temperature at 20–30°C for at least 1.0 hour. Stir the mixture at 20–30°C for at least 1.0 hour. Stop stirring and allow the mixture to stand at 20–30°C for at least 1.0 hour, then separate and remove the bottom aqueous layer. Add a 1N sodium hydroxide (NaOH; 4.73–5.33X) aqueous solution to the reactor, maintain the temperature at 20–30°C, and stir the two-phase mixture at 20–30°C for at least 1.0 hour. Stop stirring and allow the mixture to stand at 20–30°C for at least 1.0 hour, then separate and remove the bottom aqueous layer. Add an 8% sodium bicarbonate (NaHCO3) aqueous solution (4.75-5.25X) to the reactor, maintain the temperature at 20-30℃, and stir the two-phase mixture at 20-30℃ for at least 1.0 hour. Stop stirring and let the mixture stand at 20-30℃ for at least 1.0 hour, then separate and remove the bottom water layer. (This process is repeated three times in the original text.) Add purified water (4.75–5.25X) to the reactor, maintain the temperature at 20–30°C, and stir the two-phase mixture at 20–30°C for at least 1.0 hour. Stop stirring and allow the mixture to stand at 20–30°C for at least 1.0 hour, then separate and remove the bottom water layer. Concentrate the reactor contents under vacuum to 2.0 V at a temperature not exceeding 45°C. Add purified water (0.14–0.16X) to the reactor. Add methanol (3.75–4.15X) to the reactor. Concentrate the reactor contents under vacuum to 2.0 V at a temperature not exceeding 45°C. Add methanol (3.75–4.15X) to the reactor. Concentrate the reactor contents under vacuum to 2.0 V at a temperature not exceeding 45°C. Then, adjust the temperature to 20–30°C and add methanol (5.63–6.23X) to the reactor. Then, the water content was checked using the Karl Fischer method to confirm that the water content in the filtrate was in the range of 0.5-2.0%. The temperature of the contents was adjusted to not less than 64°C (reflux). The contents were stirred at a temperature not less than 64°C (reflux) for not less than 20 minutes to ensure complete dissolution of the solids. Then, the mixture was cooled to -5°C for not less than 6 hours and aged for not less than 6.0 hours. The resulting slurry was filtered, and the wet filter cake was treated with methanol / water (7 / 3,Wash with w / w (0.7–1.3X). Dry product D under vacuum at 45–55 °C for at least 16 hours (average yield 87%). The yield summary and test reports for compound D are shown in Tables 3 and 4 below.

[0444] Table 3: Summary of the yield of compound D ((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecylhydrofuran-4a(2H)-methyl formate)

[0445]

[0446] Table 4: Summary of the yield of compound D ((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-2,2,6a ,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecylhydrofuran-4a(2H)-methyl formate) test report instruction manual 73 / 89 pages 86 CN 121794280 A

[0447] instruction manual 74 / 89 pages 87 CN 121794280 A

[0448] instruction manual 75 / 89 pages 88 CN 121794280 A

[0449]

[0450] Example 2 – Formation of C9-C11 unsaturated triterpenoids instruction manual 76 / 89 pages 89 CN 121794280 A

[0451]

[0452] Table 5: Product C prepared from B

[0453]

[0454] Toluene (14.0-14.8X) and B (0.99-1.01X) were charged into the reactor, the batch temperature was adjusted to 28-38°C, and the mixture was stirred for at least 0.5 hours to ensure complete dissolution of the solids. The batch was cooled to a temperature between 20-30°C. Pyridine tribromide (PyHBr3; 0.89-0.95X) was charged into the reactor, the temperature was maintained at 20-35°C, and then the mixture was rinsed with toluene (1.2-1.4X) before the reaction mixture was stirred at 20-35°C for at least 9 hours until the reaction was confirmed to be complete. The batch temperature was adjusted to 25-35°C. Then, a 10% sodium sulfite solution (4.7-5.3X) was charged into the reactor, and the temperature was maintained at 25-35°C. Stir the mixture for at least 2.0 hours to quench any remaining oxidizing agent. Stop stirring and allow the mixture to stand for at least 2.0 hours.Then separate and remove the bottom water layer. Add a 2.5% sodium hydroxide (NaOH) aqueous solution (5.42–6.58X) to the reactor and stir the two-phase mixture at 25–35°C for at least 2.0 hours. Stop stirring and allow the mixture to stand for at least 2.0 hours, then separate and remove the bottom water layer. Add a 15% sodium chloride (NaCl) aqueous solution (4.73–5.27X) to the reactor and stir the two-phase mixture at 25–35°C for at least 2.0 hours. Stop stirring and allow the mixture to stand for at least 2.0 hours, then separate and remove the bottom water layer. Add purified water (3.5–4.5X) to the reaction mixture and stir the two-phase mixture at 25–35°C for at least 2.0 hours. Stop stirring and allow the mixture to stand for at least 2.0 hours, then separate and remove the bottom water layer. Concentrate the reactor contents under vacuum to 7.5°C at a temperature not exceeding 55°C. The concentrated solution is heated to 65–75°C and maintained at this temperature for at least 0.5 hours. The contents are then cooled to 45–55°C and subsequently concentrated under vacuum to 4.5 V at a temperature not exceeding 55°C. The contents are then heated to 45–55°C and stirred for at least 1.0 hour. While maintaining the temperature at 45–55°C, n-heptane (8.4–9.4X) is added for at least 5.0 hours. After stirring at 45–55°C for at least 1 hour, the mixture is cooled to 0–10°C for at least 4 hours, followed by aging for at least 4 hours. The resulting slurry is filtered, and the wet filter cake is washed with n-heptane (0.68–1.36X). The wet filter cake and toluene (6.1–7.0X) are loaded into a reactor, the contents are heated to 65–75°C, and stirred for at least 0.5 hours. The contents were then cooled to 45–55°C and subsequently concentrated under vacuum to 4.5 V at a temperature not exceeding 55°C. The contents were then adjusted to 45–55°C and stirred at 45–55°C for at least 1.0 hour. While maintaining the temperature at 45–55°C, n-heptane (8.4–9.4X) was added for at least 5.0 hours. After stirring at 45–55°C for at least 1 hour, the mixture was cooled to 0–10°C for at least 4 hours, followed by aging for at least 4 hours. The resulting slurry was filtered, and the wet filter cake was washed with n-heptane (0.68–1.36X). At 45–55°C,The obtained product C was vacuum dried for no less than 10 hours (average yield 85%). The yield summary and test report of compound C obtained from batches 1-4 are shown in Tables 6 and 7 below.

[0455] Table 6: Summary of the yields of compound C ((4aS,6aR,6bS,8aR,10S,12aS,14aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14-oxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecylhydrofuran-4a(2H)-formate)

[0456]

[0457] Table 7: Summary of the yields of compound C ((4aS,6aR,6bS,8aR,10S,12aS,14aR,14bS)-10-hydroxy-2,2,6a,6b, Test report of 9,9,12a-heptamethyl-14-oxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecylhydrofuran-4a(2H)-methyl formate) 78 / 89 pages 91 CN 121794280 A

[0458]

[0459] Example 3 – Formation of C12-oxotriterpenoid derivatives 79 / 89 pages 92 CN 121794280 A

[0460]

[0461] Table 8: Preparation of product B from A

[0462]

[0463] Dichloromethane (DCM; 11.5-12.5X) and A (0.99-1.01X) were loaded into the reactor and the temperature was adjusted to 10-30°C. While maintaining a temperature of 10–30°C, m-chloroperoxybenzoic acid (m-CPBA; 0.44–0.48X) is added to the reactor. A washing solution of dichloromethane (1.2–1.4X) is then added to the reactor. The reaction mixture is then stirred at 20–30°C for at least 13 hours until the reaction is confirmed to be complete. Afterward, while maintaining a temperature of 20–30°C, a 10% sodium sulfite solution (0.95–1.05X) is added to the reactor. The mixture is stirred for at least 0.5 hours to quench the reaction. Then, an 8% sodium bicarbonate solution (3.75–4.25X) is added to the reactor while maintaining a temperature of 20–30°C. The mixture is stirred for at least 1.5 hours. Stirring is stopped, and the mixture is allowed to stand for at least 2.5 hours. The bottom organic layer is then separated, and the upper aqueous layer is discarded. Transfer the organic layer (pages 80 / 89 of the instruction manual, CN 121794280 A) back to the reactor, add purified water (4.5-5.5X), and stir the two-phase mixture at 20-30°C for at least 1.5 hours. Stop stirring and let the mixture stand for at least 3.5 hours, then separate the bottom organic layer.The upper aqueous layer is discarded. The organic layer is transferred back to the reactor and a methanesulfonic acid / dichloromethane solution (0.058–0.066X methanesulfonic acid; 0.62–0.70X dichloromethane) is added, while maintaining the temperature at 20–30°C. The reaction mixture is then stirred at 20–30°C for at least 0.5 hours until the reaction is confirmed to be complete. Next, an 8% sodium carbonate solution (4.75–5.25X) is added to the reactor, while maintaining the temperature at 20–30°C. The mixture is stirred for at least 1.5 hours, then stirring is stopped, and the mixture is allowed to stand for at least 2.0 hours. The bottom organic layer is then separated, and the upper aqueous layer is discarded. The organic layer is transferred back to the reactor, purified water (4.5–5.5X) is added, and the two-phase mixture is stirred at 20–30°C for at least 1.5 hours. Stop stirring and allow the mixture to stand for at least 3.0 hours. Then separate the bottom organic layer and discard the upper aqueous layer. Transfer the organic layer back to the reactor and concentrate the reactor contents under vacuum to 3.0 V at a temperature not exceeding 30°C. Adjust the temperature of the concentrated solution to 20–30°C and add isopropanol (3.7–4.1X) over a period of at least 5 hours, while maintaining the temperature at 20–30°C. Stir the resulting mixture at 20–30°C for at least 1.5 hours, then concentrate the reactor contents under vacuum to 5.0 V at a temperature not exceeding 55°C. Adjust the temperature of the concentrated solution to 45–55°C and add isopropanol (3.7–4.1X) over a period of at least 3 hours, while maintaining the temperature at 45–55°C. Concentrate the reactor contents under vacuum to 5.0 V at a temperature not exceeding 55°C. The temperature of the concentrated solution was adjusted to 45-55°C, and isopropanol (3.7-4.1X) was added over a period of not less than 2 hours while maintaining the temperature at 45-55°C. Then, while maintaining the temperature at 45-55°C, purified water (0.9-1.1X) was added over a period of not less than 3 hours. The mixture was stirred at 45-55°C for not less than 1 hour, then cooled to 15-25°C over a period of not less than 3 hours, followed by aging for not less than 4 hours. The resulting slurry was filtered, and the wet filter cake was washed with an isopropanol / water (9:1, V / V; 1.8-2.2X) solution. At 45-55°C,The resulting product B was vacuum dried for at least 18 hours (average yield 74%). The yield summary and test report of compound B are shown in Tables 9 and 10.1-10.2 below.

[0464] Table 9: Summary of the yield of compound B ((4aS,6aR,6bR,8aR,10S,12aR,14aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14-oxoeicosyl-4a(2H)-formate)

[0465]

[0466] Table 10.1: Test report of compound B ((4aS,6aR,6bR,8aR,10S,12aR,14aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14-oxoeicosyl-4a(2H)-formate) 81 / 89 pages 94 CN 121794280 A

[0467]

[0468] Table 10.2: Test report for compound B ((4aS,6aR,6bR,8aR,10S,12aR,14aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-14-oxoeicosperidin-4a(2H)-formate) 82 / 89 pages 95 CN 121794280 A

[0469]

[0470] Example 4 – Formation of C17-ester triterpenoid derivatives 83 / 89 pages 96 CN 121794280 A

[0471]

[0472] Table 11: Preparation of product A from oleanolic acid

[0473]

[0474] 2-Methyltetrahydrofuran (2-MeTHF; 1.9-2.1X) and oleanolic acid (0.99-1.01X) are loaded into the reactor. Another portion of 2-methyltetrahydrofuran (2.1-2.5X) is then added to the reactor, and the temperature is adjusted to 25-35°C. While maintaining the temperature at 25-35°C, an 18-19% potassium carbonate solution (K₂CO₃; 2.23-2.69X) is added to the reactor. Tetrabutylammonium bromide (TBABr; 0.028-0.032X) is then added to the reactor. The reactor is rinsed with 2-methyltetrahydrofuran (0.05-0.15X), and the reaction mixture is then stirred at 25-35°C for at least 0.5 hours. While maintaining a temperature of 25-35°C, as per the instructions (pages 84 / 89, 97 CN 121794280 A), add dimethyl sulfate (DMS; 0.34-0.38X) to the reactor for no more than 1.0 hour. Rinse the reactor with 2-methyltetrahydrofuran (0.05-0.15X) and, while maintaining a temperature of 25-35°C, stir for no less than 1.0 hour. While maintaining a temperature of 25-35°C,Triethylamine (TEA; 0.07–0.09X) is added to the reactor. The reactor temperature is adjusted to 45–55°C, and the reaction mixture is stirred for at least 4 hours while maintaining this temperature. The reactor temperature is then adjusted to 25–35°C. Glacial acetic acid (0.12–0.16X) is added to the reactor, and the mixture is stirred for at least 1 hour while maintaining this temperature. Stirring is stopped, and the mixture is allowed to stand for at least 1.0 hour. Then, the bottom organic layer is separated and the upper aqueous layer is discarded. The organic layer is transferred back to the reactor, and while maintaining this temperature at 25–35°C, a 21% sodium chloride solution (NaCl; 1.8–2.0X) is added to the reactor. The mixture is allowed to stand for at least 0.5 hours, and then the bottom organic layer is separated and the upper aqueous layer is discarded. The organic layer is transferred back to the reactor, and the reactor contents are concentrated under vacuum to 3.5°C at a temperature not exceeding 50°C. Adjust the temperature of the concentrated solution to 45-55°C and add isopropanol (IPA; 0.35-0.45X) for at least 4 hours, while maintaining the temperature at 45-55°C. Stir the mixture at 45-55°C for at least 1.0 hour. While maintaining the temperature at 45-55°C, add isopropanol (IPA; 4.4-5.0X) for at least 4 hours. Stir the mixture at 45-55°C for at least 1.0 hour. While maintaining the temperature at 45-55°C, add purified water (1.65-1.85X) for at least 3 hours. Adjust the reactor temperature to 0-10°C for at least 4.0 hours and stir for at least 2.0 hours. Filter the resulting slurry and wash the wet filter cake with an isopropanol / water (3:1, V / V; 1.5-1.7X) solution. At 50-60°C,The resulting product A was vacuum dried for at least 30 hours (average yield 87%). The yields are summarized in Tables 12 and 13.1–13.2 below.

[0475] Table 12: Overview of the yield of compound A ((4aS,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecylhydrofuran-4a(2H)-methyl formate)

[0476]

[0477] Table 13.1. Summary of the yield of compound A ((4aS,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a) ,6b,7 ,8 ,8a ,9 ,10 ,11 ,12 ,12a ,12b,13 ,14b-octadecylhydrofuran-4a (2H)-methyl formate) test report

[0478]

[0479] Table 13.2. Compound A ((4aS,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-2,2,6a,6b,9, 9 ,12a-heptamethyl-1 ,3 ,4 ,5 ,6 ,6a ,6b,7 ,8 ,8a ,9 ,10 ,11 ,12 ,12a ,12b,13 ,14b-octadecylhydrofuran-4a) instruction manual 85 / 89 pages 98 CN 121794280 A Test report for (2H)-methyl formate

[0480]

[0481]

[0482] All methods disclosed and claimed herein can be proposed and practiced in accordance with this disclosure without excessive experimentation. Although the compositions and methods of the present invention have been described according to preferred embodiments, it will be apparent to those skilled in the art that changes may be made to the methods and steps or the order of steps described herein without departing from the concept, spirit and scope of the invention. More precisely, it will be apparent that certain chemically and physiologically relevant agents may be substituted for the agents described herein.The same or similar results will be achieved. All similar alternatives and modifications described herein are considered to be within the spirit, scope and concept of the invention as defined by the appended claims.

[0483] References

[0484] The following references are specifically incorporated herein by reference to the extent that they provide exemplary procedures or other details that supplement those set forth herein. Specification 86 / 89 pages 99 CN 121794280 A

[0485] Specification 87 / 89 pages 100 CN 121794280 A

[0486] Specification 88 / 89 pages 101 CN 121794280 A

[0487] Specification 89 / 89 pages 102 CN 121794280 A Figure 1 Specification Figure 1 / 2 pages 103 CN 121794280 A Figure 2 Specification Figure 2 / 2 pages 104 CN 121794280 A,

Claims

1. A multi-step method for preparing omasorone from oleanolic acid, the method comprising using a compound of formula I as a reagent in one or more steps, wherein formula I is defined as: (I)， in: R1, R1', and R1'' are each independently hydrogen, halo, amino, cyano, or carboxyl; or alkyl (C≤8) cycloalkyl (C≤8) alkenyl (C≤8) , acetylenic (C≤8) aryl (C≤8) Aryl alkyl (C≤8) , heteroaryl (C≤8) heteroaryl (C≤8) alkoxy (C≤8) cycloalkoxy (C≤8) ,olefin (C≤8) , acetylacetylene (C≤8) , aryloxy group (C≤8) arylalkoxy (C≤8) heteroaryloxy (C≤8) , heteroaryloxy (C≤8) alkylamino (C≤8) Dialkylamino (C≤8) amide group (C≤8) Or a substituted form of any of these groups.

2. The method of claim 1, wherein R1, R1' and R1'' are each propyl.

3. The method according to claim 1 or claim 2, wherein the method comprises reacting oleanolic acid with an alkylating agent in a reaction mixture to form compound A, wherein compound A is defined as: (A)。 4. The method of claim 3, wherein the reaction mixture further comprises potassium carbonate.

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

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

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

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

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

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

11. The method according to any one of claims 1 to 10, wherein the method further comprises causing compound A: (A) It reacts with an oxidizing agent in the reaction mixture to form compound B, wherein compound B is defined as: (B)。 12. The method of claim 11, wherein the oxidant comprises m-chloroperoxybenzoic acid.

13. The method according to claim 11 or claim 12, wherein the molar ratio of compound A to the oxidant is about 4:

5.

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

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

16. The method according to any one of claims 11 to 15, wherein the reaction is carried out over a period of about 15 hours.

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

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

19. The method according to any one of claims 1 to 18, wherein the method further comprises causing compound B: (B) It reacts with an oxidizing agent in the reaction mixture to form compound C, wherein compound C is defined as: (C)。 20. The method of claim 19, wherein the oxidant is pyridine perbromin.

21. The method of claim 19 or claim 20, wherein the reaction mixture comprises compound B in a molar ratio of about 1:1 to about 1:2 with respect to the oxidant.

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

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

24. The method according to any one of claims 19 to 23, wherein the method further comprises a reaction time period of about 2 hours during which compound B reacts with the oxidant.

25. The method according to any one of claims 1 to 24, wherein the method further comprises causing compound C: (C) With oxidizing agents in the presence of compound I: (I) The reaction mixture reacts to form compound D, wherein compound D is defined as: (D)， in: R1, R1', and R1'' are each independently hydrogen, halo, amino, cyano, or carboxyl; or alkyl (C≤8) cycloalkyl (C≤8) alkenyl (C≤8) , acetylenic (C≤8) aryl (C≤8) Aryl alkyl (C≤8) , heteroaryl (C≤8) heteroaryl (C≤8) alkoxy (C≤8) cycloalkoxy (C≤8) ,olefin (C≤8) , acetylacetylene (C≤8) , aryloxy group (C≤8) arylalkoxy (C≤8) heteroaryloxy (C≤8) , heteroaryloxy (C≤8) alkylamino (C≤8) Dialkylamino (C≤8) amide group (C≤8) Or a substituted form of any of these groups.

26. The method of claim 25, wherein R1, R1' and R1'' are each propyl.

27. The method according to claim 25 or claim 26, wherein the reaction mixture comprises compound C in a molar ratio of about 1:1 to about 1:2 with respect to the compound of formula I.

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

29. The method of claim 28, wherein the reaction mixture comprises compound C and diisopropylethylamine in a molar ratio of about 1:1 to about 1:

2.

30. The method according to any one of claims 25 to 29, wherein the oxidant is dimethyl sulfoxide.

31. The method of claim 30, wherein the reaction mixture comprises compound C and dimethyl sulfoxide in a molar ratio of about 1:5 to about 1:

7.

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

33. The method according to any one of claims 25 to 32, wherein the method comprises contacting compound C with a solution containing the compound of formula I.

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

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

36. The method according to any one of claims 25 to 35, wherein the reaction of compound C with dimethyl sulfoxide in the presence of the compound of formula I is carried out at a temperature of about 25°C.

37. The method according to any one of claims 25 to 36, wherein the reaction of compound C with dimethyl sulfoxide in the presence of the compound of formula I is carried out for a reaction period of about 3 hours.

38. A method for preparing a compound of formula III, the method comprising obtaining a compound of formula II: (II), And to react the compound of formula II with the oxidant in the presence of the compound of formula I: (I) The reaction mixture is reacted to form a compound of formula III: (III), in: R1, R1', and R1'' are each independently hydrogen, halo, amino, cyano, or carboxyl; or alkyl (C≤8) cycloalkyl (C≤8) alkenyl (C≤8) , acetylenic (C≤8) aryl (C≤8) Aryl alkyl (C≤8) , heteroaryl (C≤8) heteroaryl (C≤8) alkoxy (C≤8) cycloalkoxy (C≤8) ,olefin (C≤8) , acetylacetylene (C≤8) , aryloxy group (C≤8) arylalkoxy (C≤8) heteroaryloxy (C≤8) , heteroaryloxy (C≤8) alkylamino (C≤8) Dialkylamino (C≤8) amide group (C≤8) Or a substituted form of any of these groups; and R2 is: C1-C 15 -acyl or C1-C 15 -alkyl, wherein any of these groups is substituted or unsubstituted.

39. The method of claim 38, wherein R1, R1' and R1'' are each propyl.

40. The method of claim 38 or claim 39, wherein R2 is C1-C 15 -acyl group or substituted C1-C 15 -Acyl group.

41. The method of claim 40, wherein R2 is the substituted C1-C 15 -Acyl group.

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

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

2.

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

45. The method of claim 44, wherein the reaction mixture comprises the compound of formula II and diisopropylethylamine in a molar ratio of about 1:1 to about 1:

2.

46. ​​The method according to any one of claims 38 to 45, wherein the reaction mixture further comprises dimethyl sulfoxide.

47. The method of claim 46, wherein the reaction mixture comprises the compound of formula II and dimethyl sulfoxide in a molar ratio of about 1:5 to about 1:

7.

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

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

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

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

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

53. The method according to any one of claims 38 to 52, wherein the method further comprises a reaction time period of about 3 hours during which the compound of formula II reacts with the compound of formula I.

54. A method for preparing compound A, the method comprising obtaining oleanolic acid, and reacting oleanolic acid with an alkylating agent in a reaction mixture to form compound A: (A)， The reaction mixture contains a solvent that is immiscible with water.

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

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

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

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

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

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

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

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

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

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

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

66. The method according to any one of claims 54 to 65, wherein compound A with a purity greater than 90% is prepared by high performance liquid chromatography.

67. The method of claim 66, wherein compound A with a purity greater than 95% is prepared by high performance liquid chromatography.

68. The method of claim 67, wherein compound A is prepared with a purity greater than 98% by high performance liquid chromatography.

69. A method for preparing compound C, the method comprising obtaining compound B: (B)， And to react compound B with perbrominated pyridine in the reaction mixture to form compound C: (C)。 70. The method of claim 69, wherein the molar ratio of compound B to perbrominated pyridine is about 1:1 to about 1:

2.

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

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

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

74. The method according to any one of claims 69 to 73, wherein the reaction is carried out over a reaction period of about 1 hour to about 4 hours.

75. The method of claim 74, wherein the reaction time period is approximately 2 hours.

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

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

78. The method according to any one of claims 69 to 77, wherein compound C is prepared with a purity greater than 90% by means of high performance liquid chromatography.

79. The method of claim 78, wherein compound C is prepared with a purity greater than 95% by high performance liquid chromatography.

80. The method of claim 79, wherein compound C is prepared with a purity greater than 98% by high performance liquid chromatography.

81. A method for preparing omasorone, the method comprising: (a) make It reacts with dimethyl sulfate and potassium carbonate in the presence of tetrabutylammonium bromide to form ； (b) make Reaction with m-chloroperoxybenzoic acid to form ； (c) make ； Reaction with perbromopyridine to form ； (d) make ； and 、 Diisopropylethylamine and dimethyl sulfoxide react to form ； (e) make ； Reacts with sodium methoxide to form ； (f) make ； Reacts with hydroxylamine and hydrochloric acid to form ； (g) make ； Reacts with sodium methoxide to form ； (h) make ； and The reaction forms ； (i) to make ； Reacts with pyridine to form ； (j) make ； In suitable formation The reaction occurs under the following conditions; (k) make ； Reaction with diphenylphosphine azide and triethylamine to form ； (l) Heating ； To form ； (m) make ； In suitable formation The reaction under the conditions; and (n) make and The reaction forms omasorone.

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