Optically resolved Trolox intermediate and method for producing same

Abstract

A method for the chiral resolution of Trolox is provided. [Solution] A method for producing a solid salt of the compound (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter referred to as R-Trolox), which comprises adding an amide solvent to a sample that contains R-Trolox and is suspected to contain the compound (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter referred to as S-Trolox) in the presence of an optical resolution agent.

Description

[Technical Field]

[0001] The present application provides methods for the chiral resolution of Trolox. The present application also provides compositions and methods for the optical resolution of compounds, including amide solvents. [Background technology]

[0002] WO 2009 / 061744 describes the synthesis of racemic 2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide from racemic Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), which is useful for treating and / or suppressing mitochondrial disorders and certain pervasive developmental disorders.

[0003] Chiral resolving agents can be useful for separating enantiomers. For example, a chiral resolving agent can form a solid salt with one enantiomer but not with the other (which remains in solution or as an oil). Thus, the two enantiomers can be separated by filtering the solid. However, not all resolving agents are useful for separating the enantiomers of a particular compound. Furthermore, resolving agents differ in their ability to provide, for example, better resolution, higher yields, easier scale-up, and / or improved ease of use.

[0004] Racemic Trolox has previously been resolved into its (R) and (S)-isomers using α-methylbenzylamine (MBA) and R-(+)-N-benzyl-α-phenylethylamine resolving agents. See, e.g., U.S. Patent Nos. 3,947,473, 4,003,919, and 4,026,907, and U.S. Patent Application Publication No. 2011 / 0251407. [Prior art documents] [Patent documents]

[0005] Patent Document 1: International Publication No. 2009 / 061744 Patent Document 2: U.S. Patent No. 3,947,473 Patent Document 3: U.S. Patent No. 4,003,919 Patent Document 4: U.S. Patent No. 4,026,907 Patent Document 5: U.S. Patent Application Publication No. 2011 / 0251407 Summary of the Invention Summary of the Invention [Means for solving the problem]

[0006] As a result of extensive research, the present inventors have discovered a method for stably optically resolving Trolox, and have completed the present disclosure. The present application has also discovered that amide solvents are useful for optically resolving compounds.

[0007] For example, the present disclosure provides the following: (Item 1) A method for preparing a solid salt of a compound of formula I, comprising adding an amide solvent to a sample containing a compound of formula I and suspected of containing a compound of formula II in the presence of an optical resolving agent: [ka] Formula I: (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter referred to as R-Trolox) [ka] Formula II: (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter S-Trolox). (Item 2) 2. The method according to item 1, wherein the optical resolution agent comprises at least a moiety capable of forming a salt with R-Trolox and S-Trolox and an asymmetric carbon. (Item 3) 3. The method according to item 1 or 2, further comprising adding the optical resolving agent to the sample. (Item 4) 4. The method according to any one of items 1 to 3, wherein the addition of the amide solvent comprises adding a mixture of the optical resolution agent and the amide solvent to the sample. (Item 5) 5. The method according to any one of items 1 to 4, wherein the sample contains a complex with an optical resolution agent. (Item 6) 6. The method according to any one of items 1 to 5, wherein the sample comprises a mixture of a compound of formula I and a compound of formula II. (Item 7) 7. The method according to any one of items 1 to 6, wherein the optical resolution agent is selected from phenylethylamine, N-methylglucamine, arginine, lysine, pseudoephedrine, leucinol, and aminophenylpropanol. (Item 8) 8. The method according to any one of items 1 to 7, wherein the optical resolution agent is phenylethylamine. (Item 9) 9. The method according to any one of items 1 to 8, wherein the amide solvent is one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), tetramethylurea (TMU), and hexamethylphosphoric triamide (HMPA). (Item 10) Item 10. The method according to item 9, wherein the amide solvent is N-methylpyrrolidone. (Item 11) Item 10. The method according to item 9, wherein the amide solvent is dimethylacetamide. (Item 12) Item 10. The method according to item 9, wherein the amide solvent is N,N-dimethylformamide. (Item 13) 13. The method according to any one of items 7 to 12, wherein the phenylethylamine is (R)-phenylethylamine. (Item 14) 14. The method according to any one of items 1 to 13, wherein the solid salt is an R-phenylethylamine salt. (Item 15) 15. The method according to any one of items 1 to 14, wherein the solid salt is an amide solvate. (Item 16) Item 16. The method according to item 15, wherein the amide solvent is one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), and N,N-dimethylformamide (DMF). (Item 17) Item 17. The method according to item 16, wherein the amide solvent is N-methylpyrrolidone. (Item 18) Item 17. The method according to item 16, wherein the amide solvent is dimethylacetamide. (Item 19) Item 17. The method according to item 16, wherein the amide solvent is N,N-dimethylformamide. (Item 20) 20. The method according to any one of items 1 to 19, wherein the enantiomeric excess of the solid salt of the compound of formula I produced is at least 98% or more. (Item 21) 21. The method according to any one of items 1 to 20, wherein the enantiomeric excess of the solid salt of the compound of formula I produced is at least 99% or more. (Item 22) 22. The method according to any one of items 1 to 21, further comprising the step of dissolving the phenylethylamine in toluene. (Item 23) 23. The method according to any one of items 1 to 22, comprising adding an antisolvent to the sample. (Item 24) 24. The method of claim 23, wherein the anti-solvent is toluene or ethyl acetate. (Item 25) 25. The method according to any one of items 1 to 24, further comprising the step of removing the amide solvent. (Item 26) A method for preparing a compound of formula IIIa, comprising converting a solid salt of a compound of formula I, prepared by the method according to any one of items 1 to 25, into a compound of formula IIIa: [ka] Formula IIIa: (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide. (Item 27) Compounds according to formula IVa: [ka] Formula IVa or a solvate thereof. (Item 28) 28. The compound according to item 27, which is an amide solvate. (Item 29) 29. The solvate according to any one of items 27 to 28, wherein the amide solvent is one or more solvents selected from NMP (N-methylpyrrolidone), DMA (dimethylacetamide), and DMF (N,N-dimethylformamide). (Item 30) Item 30. The solvate according to item 29, wherein the amide solvent is N-methylpyrrolidone. (Item 31) Item 30. The solvate according to item 29, wherein the amide solvent is dimethylacetamide. (Item 32) Item 30. The solvate according to item 29, wherein the amide solvent is N,N-dimethylformamide. (Item 33) A pharmaceutical material comprising the compound or solvate according to any one of items 27 to 32. (Item 34) A method for preparing a solid salt of a compound of formula II, comprising adding an amide solvent to a sample containing a compound of formula II and suspected of containing a compound of formula I in the presence of an optical resolving agent: [ka] Formula I: (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter referred to as R-Trolox) [ka] Formula II: (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter S-Trolox). (Item 35) Item 35. The method according to item 34, wherein the optical resolution agent comprises at least a moiety capable of forming a salt with R-Trolox and S-Trolox and an asymmetric carbon. (Item 36) 36. The method according to item 34 or 35, comprising adding the optical resolving agent to the sample. (Item 37) 37. The method according to any one of items 34 to 36, wherein the addition of the amide solvent comprises adding a mixture of the optical resolution agent and the amide solvent to the sample. (Item 38) 38. The method according to any one of items 34 to 37, wherein the sample contains a complex with an optical resolution agent. (Item 39) 39. The method according to any one of items 34 to 38, wherein the sample comprises a mixture of a compound of formula I and a compound of formula II. (Item 40) 39. The method according to any one of items 34 to 39, wherein the optical resolution agent is selected from phenylethylamine, N-methylglucamine, arginine, lysine, pseudoephedrine, leucinol, and aminophenylpropanol. (Item 41) 41. The method according to any one of items 34 to 40, wherein the optical resolution agent is phenylethylamine. (Item 42) 42. The method according to any one of items 34 to 41, wherein the amide solvent is one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), and N,N-dimethylformamide (DMF). (Item 43) Item 43. The method according to item 42, wherein the amide solvent is N-methylpyrrolidone. (Item 44) Item 43. The method according to item 42, wherein the amide solvent is dimethylacetamide. (Item 45) Item 43. The method according to item 42, wherein the amide solvent is N,N-dimethylformamide. (Item 46) 46. ​​The method according to any one of items 40 to 45, wherein the phenylethylamine is (R)-phenylethylamine. (Item 47) 47. The method according to any one of items 34 to 46, wherein the solid salt is an S-phenylethylamine salt. (Item 48) 48. The method according to any one of items 34 to 47, wherein the solid salt is an amide solvate. (Item 49) 49. The method according to any one of items 34 to 48, wherein the amide solvent is one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), and N,N-dimethylformamide (DMF). (Item 50) Item 49. The method according to item 49, wherein the amide solvent is N-methylpyrrolidone. (Item 51) Item 49. The method according to item 49, wherein the amide solvent is dimethylacetamide. (Item 52) Item 49. The method according to item 49, wherein the amide solvent is N,N-dimethylformamide. (Item 53) 53. The method according to any one of items 34 to 52, wherein the enantiomeric excess of the solid salt of the compound of formula II produced is at least 98% or more. (Item 54) 54. The method according to any one of items 34 to 53, wherein the enantiomeric excess of the solid salt of the compound of formula II produced is at least 99% or more. (Item 55) 55. The method according to any one of items 34 to 54, further comprising the step of dissolving the phenylethylamine in toluene. (Item 56) 56. The method according to any one of items 34 to 55, comprising adding an antisolvent to the sample. (Item 57) 57. The method of claim 56, wherein the anti-solvent is toluene or ethyl acetate. (Item 58) 58. The method according to any one of Items 34 to 57, further comprising the step of removing the amide solvent. (Item 59) A method for preparing a compound of formula IIIb, comprising converting a solid salt of a compound of formula II, prepared by the method according to any one of items 34 to 58, into a compound of formula IIIb: [ka] Formula IIIb: (S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide. (Item 60) Compounds according to formula IVb: [ka] Formula IVb or a solvate thereof. (Item 61) 61. The compound according to item 60, which is an amide solvate. (Item 62) 62. The solvate according to any one of items 60 to 61, wherein the amide solvent is one or more solvents selected from NMP (N-methylpyrrolidone), DMA (dimethylacetamide), and DMF (N,N-dimethylformamide). (Item 63) 63. The solvate according to item 62, wherein the amide solvent is N-methylpyrrolidone. (Item 64) Item 63. The solvate according to Item 62, wherein the amide solvent is dimethylacetamide. (Item 65) 63. The solvate according to item 62, wherein the amide solvent is N,N-dimethylformamide. (Item 66) 66. A pharmaceutical material comprising the compound or solvate according to any one of items 60 to 65. (Item 67) A composition for optical resolution of a compound, comprising an amide solvent. (Item 68) The compound is a mixture of a compound of formula I and a compound of formula II: [ka] Formula I: (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter referred to as R-Trolox) [ka] Formula II: (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter referred to as S-Trolox) Item 68. The composition according to item 67, wherein (Item 69) 69. The composition according to item 67 or 68, wherein the composition is used together with other optical resolving agents. (Item 70) Item 70. The composition according to Item 69, wherein the other optical resolving agent is itself optically active. (Item 71) 71. The composition according to any one of items 67 to 70, wherein the amide solvent is one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), and N,N-dimethylformamide (DMF). (Item 72) Item 72. The composition according to item 71, wherein the amide solvent is N-methylpyrrolidone. (Item 73) Item 72. The composition according to item 71, wherein the amide solvent is dimethylacetamide. (Item 74) 72. The composition according to item 71, wherein the amide solvent is N,N-dimethylformamide. (Item 74A) Item 67. The method according to item 67, further comprising the features according to any one or more of items 1 to 74. (Item 75) A method for optically resolving a compound, comprising adding an amide solvent to the compound. (Item 75A) Item 76. The method according to item 75, further comprising the features according to any one or more of items 1 to 74. (Item 76) Use of amide solvents for the optical resolution of compounds. (Item 76A) 77. Use according to item 76, further comprising the features according to any one or more of items 1 to 75.

[0008] It is contemplated that the present disclosure may provide one or more of the above-described features in combinations other than those explicitly stated. Still further embodiments and advantages of the present disclosure will be recognized by those skilled in the art upon reading and understanding the following detailed description, if necessary. [Effects of the Invention]

[0009] The present application provides a method for stable chiral resolution of Trolox with high optical purity. [Brief explanation of the drawings]

[0010] [Figure 1] Figure 1 shows the single crystal X-ray structure of RS-Trolox·R-PEA (racemic form: R-Trolox·R-PEA·S-Trolox·R-PEA). [Figure 2] Figure 2 shows the single crystal X-ray structure of R-Trolox·R-PEA·NMP. [Figure 3] Figure 3 shows the results of powder X-ray diffraction (XRPD) for RS-Trolox R-PEA (racemate), R-Trolox R-PEA, and R-Trolox R-PEA NMP (solvate). Note that the value at the left end of the horizontal axis in Figure 3 is "5." DETAILED DESCRIPTION OF THE INVENTION

[0011] The present disclosure will be described in more detail below. Throughout this specification, unless otherwise specified, singular expressions should be understood to include the plural concept. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, it should be understood that terms used in this specification are used in the sense commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present specification (including definitions) will prevail.

[0012] The present disclosure will be described in further detail below.

[0013] Abbreviations used herein have their conventional meaning within the art unless otherwise specified.

[0014] References herein to "about" a value or parameter include the variation that is directed to the value or parameter itself. For example, "about X" includes "X" itself as well as values ​​that allow for ±10% error, unless otherwise specified.

[0015] As used herein, "Trolox" refers to 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. The R-form is referred to as R-Trolox, and the S-form is referred to as S-Trolox. Trolox can be prepared by synthetic methods well known to those skilled in the art, such as those described in U.S. Pat. Nos. 3,947,473, 4,003,919, and 4,026,907.

[0016] As used herein, the term "optical resolution agent" refers to an optically active reagent useful for separating a racemate into its respective enantiomers, i.e., optically active substances. In the present disclosure, the optical resolution agent may contain at least a moiety capable of forming a salt with R-Trolox and S-Trolox and an asymmetric carbon. In the present disclosure, the optical resolution agent may contain a base moiety. The base moiety may contain an amine moiety. Examples of optical resolution agents include optically active substances such as phenylethylamine, N-methylglucamine, arginine, lysine, pseudoephedrine, leucinol, and aminophenylpropanol.

[0017] As used herein, the term "moiety capable of forming a salt with R Trolox and S Trolox" refers to a moiety containing a functional group capable of forming a salt with a functional group contained in R Trolox and S Trolox. For example, since Trolox contains a carboxyl group, the "moiety capable of forming a salt with R Trolox and S Trolox" may be a moiety containing a base capable of forming a salt with the carboxyl group. The "moiety capable of forming a salt with R Trolox and S Trolox" in the optical resolution agent may or may not overlap with the asymmetric carbon in the optical resolution agent. If it overlaps, the asymmetric carbon must function effectively (behave differently from asymmetric carbons of other configurations) when or after forming a salt with R Trolox and S Trolox in the optical resolution agent. Examples of the "moiety capable of forming a salt with R Trolox and S Trolox" include moieties containing amino groups, imino groups, guanidyl groups, and heterocyclic groups (nitrogen-containing heterocyclic groups such as pyridine, imidazole, indole, and purine). Compounds containing an asymmetric carbon include tartaric acid, phenylethylamine, N-methylglucamine, amino acids (arginine, lysine, etc.), pseudoephedrine, leucinol, aminophenylpropanol, etc., and asymmetric carbons having the same skeleton as such compounds can be used.

[0018] As used herein, the term "amide solvent" refers to a solvent of a compound containing an amide group (acid amide group). Examples of the amide group include carboxylic acid amide and phosphoric acid amide groups. Examples of amide solvents include N-methylpyrrolidone (NMP), dimethylacetamide (DMA), N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), tetramethylurea (TMU), and hexamethylphosphoric acid triamide (HMPA).

[0019] As used herein, the term "poor solvent" refers to a solvent that has the ability to dissolve a solute (target substance) but has limited solubility (a solvent with low ability to dissolve the solute). Examples of poor solvents in the present disclosure include ethyl acetate and toluene.

[0020] As used herein, the term "salt" refers to a compound formed by the neutralization reaction of an acid with a base, consisting of the negative component of the acid and the positive component of the base. Trolox has a carboxylic acid group and can form salts with basic substances.

[0021] In this specification, the term "solid salt" refers to a salt in a solid state, which is one of the three states of matter (gas, liquid, and solid).

[0022] As used herein, the term "suspect" indicates that something is not confirmed, but is reasonably predicted. The thing does not necessarily have to exist after actual confirmation. For example, "a sample containing a compound of formula I and suspected to contain a compound of formula II" refers to a sample that contains a compound of formula I and has not been confirmed to contain a compound of formula II, but contains a compound of formula I and is reasonably predicted to contain a compound of formula II.

[0023] As used herein, the term "mixture" refers to a mixture of two or more substances. The mixture ratio may be any. For example, in the case of a mixture of two substances, the ratio may be 50:50, 45:55, 40:60, 35:65, 30:70, 25:75, 20:80, 15:85, 10:90, 5:95, 1:99, 0.1:99.9, etc.

[0024] In this specification, "enantiomeric excess" refers to a measure of the mixture ratio of the right- and left-handed enantiomers, and is abbreviated as "ee." If the ratios of the right- and left-handed enantiomers in a sample are R and S, respectively, then it can be calculated using the following formula: ee(%)=(RS) / (R+S)×100, or (SR) / (R+S)×100 For example, if the enantiomeric excess of the R-form is 90:10, then (90-10) / (90+10)×100=80%ee.

[0025] (Preferred embodiment) In one embodiment of the present disclosure, there is provided a method for producing a solid salt of a compound of formula I, the method comprising adding an amide solvent to a sample containing a compound of formula I and suspected of containing a compound of formula II in the presence of an optical resolving agent: [ka] Formula I: (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter referred to as R-Trolox) [ka] Formula II: (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter, S-Trolox). The disclosed method enables stable optical resolution of R-Trolox. The method is easier to scale up, easier to stir, provides a solid that is easily filterable, and provides better resolution and / or purity of the desired product.

[0026] The solid salt of the compound of formula I may be a salt of the compound of formula I and an optical resolution agent, or a solvate of the salt of the compound of formula I and an optical resolution agent with an amide solvent.

[0027] In the present disclosure, the optical resolution agent may contain at least a moiety capable of forming a salt with R-Trolox and S-Trolox and an asymmetric carbon. Since Trolox contains a carboxylic acid moiety, the optical resolution agent may contain a base moiety that forms a salt with the carboxylic acid. The base moiety may be an amine. For example, when the optical resolution agent is R-phenylethylamine, R-Trolox and R-phenylethylamine are represented by the following formula: [ka] When the salt of R-Trolox and R-phenylethylamine is solvated with N-methylpyrrolidone, the following salt can be formed: [ka] When the optical resolving agent contains an amine moiety such as N-methylglucamine, arginine, lysine, pseudoephedrine, leucinol, or aminophenylpropanol, it can form a salt in which the amine moiety is ammonium.

[0028] The method of the present disclosure may include adding an optical resolving agent to the sample.

[0029] The addition of the amide solvent may be achieved by adding a mixture of the optical resolution agent and the amide solvent to the sample. When the amide solvent is added, the optical resolution agent and / or the amide solvent may already be present in the sample (hence, it does not matter whether a new amide solvent is added). When the optical resolution agent and the amide solvent are added, they may be added simultaneously or separately.

[0030] In the present disclosure, the sample may contain a complex with an optical resolution agent.

[0031] In the present disclosure, the sample may comprise a mixture of a compound of formula I and a compound of formula II.

[0032] In the present disclosure, the optical resolution agent may be selected from phenylethylamine, N-methylglucamine, arginine, lysine, pseudoephedrine, leucinol, and aminophenylpropanol. The optical resolution agent may be R-phenylethylamine, S-phenylethylamine, N-methyl-D-glucamine, N-methyl-L-glucamine, D-arginine, L-arginine, D-lysine, L-lysine, (1S,2S)-(+)-pseudoephedrine, (1R,2R)-(-)-pseudoephedrine, (R)-(-)-leucinol, (S)-(+)-leucinol, (S)-(-)-2-amino-3-phenyl-1-propanol, or (R)-(+)-2-amino-3-phenyl-1-propanol.

[0033] In the present disclosure, the optical resolving agent may be phenylethylamine.

[0034] In the present disclosure, the amide solvent may be one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), tetramethylurea (TMU), and hexamethylphosphoric triamide (HMPA).

[0035] In the present disclosure, the amide solvent may be N-methylpyrrolidone.

[0036] In the present disclosure, the amide solvent may be dimethylacetamide.

[0037] In the present disclosure, the amide solvent may be N,N-dimethylformamide.

[0038] In the present disclosure, the phenylethylamine may be (R)-phenylethylamine.

[0039] In the present disclosure, the solid salt may be an R-phenylethylamine salt.

[0040] In the present disclosure, the solid salt may be an amide-based solvate.

[0041] In the present disclosure, the amide solvent may be one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), and N,N-dimethylformamide (DMF).

[0042] In the present disclosure, the amide solvent may be N-methylpyrrolidone.

[0043] In the present disclosure, the amide solvent may be dimethylacetamide.

[0044] In the present disclosure, the amide solvent may be N,N-dimethylformamide.

[0045] In the present disclosure, the enantiomeric excess of the solid salt of the compound of formula I prepared may be at least 98% or greater.

[0046] In the present disclosure, the enantiomeric excess of the solid salt of the compound of formula I prepared may be at least 99% or greater.

[0047] The present disclosure may further include a step of dissolving the phenylethylamine in toluene.

[0048] The present disclosure may include a step of adding an anti-solvent to the sample. The use of an anti-solvent can improve filterability. Addition of an anti-solvent can reduce the viscosity of the amide-based solvent and improve its practicality, but the present disclosure is not limited thereto. Addition of an anti-solvent can also slightly improve optical purity.

[0049] In the present disclosure, the anti-solvent can be toluene or ethyl acetate.

[0050] The present disclosure may further include a step of removing the amide solvent.

[0051] In one embodiment of the present disclosure, there is provided a method for preparing a compound according to formula IIIa, comprising converting a solid salt of a compound of formula I prepared by the above method to a compound according to formula IIIa: [ka] Formula IIIa: (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide.

[0052] In one embodiment of the present disclosure, the compound according to formula IVa: [ka] Formula IVa or a solvate thereof is provided.

[0053] In the present disclosure, the compound may be an amide solvate.

[0054] In the present disclosure, the amide solvent may be one or more solvents selected from NMP (N-methylpyrrolidone), DMA (dimethylacetamide), or DMF (N,N-dimethylformamide).

[0055] In the present disclosure, the amide solvent may be N-methylpyrrolidone.

[0056] In the present disclosure, the amide solvent may be dimethylacetamide.

[0057] In the present disclosure, the amide solvent may be N,N-dimethylformamide.

[0058] In the present disclosure, a pharmaceutical substance comprising the compound or solvate may be provided.

[0059] In one embodiment of the present disclosure, there is provided a method for preparing a solid salt of a compound of formula II, the method comprising adding an amide solvent to a sample containing a compound of formula II and suspected of containing a compound of formula I in the presence of an optical resolving agent: [ka] Formula I: (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter referred to as R-Trolox) [ka] Formula II: (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter, S-Trolox). The disclosed method allows for stable optical resolution of Trolox. The method is easier to scale up, easier to stir, provides solids that are easily filterable, and provides better resolution and / or purity of the desired product.

[0060] The solid salt of the compound of formula II may be a salt of the compound of formula II and an optical resolution agent, or a solvate of the salt of the compound of formula II and an optical resolution agent with an amide solvent.

[0061] In the present disclosure, the optical resolution agent may contain at least a moiety capable of forming a salt with R-Trolox and S-Trolox and an asymmetric carbon. Because Trolox contains a carboxylic acid moiety, the optical resolution agent may contain a base moiety that forms a salt with the carboxylic acid. The base moiety may be an amine. For example, when the optical resolution agent is S-phenylethylamine, S-Trolox and S-phenylethylamine may form a salt that is an enantiomer of the R-enantiomer.

[0062] The method of the present disclosure may include adding an optical resolving agent to the sample.

[0063] The addition of the amide solvent may be achieved by adding a mixture of the optical resolution agent and the amide solvent to the sample. When the amide solvent is added, the optical resolution agent and / or the amide solvent may already be present in the sample (hence, it does not matter whether a new amide solvent is added). When the optical resolution agent and the amide solvent are added, they may be added simultaneously or separately.

[0064] In the present disclosure, the sample may contain a complex with an optical resolution agent.

[0065] In the present disclosure, the sample may comprise a mixture of a compound of formula I and a compound of formula II.

[0066] In the present disclosure, the optical resolution agent may be selected from phenylethylamine, N-methylglucamine, arginine, lysine, pseudoephedrine, leucinol, and aminophenylpropanol. The optical resolution agent may be R-phenylethylamine, S-phenylethylamine, N-methyl-D-glucamine, N-methyl-L-glucamine, D-arginine, L-arginine, D-lysine, L-lysine, (1S,2S)-(+)-pseudoephedrine, (1R,2R)-(-)-pseudoephedrine, (R)-(-)-leucinol, (S)-(+)-leucinol, (S)-(-)-2-amino-3-phenyl-1-propanol, or (R)-(+)-2-amino-3-phenyl-1-propanol.

[0067] In the present disclosure, the optical resolution agent may be phenylethylamine.

[0068] In the present disclosure, the amide solvent may be one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), and N,N-dimethylformamide (DMF).

[0069] In the present disclosure, the amide solvent may be N-methylpyrrolidone.

[0070] In the present disclosure, the amide solvent may be dimethylacetamide.

[0071] In the present disclosure, the amide solvent may be N,N-dimethylformamide.

[0072] In the present disclosure, the phenylethylamine may be (R)-phenylethylamine.

[0073] In the present disclosure, the solid salt may be an S-phenylethylamine salt.

[0074] In the present disclosure, the solid salt may be an amide-based solvate.

[0075] In the present disclosure, the amide solvent may be one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), and N,N-dimethylformamide (DMF).

[0076] In the present disclosure, the amide solvent may be N-methylpyrrolidone.

[0077] In the present disclosure, the amide solvent may be dimethylacetamide.

[0078] In the present disclosure, the amide solvent may be N,N-dimethylformamide.

[0079] In the present disclosure, the enantiomeric excess of the solid salt of the compound of formula II prepared may be at least 98% or more.

[0080] In the present disclosure, the enantiomeric excess of the solid salt of the compound of formula II prepared may be at least 99% or more.

[0081] The present disclosure may further include a step of dissolving the phenylethylamine in toluene.

[0082] The present disclosure may include a step of adding an anti-solvent to the sample. The use of an anti-solvent can improve filterability. Addition of an anti-solvent can reduce the viscosity of the amide-based solvent and improve its practicality, but the present disclosure is not limited thereto. Addition of an anti-solvent can also slightly improve optical purity.

[0083] In the present disclosure, the anti-solvent can be toluene or ethyl acetate.

[0084] The present disclosure may further include a step of removing the amide solvent.

[0085] In one embodiment of the present disclosure, there is provided a method for preparing a compound according to formula IIIb, comprising converting a solid salt of a compound of formula II prepared by the above method to a compound according to formula IIIb: [ka] Formula IIIb: (S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide.

[0086] In one embodiment of the present disclosure, the compound according to formula IVb: [ka] Formula IVb or a solvate thereof is provided.

[0087] In the present disclosure, it may be an amide-based solvate.

[0088] In the present disclosure, the amide solvent may be one or more solvents selected from NMP (N-methylpyrrolidone), DMA (dimethylacetamide), or DMF (N,N-dimethylformamide).

[0089] In the present disclosure, the amide solvent may be N-methylpyrrolidone.

[0090] In the present disclosure, the amide solvent may be dimethylacetamide.

[0091] In the present disclosure, the amide solvent may be N,N-dimethylformamide.

[0092] In the present disclosure, a pharmaceutical substance comprising the compound or solvate may be provided.

[0093] In one embodiment of the present disclosure, a composition for optically resolving a compound is provided, comprising an amide solvent.

[0094] In the present disclosure, the compound is a mixture of a compound of formula I and a compound of formula II: [ka] Formula I: (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter referred to as R-Trolox) [ka] Formula II: (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter referred to as S-Trolox) It could be.

[0095] In the present disclosure, the composition may be used together with other optical resolving agents.

[0096] In the present disclosure, the other optical resolution agent may itself be optically active.

[0097] In the present disclosure, the amide solvent may be one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), and N,N-dimethylformamide (DMF).

[0098] In the present disclosure, the amide solvent may be N-methylpyrrolidone.

[0099] In the present disclosure, the amide solvent may be dimethylacetamide.

[0100] In the present disclosure, the amide solvent may be N,N-dimethylformamide.

[0101] In one embodiment of the present disclosure, there is provided a method for optically resolving a compound, comprising adding an amide solvent to the compound.

[0102] In one embodiment of the present disclosure, there is provided the use of an amide solvent for the optical resolution of a compound.

[0103] In one embodiment of the present disclosure, the powder X-ray diffraction (XRPD) of RS-Trolox·R-PEA (racemate) exhibits 2θ peaks at, but not limited to, 8.54°, 12.55°, 13.45°, 15.41°, 17.11°, 18.87°, 21.00°, 22.19°, and 23.83°, and may have an appropriate number of peaks (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or any integer value greater) selected from those with high gross intensities listed in Table 6. Note that in the present disclosure, with regard to the assignment of powder X-ray diffraction (XRPD), 2θ may have an error of ±0.2° from the indicated value.

[0104] In one embodiment of the present disclosure, the powder X-ray diffraction (XRPD) of R-Trolox·R-PEA exhibits 2θ peaks at, but not limited to, 6.75°, 7.19°, 9.86°, 13.49°, 14.37°, 14.67°, 15.29°, 21.51°, 22.71°, 23.31°, 27.10°, and 28.03°. The powder may have any number of peaks (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or any integer value greater) selected from those with large gross intensities listed in Table 6.

[0105] In one embodiment of the present disclosure, R-Trolox·R-PEA·NMP (solvate) exhibits characteristic 2θ peaks in its powder X-ray diffraction (XRPD) at 5.30°, 7.69°, 8.94°, 10.55°, 12.78°, 14.41°, 15.04°, 15.35°, 15.83°, 17.86°, 19.56°, 22.34°, 25.43°, 26.48°, and 27.47°. However, the present invention is not limited to these peaks, and the R-Trolox·R-PEA·NMP may have any number of peaks (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or any integer value greater) selected from those having high gross intensities as listed in Table 6.

[0106] Crystals exhibit various structures, shapes, sizes, aggregation states, etc. depending on the crystallization conditions. Solvates, in which a solvent is incorporated into a crystal, are sometimes called pseudopolymorphs to distinguish them from crystalline polymorphs in the strict sense. In this case, the physicochemical properties of the crystals can be largely determined by the contribution of the solvent to the crystal lattice formation and its interaction with the molecules being crystallized. Various factors related to the crystallization conditions, such as the solvent properties, degree of supersaturation, and temperature, can determine the properties of the crystals. The present disclosure enables stable chiral resolution of Trolox with high optical purity by appropriately selecting an optical resolution agent and solvent.

[0107] In the optical resolution of Trolox, when phenethylamine was used as an optical resolution agent in a non-amide solvent, optical resolution was not possible. However, by using an amide solvent, optical resolution of Trolox could be performed stably.

[0108] The disclosed methods utilize an optical resolving agent to separate (R)- and (S)-Trolox enantiomers, where the resolving agent forms a solid salt with one of (R)-Trolox and (S)-Trolox and does not substantially form a solid salt with the other under certain reaction conditions. In some embodiments, when the resolving agent forms a solid salt with a Trolox enantiomer, at least about 50% of the Trolox enantiomer forms a solid salt with the resolving agent under certain reaction conditions. In various embodiments, when the resolving agent forms a solid salt with a Trolox enantiomer, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the Trolox enantiomer forms a solid salt with the resolving agent under certain reaction conditions. "Substantially does not form a solid salt" indicates that less than about 10% of the (non-solid salt-forming) Trolox enantiomers form a solid salt with the resolving agent under the specified reaction conditions. In various embodiments, "substantially does not form a solid salt" indicates that less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.1% of the (non-solid salt-forming) Trolox enantiomers form a solid salt with the resolving agent under the specified reaction conditions. The solid salt may be a solvate with an amide-based solvent.

[0109] "Yield" refers to the percentage of Trolox enantiomer obtained relative to the amount of starting material. For example, if 100 g of a 50 / 50 racemic mixture of (R) / (S)-Trolox is resolved and 50 g of (S)-Trolox is recovered, the yield is 50%. If 30 g of (S)-Trolox is recovered, the yield is 30%. For the recovery of Trolox salts, the yield is calculated assuming only Trolox is present, not the salt counterion. For example, if 100 g of a 50 / 50 racemic mixture of (R) / (S)-Trolox is resolved and 40 g of (S)-Trolox salt is recovered, and the theoretical weight of (S)-Trolox contained within that salt is 30 g, the yield is 30%. If both (R)-Trolox and (S)-Trolox are resolved and 50 g of each is recovered, the yield is 100%.

[0110] While the compounds described herein can occur and be used as neutral (non-salt) compounds, the present description is intended to encompass all salts of the compounds described herein, as well as methods of using such salts of the compounds. In one embodiment, the salts of the compounds include pharmaceutically acceptable salts. Pharmaceutically acceptable salts are salts that can be administered to humans and / or animals as drugs or pharmaceuticals and that, upon administration, retain at least some of the biological activity of the free compound (neutral or non-salt). The desired salt of a basic compound can be prepared by methods known to those skilled in the art by treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acid, and salicylic acid. Salts of basic compounds with amino acids, such as aspartate and glutamate salts, can also be prepared. Desired salts of acidic compounds can be prepared by treating the compound with a base using methods known to those skilled in the art. Examples of inorganic salts of acidic compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium, potassium, magnesium, and calcium salts; ammonium salts; and aluminum salts. Examples of organic salts of acidic compounds include, but are not limited to, salts of procaine, dibenzylamine, N-ethylpiperidine, N,N-dibenzylethylenediamine, and triethylamine. Salts of acidic compounds with amino acids, such as lysine salts, can also be prepared. Additional salts particularly useful for pharmaceutical preparations are described in Berge SM et al., "Pharmaceutical Salts," 1. Pharm. Sci., January 1977; 66(1):1-19.

[0111] Purpose The compounds produced by the methods of the present disclosure are useful as pharmaceutical raw materials and can be used as intermediates for producing optically active drugs.

[0112] Synthesis reaction parameters Solvents utilized in the synthesis of the compounds and compositions of the present disclosure include, for example, water, acetonitrile ("ACN"), diethyl ether, 2-methyl-tetrahydrofuran ("2-MeTHF"), ethyl acetate ("EtOAc"), ethanol ("EtOH"), isopropyl alcohol ("IPA"), isopropyl acetate ("IPAc"), methanol (MeOH), and the like, as well as mixtures thereof.

[0113] The term "qs" (quantity) means adding a quantity sufficient to achieve a stated function, for example, to bring a solution to the desired volume (ie, 100%).

[0114] The techniques useful for synthesizing the compounds and compositions herein are readily apparent and accessible to those skilled in the art in light of the teachings set forth herein. The following discussion is provided to illustrate certain of the various methods available for use in constructing the compounds and compositions herein. However, this discussion is not intended to define the scope of reactions or reaction sequences useful for preparing the compounds and compositions herein.

[0115] Other methods for producing the compounds and compositions of the present disclosure will be apparent to those of skill in the art in view of the teachings herein. [Example]

[0116] To simplify the description in the specification, the following abbreviations may be used in the examples and tables therein. Trolox: Trolox, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid R-Trolox: R-Trolox, R-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid S-Trolox: S-Trolox, S-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid RS-Trolox: RS-Trolox, RS-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (racemic) PEA: 1-phenylethylamine R-PEA: R-1-phenylethylamine S-PEA: S-1-phenylethylamine EtOAc: ethyl acetate i PrOAc: Isopropyl acetate NMP: N-methylpyrrolidone DMA: Dimethylacetamide DMF: N,N-dimethylformamide DMP: N,N-dimethylpropionamide MTBE: Methyl tertiary butyl ether DME: 1,2-dimethoxyethane; 2-MeTHF: 2-methyltetrahydrofuran, MEK: Methyl ethyl ketone DMSO: Dimethyl sulfoxide CDCl3: deuterated chloroform MeOH: Methanol MeCN: acetonitrile IPA: 2-propanol CDI: carbonyldiimidazole The symbols used in NMR are δ for chemical shift, s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, and J for spin coupling constant.

[0117] S-Trolox used in the examples was purchased from Sigma-Aldrich. RS-Trolox used in the examples was purchased from D-STONE. When producing the compound of the present disclosure using seed crystals for the first time, the method can be carried out by using a small amount of product produced without using seed crystals as seed crystals for the next production.

[0118] (Method for measuring optical purity) The optical purity was measured by high performance liquid chromatography (HPLC) and calculated by comparing the peak areas. The measurement conditions are as follows, and the retention time is indicated as Rt (minutes).

[0119] optical purity Column: Chiralpak AD-3 3μm (250×4.6mm) Mobile phase: hexane / 2-propanol / trifluoroacetic acid: 900 / 100 / 1 Flow rate: 1.0mL / min Column temperature: 35℃ Wavelength: 205nm

[0120] The Rt of each compound measured under the above measurement conditions is shown in the table below. [Table 1]

[0121] Example 1 Consider solvents (other than amides) S-Trolox (0.67 g), R-PEA (0.11 g), and solvent were added to R-Trolox·R-PEA (1.0 g) at room temperature to reslurry. After incubating at 30°C for 3 hours, the mixture was cooled to 5°C and stirred overnight. After stirring overnight at 5°C, the crystals were filtered and their optical purity was measured. [Table 2]

[0122] Although optical resolution was demonstrated in the non-amide solvent 2-MeTHF, it subsequently became impossible to achieve optical resolution in these solvents. Although high optical purity was achieved in 2-MeTHF and chlorobenzene, the starting material R-Trolox·R-PEA (1.0 g) was reduced to approximately half (0.55 g and 0.53 g, respectively).

[0123] Example 2 Consideration of amide solvents (NMP or DMA) To 10.0 g of Trolox, 70.0 g of NMP or 70.0 g of DMA and R-PEA were added at room temperature, heated to 50°C, filtered to remove debris, and washed with 20.0 g of NMP. After cooling to 25°C, the solution was seeded with 0.01 g of R-Trolox·R-PEA and incubated for 3 hours. After cooling to 10°C and incubating overnight, the precipitate was collected by filtration. The precipitate was washed with 15.0 g of NMP or DMA, washed twice with 15.0 g of IPAc, and then dried to obtain the amide solvate of R-Trolox·R-PEA. [Table 3]

[0124] Example 3 Method for obtaining R-Trolox·R-PEA·NMP (solvate) from RS-Trolox·R-PEA (racemate) (NMP / DMA mixed solvent) NMP (10.0 g), DMA (10.0 g), and RS-Trolox (2.00 g) were added at room temperature, and the mixture was heated to 50°C. The mixture was then cooled to 25°C, seeded with R-Trolox·R-PEA (0.01 g), and incubated for 1 hour. The mixture was then cooled to 10°C and incubated overnight, after which the precipitate was collected by filtration. The precipitate was washed with an NMP / DMA mixed solvent (1.5 g / 1.5 g), washed twice with IPAc (3.0 g), and then dried to obtain the NMP solvate of R-Trolox·R-PEA (yield: 0.76 g, yield: 30.1%, optical purity: 98.3% ee).

[0125] Example 4 Method for obtaining R-Trolox·R-PEA·NMP (solvate) from RS-Trolox·R-PEA (racemic form) (NMP solvent) RS-Trolox·R-PEA (100 mg) was dissolved in NMP (1 mL) and stirred for 3 hours, and the precipitated crystals were collected by filtration (optical purity: 98.7% ee).

[0126] Example 5 Solubility of RS-Trolox R-PEA, R-Trolox R-PEA, and S-Trolox R-PEA in ethyl acetate Ethyl acetate was added to each crystal to reslurry it. The solubility was calculated from the content analysis of the supernatant solution of each reaction solution at each temperature.

[0127] [Table 4]

[0128] Example 6 Solubility of R-Trolox·R-PEA, S-Trolox·R-PEA, and S-Trolox in NMP and DMA The crystals were reslurried in an amide solvent (NMP, DMA). The solubility was calculated from the content analysis of the supernatant solution of each reaction mixture at each temperature.

[0129] [Table 5]

[0130] Example 7 Two-step crystallization using NMP solvent to improve optical purity (first step: optical resolution, second step : recrystallization) NMP (490.4 g) and R-PEA (28.90 g) were added to Trolox (70.0 g) at room temperature, the mixture was heated to 50°C, filtered to remove debris, and washed with NMP (140.59 g). The solution was cooled to 25°C, seeded with R-Trolox·R-PEA (0.693 g) and incubated for 3 hours. The mixture was cooled to 10°C and incubated overnight, after which the precipitate was collected by filtration. The precipitate was washed with NMP (105.0 g) and twice with IPAc (105.0 g), then dried to obtain the amide solvate of R-Trolox·R-PEA (yield: 43.57 g, 33.1%, optical purity: 97.2% ee). To the crystals (10 g) obtained above, NMP (47.87 g) was added, the mixture was heated to 60°C, cooled to 40°C, and then seeded with R-Trolox·R-PEA (0.1 g) and kept at that temperature for 2 hours. The mixture was cooled to 10°C and kept at that temperature for 1.5 hours, after which the precipitate was collected by filtration. The precipitate was washed with NMP (16 g), washed twice with isopropyl acetate (8 g), and then dried to obtain an amide solvate of R-Trolox·R-PEA (yield: 7.61 g, yield 76.1%, optical purity: 99.8% ee).

[0131] Example 8 Two-step crystallization using NMP / toluene mixed solvent to improve optical purity and filterability (first step: optical resolution, second step: recrystallization) NMP (1440 g) and toluene (5760 g) were added to Trolox (800 g) at room temperature, and the mixture was heated to 50°C. The mixture was filtered to remove debris and washed with an NMP / toluene mixed solvent (160 g / 640 g). R-PEA (232 g) was added at 50°C, and the mixture was cooled to 45°C. After cooling, R-Trolox·R-PEA (0.8 g) seed crystals were added and the mixture was incubated for 2 hours. R-PEA (97 g) was added dropwise over 1 hour, and the mixture was then incubated for 30 minutes. The mixture was cooled to 0°C and incubated overnight, after which the precipitate was collected by filtration. The precipitate was washed twice with an NMP / toluene mixed solvent (320 g / 1280 g) and then with toluene (1600 g), and then dried to obtain an amide solvate of R-Trolox·R-PEA (yield: 624 g, yield: 41.5%, optical purity: 96.8% ee).

[0132] To the crystals (550 g) obtained above, NMP (1650 g) and toluene (4950 g) were added, and the mixture was heated to 70°C and maintained at this temperature for 30 minutes. The mixture was then cooled to 60°C, seeded with R-Trolox·R-PEA (0.6 g) and maintained at this temperature for 30 minutes. The mixture was then cooled to 0°C and maintained at this temperature overnight. The precipitate was then collected by filtration. The precipitate was washed with an NMP / toluene mixed solvent (206 g / 619 g) and then with toluene (825 g), and then dried to obtain an amide solvate of R-Trolox·R-PEA (yield: 514 g, yield: 93.4%, optical purity: >99.9% ee).

[0133] Example 9 Two-step crystallization using NMP / ethyl acetate mixed solvent to improve optical purity and filterability (first step: optical resolution, second step: recrystallization)

[0134] NMP (10.80 kg) and ethyl acetate (43.20 kg) were added to Trolox (6.00 kg) at room temperature, and the mixture was heated to 50°C. After filtering to remove debris, the mixture was washed with an NMP / ethyl acetate mixed solvent (1.20 kg / 4.80 kg). R-PEA (1.74 kg) was added at 50°C, and then R-Trolox·R-PEA·NMP (6.04 g) was added as seed crystals and the mixture was kept warm for 2 hours. R-PEA (0.73 kg) was added dropwise over 1 hour, and the mixture was kept warm for 30 minutes. The mixture was cooled to 5°C and kept warm overnight, after which the precipitate was collected by filtration. The precipitate was washed twice with an NMP / ethyl acetate mixed solvent (2.40 kg / 9.60 kg) and twice with toluene (12.00 kg), and then dried to obtain an NMP solvate of R-Trolox·R-PEA (yield: 4.53 kg, yield: 40.2%, optical purity: 96.6% ee).

[0135] To the crystals obtained above (3.00 kg), NMP (9.00 kg) and ethyl acetate (27.00 kg) were added, and the mixture was heated to 68°C. After cooling to 60°C, R-Trolox·R-PEA·NMP (3.02 g) was added as seed crystals and the mixture was kept at the same temperature for 1 hour. The mixture was cooled to 5°C and kept at the same temperature overnight, after which the precipitate was collected by filtration. The precipitate was washed twice with an NMP / ethyl acetate mixed solvent (1.13 kg / 3.38 kg) and twice with ethyl acetate (4.50 kg), and then dried to obtain the NMP solvate of R-Trolox·R-PEA (yield: 2.71 g, 90.3%, optical purity: >99.9% ee).

[0136] Example 10 Single crystal X-ray structural analysis of RS-Trolox·R-PEA (racemic body) and R-Trolox·R-PEA·NMP (solvate) Single crystal X-ray structural analysis was performed on RS-Trolox R-PEA (racemate) and R-Trolox R-PEA NMP (solvate). The results are shown in Figures 1 and 2. Measurement equipment: Rigaku single crystal X-ray diffractometer (model number: VariMax RAPID RA-Micro7). Measurement temperature: -170°C. Analysis program: CrystalStructure crystallographic software package.

[0137] Specifically, RS-Trolox·R-PEA (racemic form) was measured as follows. (Data Collection) C with approximate dimensions of 0.200 x 0.110 x 0.090 mm 22 H 29 A colorless prism crystal of NO4 was mounted on a glass fiber. All measurements were performed on a Rigaku R-AXIS RAPID diffractometer using a multilayer mirror monochromator Mo-Kα radiation.

[0138] The crystal-to-detector distance was 127.40 mm.

[0139] The cell constants and rotation matrices for data collection corresponded to a simple triclinic unit cell with dimensions:

number

[0140] For Z=2 and formula weight=371.48, the calculated density is 1.285 g / cm 3 Based on statistical analysis of the intensity distribution and successful solution and refinement of the structure, the space group is P1(#1) It was determined that.

[0141] Data were collected at a temperature of -170°C ± 1°C up to a maximum 2θ value of 55.0°. A total of 192 oscillation images were collected. A data sweep was performed using an ω scan from 130.0° to 190° in 2.00° steps at χ = ​​45.0° and φ = 0.0°. The exposure rate was 80.0 s / °. A second sweep was performed using an ω scan from 0.0° to 162.0° in 2.00° steps at χ = ​​45.0° and φ = 180.0°. The exposure rate was 80.0 s / °. Another sweep was performed using an ω scan from 0.0° to 162.0° in 2.00° steps at χ = ​​45.0° and φ = 90.0°. The exposure rate was 80.0 s / °. The crystal-to-detector distance was 127.40 mm. The reading was done in 0.100 mm pixel mode.

[0142] (Data Reduction) Of the 0 reflections collected, 0 are unique (R int = 0.0115), equal reflections were merged.

[0143] The linear absorption coefficient μ for Mo-Kα is 0.875 cm -1 An empirical absorption correction was applied, yielding transmittance values ​​ranging from 0.958 to 0.992. Data were corrected for Lorentzian and polarization effects.

[0144] (Structure analysis and refinement) Direct method ( SHELXT Version 2014 / 5 : Sheldrick, GM (2014). Acta Cryst. A70, C1437) and extended using Fourier techniques. Non-hydrogen atoms were refined anisotropically. Hydrogen atoms were refined using the riding model. F 2 The final cycle of full-matrix least-squares refinement for converged based on 8184 observed reflections and 501 variable parameters, with the following unweighted and weighted agreement factors (the largest parameter shift was 0.00 times its esd):

number

[0145] The goodness of fit was 1.06. Goodness of fit is defined as: [Σw(Fo 2 -Fc 2 ) 2 / (No-Nv)] 1 / 2 Where: No = number of observations Nv = number of variables Unit weights were used. The maximum and minimum peaks in the final difference Fourier map were 0.31 and -0.20 e, respectively. - / Å 3 Corresponding to the final Flack parameter (Parsons, S. and Flack, H. (2004), Acta Cryst. A60, s61) is 0.11(11) This indicates that the absolute structure present is correct (Flack, HD and Bernardinelli (2000), J. Appl. Cryst. 33, 114-1148).

[0146] Neutral atom scattering factors were taken from the International Table in Crystallography (IT), Vol. C, Table 6.1.1.4 (International Tables for Crystallography, Vol. C (1992). Ed. AJC Wilson, Kluwer Academic Publishers, Dordrecht, Netherlands, Table 6.1.1.4, pp. 572). Anomalous dispersion effects were included in Fcalc (Ibers, JA & Hamilton, WC; Acta Crystallogr., 17, 781 (1964)); Δf' and Δf'' values ​​were from Creagh and McAuley (Creagh, DC & McAuley, WJ .; "International Tables for Crystallography", Vol. C, (AJC Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.6.8, pages 219-222 (1992)). The values ​​of the mass attenuation coefficients are those of Creagh and Hubbell (Creagh, DC & Hubbell, JH.; “International Tables for Crystallography”, Vol C, (AJC Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.4.3, pages 200-206 (1992).) All calculations were performed using the CrystalStructure (CrystalStructure 4.3: Crystal Structure Analysis Package, Rigaku Corporation (2000-2018). Tokyo 196-8666, Japan) crystallography software package, except for refinements, which were performed using SHELXL Version 2017 / 1 (SHELXL Version 2017 / 1: Sheldrick, GM (2008). Acta Cryst. A64, 112-122).

[0147] The crystal data were as follows:

number

number

number

[0148] Example 11 X-ray powder diffraction (XRPD) of RS-Trolox R-PEA (racemic), R-Trolox R-PEA, and R-Trolox R-PEA NMP (solvate) Powder X-ray diffraction (XRPD) was performed on RS-Trolox R-PEA (racemate), R-Trolox R-PEA, and R-Trolox R-PEA NMP (solvate). The results are shown in Figure 3 and Table 6. Powder X-ray diffraction (XRPD) was performed using a Bruker AXS D Measurements were taken at room temperature using 8 ADVANCE at a diffraction angle 2θ range of 5 to 40 degrees, using Cu Kα radiation, an X-ray tube current of 40 milliamperes, a voltage of 40 kilovolts, steps of 0.015 degrees, and a measurement time of 48 seconds per step. [Table 6-1] [Table 6-2]

[0149] Example 12 Two-step crystallization using a DMP / toluene mixed solvent (first step: optical resolution, second step: recrystallization) To 25.00 g of Trolox, 50.0 g of DMP and 200.0 g of toluene were added at room temperature, and the mixture was heated to 50°C. 7.26 g of R-PEA was added, cooled to 45°C, and then seeded with 0.03 g of R-Trolox·R-PEA crystals and incubated for 2 hours. 3.03 g of R-PEA was added dropwise over 20 minutes, followed by incubation for 40 minutes. After cooling to 5°C, the precipitate was collected by filtration. The precipitate was washed twice with a DMP / toluene mixed solvent (10.0 g / 40.0 g) and twice with 50 g of toluene, then dried to obtain R-Trolox·R-PEA as a DMP solvate (yield: 19.32 g, yield: 40.9%, optical purity: 94.7% ee).

[0150] To the crystals (18.00 g) obtained above, DMP (54.0 g) and toluene (162.0 g) were added, and the mixture was heated to 80°C. After cooling to 70°C, R-Trolox·R-PEA (0.02 g) was added and the mixture was kept at this temperature for 1 hour. After cooling to 5°C, the precipitate was collected by filtration. The precipitate was washed with a DMP / toluene mixed solvent (6.8 g / 20.3 g) and twice with toluene (27.0 g), and then dried to obtain a DMP solvate of R-Trolox·R-PEA (yield: 16.82 g, yield 93.4%, optical purity: 99.9% ee).

[0151] Example 13 Optical resolution to obtain S-Trolox·S-PEA·NMP NMP (50.00 g) and toluene (200.0 g) were added to Trolox (25.00 g) at room temperature, and the mixture was heated to 50°C. S-PEA (7.26 g) was added, cooled to 45°C, and seeded with S-Trolox·S-PEA (0.03 g) and incubated for 2 hours. S-PEA (3.03 g) was added dropwise over 30 minutes, and the mixture was incubated for 2 hours. After cooling to 0°C and incubation overnight, the precipitate was collected by filtration. The precipitate was washed twice with an NMP / toluene mixed solvent (10.0 g / 40.0 g) and twice with toluene (50 g), and then dried to obtain the NMP solvate of S-Trolox·S-PEA (yield: 19.32 g, yield: 41.1%, optical purity: 97.0% ee).

[0152] Example 14A Preparation of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid [ka]

[0153] Isopropyl acetate (110 kg) and water (10.99 kg) were added to R-Trolox·PEA·NMP (10.00 kg, 21.25 mol), followed by dropwise addition of 35% hydrochloric acid (3.80 kg, 36.55 mol) and stirring at 25±5°C for 20 minutes. After allowing to stand and separating, the organic layer was washed twice with water (15.80 kg, 15.83 kg) and concentrated under reduced pressure at 45°C or below (distillate volume: 92.0 kg). Isopropyl acetate (8.38 kg) was added to prepare a 16.7% R-Trolox in isopropyl acetate solution (31.9 kg), which was used in the next step (assuming a 100% yield).

[0154] Example 14B Preparation of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide [ka]

[0155] To a slurry of CDI (Hodogaya Chemical) (8.61 kg, 52.12 mol) and isopropyl acetate (26.6 kg), a solution of R-Trolox in isopropyl acetate (16.7%, 31.8 kg, 21.25 mol (assumed)) was added dropwise over 1 hour at 20±5°C, washed in with isopropyl acetate (2.94 kg), and kept warm for 2 hours. While maintaining the temperature below 15±5°C, this isopropyl acetate solution was added dropwise over 1 hour to 28% aqueous ammonia (Nacalaix, 16.15 kg, 265.61 mol) pre-cooled to 15±5°C, washed in with isopropyl acetate (1.33 kg). After stirring for 1.5 hours, isopropyl acetate (43.5 kg) and water (21.27 kg) were added, and an aqueous phosphoric acid solution prepared by mixing water (10.64 kg) and 85% phosphoric acid (19.60 kg) was added dropwise at 10-60°C, followed by washing in with water (1.06 kg). After separation, an isopropyl acetate solution (109.09 kg) of the title compound was obtained, which was used in the next step (assuming a 100% yield).

[0156] Example 14C Preparation of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide [ka]

[0157] To a solution of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide in isopropyl acetate (109.58 kg, 21.25 mol (assumed)), 33.9% aqueous iron nitrate solution (Kokusan Chemical) (33.64 kg, 48.66 mol) was added dropwise over 1 hour at 30°C or below. The mixture was then incubated at 25±5°C for 2.5 hours, after which sodium chloride (3.71 kg) was added, stirred for 15 minutes, and allowed to stand. After separation, the mixture was heated to 40±5°C, and washed with 12.1% aqueous citric acid (13.52 kg). Further washing was performed with 10% aqueous sodium carbonate (13.24 kg), followed by water (10.60 kg). The organic layer obtained after separation was concentrated under reduced pressure at 45°C or below (distillate: 52.7 kg). The mixture was heated to 80±5°C and maintained at this temperature for 1 hour, after which seed crystals (0.003 kg) were added and maintained at this temperature for 1 hour. The mixture was cooled to 0°C at a cooling rate of 10°C / h and maintained at this temperature for 11 hours. The precipitate was collected by filtration and washed twice with pre-cooled isopropyl acetate (13.24 kg x 2). The mixture was dried under nitrogen at 45°C or below to obtain crude crystals (yield: 4.47 kg, yield over 3 steps: 79.3%, quality: 100.00%, optical purity: >99.9%ee).

[0158] The obtained crude crystals (4.01 kg) were recrystallized from an isopropanol / heptane mixed solvent to obtain the title compound (3.77 kg, recrystallization yield: 94.0%, quality: 100.00%, optical purity: >99.9% ee).

[0159] As described above, the present disclosure has been illustrated using preferred embodiments thereof, but it is understood that the scope of the present disclosure should be interpreted solely by the claims. This application claims priority to Japanese Patent Application No. 2020-28614 (filed February 21, 2020), the contents of which are incorporated herein by reference in their entirety. It is understood that the patents, patent applications, and other documents cited herein are incorporated herein by reference in their entirety as if the contents themselves were specifically set forth herein. [Industrial Applicability]

[0160] The present disclosure is useful for producing optically active pharmaceutical ingredients.

Claims

1. A method for preparing a solid salt of a compound of formula I, comprising adding an amide solvent to a sample containing a compound of formula I and suspected of containing a compound of formula II in the presence of an optical resolving agent: 【Chemistry 1】 Formula I: (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter referred to as R-Trolox) 【Chemistry 2】 Formula II: (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter S-Trolox).

2. The method according to claim 1, wherein the optical resolution agent comprises at least a moiety capable of forming a salt with R Trolox and S Trolox and an asymmetric carbon.

3. The method of claim 1 or 2, further comprising adding the optical resolving agent to the sample.

4. The method according to any one of claims 1 to 3, wherein the addition of the amide solvent comprises adding a mixture of the optical resolving agent and the amide solvent to the sample.

5. The method according to any one of claims 1 to 4, wherein the sample contains a complex with an optical resolution agent.

6. The method of any one of claims 1 to 5, wherein the sample comprises a mixture of a compound of formula I and a compound of formula II.

7. The method according to any one of claims 1 to 6, wherein the optical resolution agent is selected from the group consisting of phenylethylamine, N-methylglucamine, arginine, lysine, pseudoephedrine, leucinol, and aminophenylpropanol.

8. The method according to any one of claims 1 to 7, wherein the optical resolution agent is phenylethylamine.

9. The method according to any one of claims 1 to 8, wherein the amide solvent is one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), tetramethylurea (TMU), and hexamethylphosphoric triamide (HMPA).

10. 10. The method according to claim 9, wherein the amide solvent is N-methylpyrrolidone.

11. 10. The method of claim 9, wherein the amide solvent is dimethylacetamide.

12. 10. The method according to claim 9, wherein the amide solvent is N,N-dimethylformamide.

13. The method according to any one of claims 7 to 12, wherein the phenylethylamine is (R)-phenylethylamine.

14. The method according to any one of claims 1 to 13, wherein the solid salt is an R-phenylethylamine salt.

15. The method according to any one of claims 1 to 14, wherein the solid salt is an amide-based solvate.

16. 16. The method according to claim 15, wherein the amide solvent is one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), and N,N-dimethylformamide (DMF).

17. 17. The method of claim 16, wherein the amide solvent is N-methylpyrrolidone.

18. 17. The method of claim 16, wherein the amide solvent is dimethylacetamide.

19. 17. The method according to claim 16, wherein the amide solvent is N,N-dimethylformamide.

20. The method according to any one of claims 1 to 19, wherein the enantiomeric excess of the solid salt of the compound of formula I produced is at least 98% or more.

21. The method according to any one of claims 1 to 20, wherein the enantiomeric excess of the solid salt of the compound of formula I produced is at least 99% or more.

22. 22. The method of any one of claims 1 to 21, further comprising dissolving the phenylethylamine in toluene.

23. The method of any one of claims 1 to 22, comprising adding an anti-solvent to the sample.

24. 24. The method of claim 23, wherein the anti-solvent is toluene or ethyl acetate.

25. The method of any one of claims 1 to 24, further comprising the step of removing the amide solvent.

26. A method for preparing a compound of formula IIIa, comprising converting a solid salt of a compound of formula I, prepared by a method according to any one of claims 1 to 25, into a compound of formula IIIa: 【Transformation 3】 Formula IIIa: (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide.

27. Compounds according to formula IVa: 【Chemistry 4】 Formula IVa or a solvate thereof.

28. 28. The compound of claim 27 which is an amide solvate.

29. The solvate according to any one of claims 27 to 28, wherein the amide solvent is one or more solvents selected from NMP (N-methylpyrrolidone), DMA (dimethylacetamide), and DMF (N,N-dimethylformamide).

30. 30. The solvate according to claim 29, wherein the amide solvent is N-methylpyrrolidone.

31. 30. The solvate according to claim 29, wherein the amide solvent is dimethylacetamide.

32. The solvate according to claim 29, wherein the amide solvent is N,N-dimethylformamide.

33. A pharmaceutical substance comprising the compound or solvate according to any one of claims 27 to 32.

34. A method for preparing a solid salt of a compound of formula II, comprising adding an amide solvent to a sample containing a compound of formula II and suspected of containing a compound of formula I in the presence of an optical resolving agent: 【Transformation 5】 Formula I: (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter referred to as R-Trolox) 【Transformation 6】 Formula II: (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter S-Trolox).

35. The method according to claim 34, wherein the optical resolution agent comprises at least a moiety capable of forming a salt with R Trolox and S Trolox and an asymmetric carbon.

36. 36. The method of claim 34 or 35, comprising adding the optical resolving agent to the sample.

37. The method according to any one of claims 34 to 36, wherein the addition of the amide solvent comprises adding a mixture of the optical resolving agent and the amide solvent to the sample.

38. The method according to any one of claims 34 to 37, wherein the sample comprises a complex with an optical resolution agent.

39. 39. The method of any one of claims 34 to 38, wherein the sample comprises a mixture of a compound of formula I and a compound of formula II.

40. The method according to any one of claims 34 to 39, wherein the optical resolution agent is selected from phenylethylamine, N-methylglucamine, arginine, lysine, pseudoephedrine, leucinol, and aminophenylpropanol.

41. The method according to any one of claims 34 to 40, wherein the optical resolving agent is phenylethylamine.

42. The method according to any one of claims 34 to 41, wherein the amide solvent is one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), and N,N-dimethylformamide (DMF).

43. 43. The method of claim 42, wherein the amide solvent is N-methylpyrrolidone.

44. 43. The method of claim 42, wherein the amide solvent is dimethylacetamide.

45. 43. The method of claim 42, wherein the amide solvent is N,N-dimethylformamide.

46. 46. ​​The method of any one of claims 40 to 45, wherein the phenylethylamine is (R)-phenylethylamine.

47. 47. The method of any one of claims 34 to 46, wherein the solid salt is an S-phenylethylamine salt.

48. 48. The method according to any one of claims 34 to 47, wherein the solid salt is an amide solvate.

49. The method according to any one of claims 34 to 48, wherein the amide solvent is one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), and N,N-dimethylformamide (DMF).

50. 50. The method of claim 49, wherein the amide solvent is N-methylpyrrolidone.

51. 50. The method of claim 49, wherein the amide solvent is dimethylacetamide.

52. 50. The method of claim 49, wherein the amide solvent is N,N-dimethylformamide.

53. The method according to any one of claims 34 to 52, wherein the enantiomeric excess of the solid salt of the compound of formula II produced is at least 98% or more.

54. The method according to any one of claims 34 to 53, wherein the enantiomeric excess of the solid salt of the compound of formula II produced is at least 99% or more.

55. 55. The method of any one of claims 34 to 54, further comprising dissolving the phenylethylamine in toluene.

56. 56. The method of any one of claims 34 to 55, comprising adding an anti-solvent to the sample.

57. 57. The method of claim 56, wherein the anti-solvent is toluene or ethyl acetate.

58. 58. The method of any one of claims 34 to 57, further comprising the step of removing the amide solvent.

59. A method for preparing a compound of formula IIIb, comprising converting a solid salt of a compound of formula II, prepared by a method according to any one of claims 34 to 58, into a compound of formula IIIb: 【Transformation 7】 Formula IIIb: (S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide.

60. Compounds according to formula IVb: 【Transformation 8】 Formula IVb or a solvate thereof.

61. 61. The compound of claim 60 which is an amide solvate.

62. The solvate according to any one of claims 60 to 61, wherein the amide solvent is one or more solvents selected from NMP (N-methylpyrrolidone), DMA (dimethylacetamide), and DMF (N,N-dimethylformamide).

63. The solvate according to claim 62, wherein the amide solvent is N-methylpyrrolidone.

64. The solvate of claim 62, wherein the amide solvent is dimethylacetamide.

65. The solvate according to claim 62, wherein the amide solvent is N,N-dimethylformamide.

66. A pharmaceutical substance comprising a compound or solvate according to any one of claims 60 to 65.

67. A composition for optical resolution of a compound, comprising an amide solvent.

68. The compound is a mixture of a compound of formula I and a compound of formula II: 【Chemistry 9】 Formula I: (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter referred to as R-Trolox) 【Chemistry 10】 Formula II: (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (hereinafter referred to as S-Trolox) 68. The composition of claim 67, wherein:

69. 69. The composition of claim 67 or 68, wherein the composition is used in conjunction with other optical resolving agents.

70. The composition of claim 69, wherein the other optical resolving agent is itself optically active.

71. The composition according to any one of claims 67 to 70, wherein the amide solvent is one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), and N,N-dimethylformamide (DMF).

72. 72. The composition of claim 71, wherein the amide solvent is N-methylpyrrolidone.

73. 72. The composition of claim 71, wherein the amide solvent is dimethylacetamide.

74. 72. The composition according to claim 71, wherein the amide solvent is N,N-dimethylformamide.

75. A method for optically resolving a compound, comprising adding an amide solvent to the compound.

76. Use of amide solvents for the optical resolution of compounds.

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