Optically resolved Trolox intermediate and method for producing the same

Abstract

The present invention provides a method for chiral resolution of Trolox. The present disclosure relates to a method for producing a solid salt of a compound of formula I, wherein an amide-based solvent is added to a sample, which contains a compound of formula I, while being assumed to contain a compound of formula II, in the presence of an optical resolution agent. Formula I: (R)-6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxylic acid (hereinafter referred to R Trolox) Formula II: (S)-6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxylic acid (hereinafter referred to S Trolox)

Description

[Technical Field]

[0001] This application provides a method for the chiral resolution of trorox. This application also provides compositions and methods for the optical resolution of compounds, comprising an amide solvent. [Background technology]

[0002] International Publication No. 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 may form a solid salt with one enantiomer but not with the other (it will remain in solution or as an oil). Thus, these 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 offer, for example, better resolution, higher yield, easier scale-up, and / or improved ease of use.

[0004] Racemic trolox has been previously divided into its (R) and (S) isomers using α-methylbenzylamine (MBA) and R-(+)-N-benzyl-α-phenylethylamine resolving agents. See, for example, U.S. Patents 3,947,473, 4,003,919, and 4,026,907, and U.S. Patent Application Publication 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 [Overview of the project] [Means for solving the problem]

[0006] As a result of diligent research, the inventors have found a method for the stable optical resolution of Trolox and have completed this disclosure. This application also finds that amide solvents are useful for the optical resolution of compounds.

[0007] For example, this disclosure provides the following items: (Item 1) A method for producing a solid salt of a compound of formula I, comprising adding an amide solvent to a sample containing a compound of formula I and presumed to contain 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 referred to as S-trolox). (Item 2) The method according to item 1, wherein the optical resolving agent comprises at least a portion capable of forming a salt with R-trolux and S-trolux and an asymmetric carbon. (Item 3) The method according to item 1 or 2, comprising adding the optical resolving agent to the sample. (Item 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 resolving agent and the amide solvent to the sample. (Item 5) The method according to any one of items 1 to 4, wherein the sample comprises a complex with an optical resolving agent. (Item 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) The method according to any one of items 1 to 6, wherein the optical resolving agent is selected from phenylethylamine, N-methylglucamine, arginine, lysine, pseudoephedrine, leucinol, aminophenylpropanol. (Item 8) The method according to any one of items 1 to 7, wherein the optical resolving agent is phenylethylamine. (Item 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) or hexamethylphosphoric triamide (HMPA). (Item 10) The method according to item 9, wherein the amide solvent is N-methylpyrrolidone. (Item 11) The method according to item 9, wherein the amide solvent is dimethylacetamide. (Item 12) The method according to item 9, wherein the amide solvent is N,N-dimethylformamide. (Item 13) The method according to any one of items 7 to 12, wherein the phenylethylamine is (R)-phenylethylamine. (Item 14) The method according to any one of items 1 to 13, wherein the solid salt is an R-phenylethylamine salt. (Item 15) The method according to any one of items 1 to 14, wherein the solid salt is an amide solvate. (Item 16) The method according to item 15, wherein the amide solvent is one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), or N,N-dimethylformamide (DMF). (Item 17) The method according to item 16, wherein the amide solvent is N-methylpyrrolidone. (Item 18) The method according to item 16, wherein the amide solvent is dimethylacetamide. (Item 19) The method according to item 16, wherein the amide solvent is N,N-dimethylformamide. (Item 20) The method according to any one of items 1 to 19, wherein the enantiomer excess of the solid salt of the compound of formula I produced is at least 98%. (Item 21) The method according to any one of items 1 to 20, wherein the enantiomer excess of the solid salt of the compound of formula I produced is at least 99%. (Item 22) The method according to any one of items 1 to 21, further comprising the step of dissolving the phenylethylamine in toluene. (Item 23) The method according to any one of items 1 to 22, comprising the step of adding a poor solvent to the sample. (Item 24) The method according to item 23, wherein the poor solvent is toluene or ethyl acetate. (Item 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 producing the compound described in formula IIIa, comprising converting a solid salt of the compound of formula I, produced by the method described in any one of items 1 to 25, into the compound described in 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 described in formula IVa: [ka] Formula IVa or its solvate. (Item 28) A compound described in item 27, which is an amide solvate. (Item 29) A 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), or DMF (N,N-dimethylformamide). (Item 30) The solvate described in item 29, wherein the amide solvent is N-methylpyrrolidone. (Item 31) The solvate described in item 29, wherein the amide solvent is dimethylacetamide. (Item 32) The solvate described in item 29, wherein the amide solvent is N,N-dimethylformamide. (Item 33) A pharmaceutical raw material containing a compound or solvate described in any one of items 27 to 32. (Item 34) A method for producing a solid salt of the compound of formula II, comprising adding an amide solvent to a sample containing the compound of formula II and presumed to contain the 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 referred to as S-trolox). (Item 35) The method according to item 34, wherein the optical resolution agent comprises at least a portion that can form salts with R-trolox and S-trolox and an asymmetric carbon. (Item 36) The method according to item 34 or 35, comprising adding the optical resolution agent to the sample. (Item 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 resolving agent and the amide solvent to the sample. (Item 38) The method according to any one of items 34 to 37, wherein the sample comprises a composite with an optical resolution agent. (Item 39) The method according to any one of items 34 to 38, wherein the sample comprises a mixture of the compound of formula I and the compound of formula II. (Item 40) The method according to any one of items 34 to 39, wherein the optical resolving agent is selected from phenylethylamine, N-methylglucamine, arginine, lysine, pseudoephedrine, leucinol, and aminophenylpropanol. (Item 41) The method according to any one of items 34 to 40, wherein the optical resolution agent is phenylethylamine. (Item 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), or N,N-dimethylformamide (DMF). (Item 43) The method according to item 42, wherein the amide solvent is N-methylpyrrolidone. (Item 44) The method according to item 42, wherein the amide solvent is dimethylacetamide. (Item 45) The method according to item 42, wherein the amide solvent is N,N-dimethylformamide. (Item 46) The method according to any one of items 40 to 45, wherein the phenylethylamine is (R)-phenylethylamine. (Item 47) The method according to any one of items 34 to 46, wherein the solid salt is an S-phenylethylamine salt. (Item 48) The method according to any one of items 34 to 47, wherein the solid salt is an amide solvate. (Item 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), or N,N-dimethylformamide (DMF). (Item 50) The method according to item 49, wherein the amide solvent is N-methylpyrrolidone. (Item 51) The method according to item 49, wherein the amide solvent is dimethylacetamide. (Item 52) The method according to item 49, wherein the amide solvent is N,N-dimethylformamide. (Item 53) The method according to any one of items 34 to 52, wherein the enantiomer excess of the solid salt of the compound of formula II produced is at least 98%. (Item 54) The method according to any one of items 34 to 53, wherein the enantiomer excess of the solid salt of the compound of formula II produced is at least 99%. (Item 55) Furthermore, the method according to any one of items 34 to 54, further comprising the step of dissolving the phenylethylamine in toluene. (Item 56) The method according to any one of items 34 to 55, comprising the step of adding a poor solvent to the sample. (Item 57) The method according to item 56, wherein the poor solvent is toluene or ethyl acetate. (Item 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 producing the compound described in formula IIIb, comprising converting a solid salt of the compound of formula II produced by the method described in any one of items 34 to 58 into the compound described in 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 described in formula IVb: [ka] Formula IVb or its solvate. (Item 61) A compound described in item 60, which is an amide solvate. (Item 62) A 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), or DMF (N,N-dimethylformamide). (Item 63) The solvate described in item 62, wherein the amide solvent is N-methylpyrrolidone. (Item 64) The solvate described in item 62, wherein the amide solvent is dimethylacetamide. (Item 65) The solvate described in item 62, wherein the amide solvent is N,N-dimethylformamide. (Item 66) A pharmaceutical raw material containing a compound or solvate described in any one of items 60 to 65. (Item 67) A composition containing an amide solvent for optical resolution of compounds. (Item 68) The aforementioned compound is a mixture of the compound of formula I and the 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) The composition described in item 67. (Item 69) The composition according to item 67 or 68, wherein the composition is used together with other optical resolving agents. (Item 70) The other optical resolution agent is the composition described in item 69, which is optically active in itself. (Item 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), or N,N-dimethylformamide (DMF). (Item 72) The composition according to item 71, wherein the amide solvent is N-methylpyrrolidone. (Item 73) The composition according to item 71, wherein the amide solvent is dimethylacetamide. (Item 74) The composition according to item 71, wherein the amide solvent is N,N-dimethylformamide. (Item 74A) The method described in item 67, further comprising the features described in any one or more items 1 through 74. (Item 75) A method for optically resolving a compound, comprising adding an amide solvent to the compound. (Item 75A) The method described in item 75, further comprising the features described in any one or more items 1 through 74. (Item 76) The use of amide solvents for optical resolution of compounds. (Item 76A) The use described in item 76, further including the characteristics described in any one or more of items 1 through 75.

[0008] In this disclosure, the one or more of the above features are intended to be provided in combinations other than those explicitly stated. Further embodiments and advantages of this disclosure will be apparent to those skilled in the art, by reading and understanding the detailed description below as necessary. [Effects of the Invention]

[0009] This application provides a method for stably performing chiral resolution of trolox with high optical purity. [Brief explanation of the drawing]

[0010] [Figure 1] Figure 1 shows the single-crystal X-ray structure of RS-Trolox·R-PEA (racemic mixture: 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). The leftmost value on the horizontal axis in Figure 3 is "5". [Modes for carrying out the invention]

[0011] The following provides further details about this disclosure. Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Accordingly, singular articles (for example, "a," "an," and "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. In case of any conflict, this specification (including definitions) shall prevail.

[0012] The following provides further details regarding this disclosure.

[0013] Unless otherwise specified, the abbreviations used herein have their conventional meanings within the scope of the art.

[0014] In this specification, any "about" reference to a value or parameter includes variability in the value or parameter itself. Unless otherwise specified, for example, "about X" includes not only X itself but also a value that allows for an error of ±10% of X.

[0015] In this specification, "Trolox" refers to 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. The R-isomer is referred to as R-trolox, and the S-isomer as S-trolox. Trolox can be prepared by synthetic methods well known to those skilled in the art, for example, the methods described in U.S. Patent No. 3,947,473, U.S. Patent No. 4,003,919, and U.S. Patent No. 4,026,907.

[0016] In this specification, “optical resolution agent” means an optically active reagent useful for separating a racemic mixture into its respective enantiomers, i.e., optically active compounds. In this disclosure, an optical resolution agent may comprise at least a moiety capable of forming salts with R-trolox and S-trolox, and an asymmetric carbon. In this disclosure, an optical resolution agent may comprise a base moiety. The base moiety may comprise an amine moiety. Examples of optically active compounds that may constitute an optical resolution agent include phenylethylamine, N-methylglucamine, arginine, lysine, pseudoephedrine, leucinol, and aminophenylpropanol.

[0017] In this specification, "a portion that can form salts with R-Trolox and S-Trolox" refers to a portion containing a functional group that can form salts with the functional groups contained in R-Trolox and S-Trolox. For example, since Trolox contains a carboxyl group, "a portion that can form salts with R-Trolox and S-Trolox" may be a portion containing a base that can form salts with the carboxyl group. In the optical resolution agent, "a portion that can form salts with R-Trolox and S-Trolox" may or may not overlap with the chiral carbon in the optical resolution agent. If there is an overlap, it is a condition that the chiral carbon functions effectively (exhibits different behavior from chiral carbons with other stereoconfigurations) when the optical resolution agent forms salts with R-Trolox and S-Trolox or after salt formation. Examples of "a portion that can form salts with R-Trolox and S-Trolox" include portions containing amino groups, imino groups, guanidyl groups, heterocyclic groups (nitrogen-containing heterocyclic groups such as pyridine, imidazole, indole, and purine). Compounds containing a chiral carbon include tartaric acid, phenylethylamine, N-methylglucamine, amino acids (arginine, lysine, etc.), pseudoephedrine, leucinol, and aminophenylpropanol, and a chiral carbon having the same skeleton as such compounds can be used.

[0018] In this specification, "amide solvent" refers to a solvent for a compound containing an amide group (acid amide group). Examples of amide groups include carboxylic acid amides and phosphate amides. Examples of amide solvents include N-methylpyrrolidone (NMP), dimethylacetamide (DMA), N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), tetramethylurea (TMU), and hexamethylphosphate triamide (HMPA).

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

[0020] In this specification, "salt" refers to a compound produced by the neutralization reaction of an acid and a base, consisting of a negatively charged component of the acid and a positively charged component of the base. Torolox has a carboxylic acid group and can form salts with basic substances.

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

[0022] In this specification, "suspect" means that something is not confirmed, but is reasonably predictable. It is not necessary for the thing to not exist after actual confirmation. For example, "a sample that contains compound I and is suspected to contain compound II" means a sample that contains compound I and compound II, but whose presence has not been confirmed, but which is reasonably predictable.

[0023] In this specification, "mixture" refers to a mixture of two or more things. The mixing ratio can be arbitrary. For example, in the case of a mixture of two things, the ratio can 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, "enantiomer excess" refers to a measure representing the mixing ratio of right-handed and left-handed enantiomers, and is abbreviated as ee. If R and S are the proportions of right-handed and left-handed enantiomers in the sample, respectively, it can be calculated by the following formula. ee(%) = (RS) / (R+S) × 100, or (SR) / (R+S) × 100 For example, if the ratio of R:S is 90:10, the enantiomer excess of the R-isomer is (90-10) / (90+10)×100 = 80%ee.

[0025] (Preferred embodiment) One embodiment of the present disclosure provides a method for producing a solid salt of a compound of formula I, comprising adding an amide solvent to a sample containing a compound of formula I and presumed to contain a compound of formula II, in the presence of an optical resolution 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 referred to as S-trolox). The method of this disclosure allows for stable optical resolution of R-trolox. This method is easier to scale up, easier to stir, provides an easily filterable solid, and provides better resolution and / or purity of the desired product.

[0026] A solid salt of the compound of formula I may be a salt of the compound of formula I and an optical resolving agent. A solid salt of the compound of formula I may be a solvate of a salt of the compound of formula I and an optical resolving agent with an amide solvent.

[0027] In this disclosure, the optical resolution agent may include at least a moiety capable of forming salts with R-trolox and S-trolox, and an asymmetric carbon. Since trolox contains a carboxylic acid moiety, the optical resolution agent may include a base moiety that forms salts with the carboxylic acid. The base moiety may be an amine. For example, if the optical resolution agent is R-phenylethylamine, then R-trolox and R-phenylethylamine are as follows: [ka] It can form salts like the following. When the salt of R-trolox and R-phenylethylamine is solvated with N-methylpyrrolidone, the following [ka] It can form solvates such as the following. If the optical resolution 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 becomes ammonium.

[0028] The method disclosed herein may include adding an optical resolution agent to the sample.

[0029] The addition of the amide solvent may be achieved by adding a mixture of the optical resolving agent and the amide solvent to the sample. When adding the amide solvent, the optical resolving agent and / or the amide solvent may already be present in the sample (therefore, the addition of a new amide solvent may or may not be necessary). When adding the optical resolving agent and the amide solvent, the addition may be simultaneous or separate.

[0030] In this disclosure, the sample may include a composite with an optical resolution agent.

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

[0032] In this 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 this disclosure, the optical resolution agent may be phenylethylamine.

[0034] In this 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), or hexamethylphosphate triamide (HMPA).

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

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

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

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

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

[0040] In this disclosure, the solid salt may be an amide solvate.

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

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

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

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

[0045] In this disclosure, the enantiomer excess of the solid salt of the compound of formula I produced may be at least 98%.

[0046] In this disclosure, the enantiomer excess of the solid salt of the compound of formula I produced may be at least 99%.

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

[0048] The present disclosure may include the step of adding a poor solvent to the sample. The advantage of using a poor solvent is improved filterability. The addition of a poor solvent can reduce the viscosity of the amide solvent, improving its practicality, but this disclosure is not limited to this. Adding a poor solvent may also slightly improve optical purity.

[0049] In this disclosure, the poor solvent may be toluene or ethyl acetate.

[0050] This disclosure may further include the step of removing the amide solvent.

[0051] One embodiment of the present disclosure provides a method for producing a compound described in formula IIIa, comprising converting a solid salt of the compound of formula I produced by the above method into the compound described in 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 this disclosure, the compound described in formula IVa: [ka] Formula IVa Or a solvate thereof is provided.

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

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

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

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

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

[0058] In this disclosure, pharmaceutical raw materials containing the above-mentioned compound or solvate may be provided.

[0059] One embodiment of the present disclosure provides a method for producing a solid salt of a compound of formula II, comprising adding an amide solvent to a sample that contains a compound of formula II and is presumed to contain a compound of formula I, in the presence of an optical resolution 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 referred to as S-trolox). The method of this disclosure allows for stable optical resolution of trolox. This method is easier to scale up, easier to stir, provides a solid that can be easily filtered, and provides better resolution and / or purity of the desired product.

[0060] A solid salt of the compound of formula II may be a salt of the compound of formula II and an optical resolving agent. A solid salt of the compound of formula II may be a solvate of a salt of the compound of formula II and an optical resolving agent with an amide solvent.

[0061] In this disclosure, the optical resolving agent may include at least a moiety capable of forming salts with R-trolox and S-trolox, and an asymmetric carbon. Since trolox contains a carboxylic acid moiety, the optical resolving agent may include a base moiety capable of forming salts with the carboxylic acid. The base moiety may be an amine. For example, if the optical resolving agent is S-phenylethylamine, S-trolox and S-phenylethylamine may form a salt that is an enantiomer of the R-isomer.

[0062] The method disclosed herein may include adding an optical resolution agent to the sample.

[0063] The addition of the amide solvent may be achieved by adding a mixture of the optical resolving agent and the amide solvent to the sample. When adding the amide solvent, the optical resolving agent and / or the amide solvent may already be present in the sample (therefore, the addition of a new amide solvent may or may not be necessary). When adding the optical resolving agent and the amide solvent, the addition may be simultaneous or separate.

[0064] In this disclosure, the sample may include a composite with an optical resolution agent.

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

[0066] In this 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 this disclosure, the optical resolution agent may be phenylethylamine.

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

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

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

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

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

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

[0074] In this disclosure, the solid salt may be an amide solvate.

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

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

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

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

[0079] In this disclosure, the enantiomer excess of the solid salt of the compound of formula II produced may be at least 98%.

[0080] In this disclosure, the enantiomer excess of the solid salt of the compound of formula II produced may be at least 99%.

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

[0082] The present disclosure may include the step of adding a poor solvent to the sample. The advantage of using a poor solvent is improved filterability. The addition of a poor solvent can reduce the viscosity of the amide solvent, improving its practicality, but this disclosure is not limited to this. Adding a poor solvent may also slightly improve optical purity.

[0083] In this disclosure, the poor solvent may be toluene or ethyl acetate.

[0084] This disclosure may further include the step of removing the amide solvent.

[0085] One embodiment of the present disclosure provides a method for producing a compound described in formula IIIb, comprising converting a solid salt of the compound of formula II produced by the above method into the compound described in 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 this disclosure, the compound described in formula IVb: [ka] Formula IVb Or a solvate thereof is provided.

[0087] In this disclosure, it may be an amide solvate.

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

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

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

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

[0092] In this disclosure, pharmaceutical raw materials containing the above-mentioned 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 this disclosure, the compound is a mixture of the compound of formula I and the 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 is possible.

[0095] In this disclosure, the composition may be used in conjunction with other optical resolution agents.

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

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

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

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

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

[0101] One embodiment of the present disclosure provides a method for optically resolving a compound, comprising adding an amide solvent to the compound.

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

[0103] In one embodiment of this disclosure, the powder X-ray diffraction (XRPD) of RS-Trolox·R-PEA (racemate) shows peaks of 2θ at 8.54°, 12.55°, 13.45°, 15.41°, 17.11°, 18.87°, 21.00°, 22.19°, and 23.83°, but is not limited to these, and may have any number of peaks (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more integer values) selected from those with large Gross Intensities as listed in Table 6. In this disclosure, with respect to the assignment of powder X-ray diffraction (XRPD), 2θ may have an error range 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 shows peaks at 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°, but may have any number of peaks (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more integer values) selected from those with large Gross Intensities as listed in Table 6.

[0105] In one embodiment of this disclosure, characteristic 2θ peaks in powder X-ray diffraction (XRPD) of R-Trolox·R-PEA·NMP (solvate) are shown 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°, but are not limited to these, and may have any number of peaks (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more integer values) selected from those with large Gross Intensity listed in Table 6.

[0106] Crystals exhibit a variety of structures, shapes, sizes, and aggregation states depending on the crystallization conditions. Solvates in which a solvent is incorporated into the crystal are sometimes called pseudo-polymorphs to distinguish them from true crystalline polymorphs. In this case, the physicochemical properties of the crystal can be largely governed by the contribution of the solvent to crystal lattice formation and its interaction with the molecules being crystallized. Various factors related to crystallization conditions, such as the properties of the solvent, degree of supersaturation, and temperature, can determine the properties of the crystal. This disclosure makes it possible to stably perform chiral resolution of trolox with high optical purity by appropriately selecting an optical resolving agent and solvent.

[0107] In the optical resolution of Trolox, it was observed that optical resolution was impossible when phenethylamine was used as an optical resolution agent in a non-amide solvent. However, by using an amide solvent, stable optical resolution of Trolox was achieved.

[0108] The method of the present disclosure utilizes an optical resolving agent to separate (R)- and (S)-trolox enantiomers, the resolving agent forming a solid salt with one of (R)-trolox and (S)-trolox, and substantially not forming 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 no solid salt formation" means that less than about 10% of the (non-solid salt-forming) trolox enantiomers form a solid salt with the resolving agent under specific reaction conditions. In various embodiments, "substantially no solid salt formation" means 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 specific reaction conditions. The solid salt may be a solvate with an amide solvent.

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

[0110] While the compounds described herein arise and can be used as neutral (non-salt) compounds, this 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, salts of compounds include pharmaceutically acceptable salts. A pharmaceutically acceptable salt is a salt that can be administered to humans and / or animals as a drug or pharmaceutical and, upon administration, retains at least some of the biological activity of the free compound (neutral or non-salt compound). Desired salts of basic compounds can be prepared by methods known to those skilled in the art by treating the compound with an acid. Examples of inorganic acids, but not limited to these, include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids, but not limited to these, include 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 aspartates and glutamates, can also be prepared. Desired salts of acidic compounds can be prepared by methods known to those skilled in the art by treating the compound with a base. Examples of inorganic salts of acidic compounds, but not limited to these, include 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, but not limited to these, include 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; Vol. 66 (No. 1): pp. 1-19.

[0111] Purpose The compounds produced by the method disclosed herein are useful as pharmaceutical raw materials. They can be used as intermediates in the production of optically active pharmaceuticals.

[0112] Synthesis reaction parameters Examples of solvents used in the synthesis of the compounds and compositions of this disclosure include water, acetonitrile ("ACN"), diethyl ether, 2-methyl-tetrahydrofuran ("2-MeTHF"), ethyl acetate ("SiO"), ethanol ("EtOH"), isopropyl alcohol ("IPA"), isopropyl acetate ("IPAc"), methanol (MeOH), and mixtures thereof.

[0113] The term "qs (appropriate amount)" means adding enough of a substance to bring the solution to the desired volume (i.e., 100%) in order to achieve the stated function.

[0114] The techniques useful for synthesizing the compounds and compositions described herein are readily apparent and accessible to those skilled in the art, given the teachings provided herein. The following discussion is provided to illustrate some of the diverse methods available for use in constructing the compounds and compositions described herein. However, this discussion is not intended to define a range of reactions or sequences of reactions useful for preparing the compounds and compositions described herein.

[0115] Other methods for producing the compounds and compositions of this disclosure will be apparent to those skilled in the art, taking into consideration the teachings herein. [Examples]

[0116] To simplify the description in the specification, the following abbreviations may be used in the examples and tables within the examples. Trolox: 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid R-Trolox: R-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid S-Trolox: S-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid RS-Trolox: RS-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (racemic mixture) PEA: 1-phenylethylamine R-PEA: R-1-phenylethylamine S-PEA: S-1-phenylethylamine æ:ethyl acetate i PrOAc: Isopropyl acetate NMP: N-methylpyrrolidone DMA: Dimethylacetamide DMF: N,N-dimethylformamide DMP: N,N-dimethylpropionamide MTBE: Methyl tert-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 In NMR, the symbols used are as follows: δ represents the chemical shift value, s represents a single line, d represents a double line, t represents a triple line, q represents a quadruple line, m represents a multiline line, and J represents the spin coupling constant.

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

[0118] (Method for measuring optical purity) Optical purity is measured by comparing the peak areas using high-performance liquid chromatography (HPLC). The measurement conditions are as follows, with retention time indicated in 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 values ​​for each compound measured under the above measurement conditions are shown in the table below. [Table 1]

[0121] (Example 1) Solvent considerations (other than amides) At room temperature, R-Trolox·R-PEA (1.0 g) was mixed with S-Trolox (0.67 g), R-PEA (0.11 g), and a solvent to create a slurry. After incubation 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 off and their optical purity was measured. [Table 2]

[0122] While optical resolution was initially shown for the non-amide solvent 2-MeTHF, subsequent studies have shown that optical resolution is no longer possible for these solvents. Although 2-MeTHF and chlorobenzene exhibit high optical purity, the amount of the starting material, R-Trolox·R-PEA (1.0g), has decreased to approximately half (0.55g and 0.53g, respectively).

[0123] (Example 2) Investigation of amide solvents (NMP or DMA) At room temperature, 10.0 g of Trolox was mixed with 70.0 g of NMP or 70.0 g of DMA and R-PEA, and the mixture was heated to 50°C. The solution was then filtered with 20.0 g of NMP to remove debris. After cooling the solution to 25°C, a seed crystal of R-Trolox·R-PEA (0.01 g) was inoculated and the mixture was incubated for 3 hours. The mixture was cooled to 10°C and incubated overnight, after which the precipitate was filtered off. 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) At room temperature, NMP (10.0 g), DMA (10.0 g), and RS-Trolox (2.00 g) were added, and the mixture was heated to 50°C. After cooling to 25°C, R-Trolox·R-PEA (0.01 g) seed crystals were inoculated and incubated for 1 hour. The mixture was cooled to 10°C and incubated overnight, after which the precipitate was filtered off. 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 (racemate) (NMP solvent) RS-Trolox·R-PEA (100 mg) was dissolved in NMP (1 mL), stirred for 3 hours, and the precipitated crystals were filtered off (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 solvent. Ethyl acetate was added to each crystal to create a reslurry. Solubility was calculated by analyzing the content of the supernatant solution of each reaction mixture at various temperatures.

[0127] [Table 4]

[0128] (Example 6) Solubility of R-Trolox·R-PEA, S-Trolox·R-PEA, and S-Trolox in NMP and DMA Each crystal was mixed with an amide solvent (NMP, DMA) and re-slurred. Solubility was calculated from the content analysis of the supernatant solution of each reaction mixture at various temperatures.

[0129] [Table 5]

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

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

[0132] To the crystals obtained above (550g), NMP (1650g) and toluene (4950g) were added, the temperature was raised to 70°C and incubated for 30 minutes, then cooled to 60°C, and R-Trolox·R-PEA (0.6g) seed crystals were inoculated and incubated for 30 minutes. After cooling to 0°C and incubation overnight, the precipitate was filtered off. The precipitate was washed with an NMP / toluene mixed solvent (206g / 619g), washed with toluene (825g), and dried to obtain the amide solvate of R-Trolox·R-PEA (yield: 514g, yield 93.4%, optical purity: >99.9%ee).

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

[0134] At room temperature, 6.00 kg of Trolox was mixed with 10.80 kg of NMP and 43.20 kg of ethyl acetate, and the mixture was heated to 50°C. After filtering to remove debris, the mixture was washed with a mixed solvent of NMP / ethyl acetate (1.20 kg / 4.80 kg). At 50°C, 1.74 kg of R-PEA was added, and then 6.04 g of R-Trolox, R-PEA, and NMP was inoculated as a seed crystal. The mixture was incubated for 2 hours. 0.73 kg of R-PEA was added dropwise over 1 hour, and the mixture was incubated for 30 minutes. The mixture was cooled to 5°C and incubated overnight, after which the precipitate was filtered off. The precipitate was washed twice with an NMP / ethyl acetate mixed solvent (2.40 kg / 9.60 kg), then twice with toluene (12.00 kg), and dried to obtain the 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 temperature was raised to 68°C. After cooling to 60°C, R-Trolox·R-PEA·NMP (3.02 g) was inoculated as a seed crystal, and the mixture was incubated for 1 hour. After cooling to 5°C and incubation overnight, the precipitate was filtered off. The precipitate was washed twice with an NMP / ethyl acetate mixed solvent (1.13 kg / 3.38 kg), then washed twice with ethyl acetate (4.50 kg), and dried to obtain the NMP solvate of R-Trolox·R-PEA (yield: 2.71 g, yield 90.3%, optical purity: >99.9%ee).

[0136] (Example 10) Single-crystal X-ray structural analysis of RS-Trolox·R-PEA (racemic mixture) 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: VariMax RAPID RA-Micro7). Measurement temperature: -170°C. Analysis program: CrystalStructure crystallographic software package.

[0137] Specifically, the following measurements were taken for RS-Trolox·R-PEA (racemate). (Data collection) C has approximate dimensions of 0.200 x 0.110 x 0.090 mm. 22 H 29 A colorless NO4 prism crystal was placed on a glass fiber. All measurements were performed using a Rigaku R-AXIS RAPID diffractometer with a multilayer monochromator and Mo-Kα radiation.

[0138] The distance between the crystal and the detector was 127.40 mm.

[0139] The cell constants and rotation matrix for data acquisition 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 / cm³. 3 Based on statistical analysis of the intensity distribution, as well as successful analysis and refinement of the structure, the space group is: P1(#1) It was determined that this was the case.

[0141] Data was 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. Data sweeping was performed using ω scanning in 2.00° steps from 130.0° to 190° at χ=45.0° and φ=0.0°. The exposure rate was 80.0 [sec / °]. A second sweep was performed using ω scanning in 2.00° steps from 0.0° to 162.0° at χ=45.0° and φ=180.0°. The exposure rate was 80.0 [sec / °]. Another sweep was performed using ω scanning in 2.00° steps from 0.0° to 162.0° at χ=45.0° and φ=90.0°. The exposure rate was 80.0 [sec / °]. The distance between the crystal and the detector was 127.40 mm. The scan was performed in 0.100mm pixel mode.

[0142] (Data reduction) Of the collected 0 reflections, 0 is unique (R int If the value is 0.0115, then the equal reflections were merged.

[0143] For Mo-Kα, the linear absorption coefficient μ is 0.875 cm⁻¹. -1 An empirical absorption correction was applied to produce transmittances in the range of 0.958 to 0.992. The data was corrected for Lorentz and polarization effects.

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

number

[0145] The goodness of fit was 1.06. The goodness of fit is defined as follows: [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 corresponded to 0.31 and -0.20 e - / Å 3 respectively. The final Flack parameter (Parsons, S. and Flack, H. (2004), Acta Cryst. A60, s61) was 0.11(11), indicating that the absolute structure present is correct (Flack, H.D. and Bernardinelli (2000), J. Appl. Cryst., 33, 114-1148).

[0146] The 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). The anomalous dispersion effect was included in Fcalc (Ibers, JA & Hamilton, WC; Acta Crystallogr., 17, 781 (1964)); the values ​​of Δf' and Δf'' were those of Creahg 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 ​​for the mass decay coefficient are those of Creahg and Hubbell (Creagh, DC & Hubbell, JH.; “International Tables for Crystallography”, Vol C, (A.J.C. 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) crystallographic software package, except for the refinement which was carried out using SHELXL Version 2017 / 1 (SHELXL Version 2017 / 1: Sheldrick, G. M. (2008). Acta Cryst. A64, 112 - 122).

[0147] The crystal data were as follows. [Number] The intensity measurements were as follows. [Number] The structure analysis and refinement are as follows. [Number]

[0148] (Example 11) Powder X - ray diffraction (XRPD) of RS - Trolox·R - PEA (racemate), R - Trolox·R - PEA, and R - Trolox·R - PEA·NMP (solvate) Powder X - ray diffraction (XRPD) of RS - Trolox·R - PEA (racemate), R - Trolox·R - PEA, and R - Trolox·R - PEA·NMP (solvate) was performed. The results are shown in Figure 3 and Table 6. The powder X - ray diffraction (XRPD) was carried out using a D from Bruker AXS Measurements were taken at room temperature using the ADVANCE system under the following conditions: diffraction angle 2θ in the range of 5 to 40 degrees, using Cu Kα rays, X-ray tube current of 40 milliamperes, voltage of 40 kilovolts, step size of 0.015 degrees, and measurement time of 48 seconds / 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) At room temperature, 25.00 g of Trolox was mixed with 50.0 g of DMP and 200.0 g of toluene, and the mixture was heated to 50°C. 7.26 g of R-PEA was added, and the mixture cooled to 45°C. A seed crystal of R-Trolox·R-PEA (0.03 g) was inoculated, and the mixture was incubated for 2 hours. 3.03 g of R-PEA was added dropwise over 20 minutes, and the mixture was incubated for 40 minutes. After cooling to 5°C, the precipitate was filtered off. The precipitate was washed twice with a DMP / toluene mixed solvent (10.0 g / 40.0 g), then twice with toluene (50 g), and finally dried to obtain the DMP solvate of R-Trolox·R-PEA (yield: 19.32 g, yield 40.9%, optical purity: 94.7% ee).

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

[0151] (Example 13) Optical resolution to obtain S-Trolox·S-PEA·NMP At room temperature, 25.00 g of Trolox was mixed with 50.00 g of NMP and 200.0 g of toluene, and the mixture was heated to 50°C. 7.26 g of S-PEA was added, and the mixture cooled to 45°C. S-Trolox·S-PEA (0.03 g) was then inoculated onto a seed crystal and incubated for 2 hours. 3.03 g of S-PEA 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 filtered off. The precipitate was washed twice with an NMP / toluene mixed solvent (10.0 g / 40.0 g), then twice with toluene (50 g), and finally 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] R-Tolox·PEA·NMP (10.00 kg, 21.25 mol) was mixed with isopropyl acetate (110 kg) and water (10.99 kg), then 35% hydrochloric acid (3.80 kg, 36.55 mol) was added dropwise, and the mixture was stirred at 25±5°C for 20 minutes. After standing and liquid-liquid extraction, the organic layer was washed twice with water (15.80 kg, 15.83 kg) and concentrated under reduced pressure below 45°C (distillate volume: 92.0 kg). Isopropyl acetate (8.38 kg) was added to prepare an isopropyl acetate solution of R-Trolox (16.7%, 31.9 kg), which was used in the next step (assuming 100% yield).

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

[0155] To the slurry obtained by adding isopropyl acetate (26.6 kg) to CDI (Hodogaya Chemical, 8.61 kg, 52.12 mol), a solution of R-Trolox in isopropyl acetate (16.7%, 31.8 kg, 21.25 mol (assumed)) was added dropwise at 20 ± 5°C over 1 hour, rinsed 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 (Nacalai Tesque, 16.15 kg, 265.61 mol) pre-cooled to 15 ± 5°C, and rinsed 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 and rinsed with water (1.06 kg). After liquid separation, an isopropyl acetate solution (109.09 kg) of the title compound was obtained and used in the next step (assuming a yield of 100%).

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

Chemical Structure

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

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

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

[0160] This disclosure is useful for the manufacture of optically active pharmaceuticals.

Claims

1. A method for producing a solid salt of a compound of formula I, comprising adding an amide solvent to a sample containing a compound of formula I and presumed to contain a compound of formula II, in the presence of an optical resolution agent, (R)-phenylethylamine: 【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 referred to as S-trolox), 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 hexamethylphosphate triamide (HMPA). A method wherein the solid salt is an amide solvate.

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

3. The method according to claim 1 or 2, comprising adding the optical resolution 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 resolution agent and the amide solvent to the sample.

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

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

7. The method according to claim 1, wherein the amide solvent is one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), and N,N-dimethylformamide (DMF).

8. The method according to claim 1, wherein the amide solvent is N-methylpyrrolidone.

9. The method according to any one of claims 1 to 8, wherein the enantiomer excess of the solid salt of the compound of formula I produced is at least 98%.

10. The method according to any one of claims 1 to 9, wherein the enantiomer excess of the solid salt of the compound of formula I produced is at least 99%.

11. Furthermore, the method according to any one of claims 1 to 10, further comprising the step of dissolving the (R)-phenylethylamine in toluene.

12. The method according to any one of claims 1 to 11, comprising the step of adding a poor solvent to the sample.

13. The method according to claim 12, wherein the poor solvent is toluene or ethyl acetate.

14. The method according to any one of claims 1 to 13, further comprising the step of removing the amide solvent.

15. A method for producing the compound described in Formula IIIa, comprising converting a solid salt of the compound of Formula I produced by the method described in any one of claims 1 to 14 into the compound described in Formula IIIa: 【Transformation 3】 Formula IIIa: (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide.

16. Compounds described in formula IVa: 【Chemistry 4】 The amide solvate of formula IVa, An amide solvate 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 hexamethyltriamide (HMPA).

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

18. The solvate according to claim 16, wherein the amide solvent is N-methylpyrrolidone.

19. A pharmaceutical raw material comprising an amide solvate according to any one of claims 16 to 18.

20. A method for producing a solid salt of the compound of formula II, comprising adding an amide solvent to a sample containing the compound of formula II and presumed to contain the compound of formula I, in the presence of (S)-phenylethylamine, which is an optical resolution 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 referred to as S-trolox), 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 hexamethylphosphate triamide (HMPA). A method wherein the solid salt is an amide solvate.

21. The method according to claim 20, wherein the optical resolution agent comprises at least a portion capable of forming a salt with R-trolox or S-trolox and an asymmetric carbon.

22. The method according to claim 20 or 21, comprising adding the optical resolution agent to the sample.

23. The method according to any one of claims 20 to 22, wherein the addition of the amide solvent comprises adding a mixture of the optical resolving agent and the amide solvent to the sample.

24. The method according to any one of claims 20 to 23, wherein the sample comprises a composite with an optical resolution agent.

25. The method according to any one of claims 20 to 24, wherein the sample comprises a mixture of the compound of formula I and the compound of formula II.

26. The method according to any one of claims 20 to 25, wherein the amide solvent is one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), and N,N-dimethylformamide (DMF).

27. The method according to claim 20, wherein the amide solvent is N-methylpyrrolidone.

28. The method according to any one of claims 20 to 27, wherein the enantiomer excess of the solid salt of the compound of formula II produced is at least 98%.

29. The method according to any one of claims 20 to 28, wherein the enantiomer excess of the solid salt of the compound of formula II produced is at least 99%.

30. The method according to any one of claims 20 to 29, further comprising the step of dissolving the phenylethylamine in toluene.

31. The method according to any one of claims 20 to 30, comprising the step of adding a poor solvent to the sample.

32. The method according to claim 31, wherein the poor solvent is toluene or ethyl acetate.

33. The method according to any one of claims 20 to 32, further comprising the step of removing the amide solvent.

34. A method for producing the compound described in formula IIIb, comprising converting a solid salt of the compound of formula II produced by the method described in any one of claims 20 to 33 into the compound described in formula IIIb: 【Transformation 7】 Formula IIIb: (S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide.

35. The following compounds: 【Transformation 8】 The amide solvate of An amide solvate 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 hexamethyltriamide (HMPA).

36. The solvate according to claim 35, wherein the amide solvent is one or more solvents selected from NMP (N-methylpyrrolidone), DMA (dimethylacetamide), and DMF (N,N-dimethylformamide).

37. The solvate according to claim 35, wherein the amide solvent is N-methylpyrrolidone.

38. A pharmaceutical raw material comprising an amide solvate according to any one of claims 35 to 37.

39. A mixture of the compound of formula I and the 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) A composition comprising an amide solvent for optical resolution with (R)-phenylethylamine or (S)-phenylethylamine, which are optical resolution agents, 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 hexamethylphosphate triamide (HMPA). A composition in which the compound of formula I or the compound of formula II forms an amide solvate.

40. The composition according to claim 39, wherein the composition is used together with other optical resolution agents.

41. The composition according to claim 40, wherein the other optical resolving agent is optically active in itself.

42. The composition according to any one of claims 39 to 41, wherein the amide solvent is one or more solvents selected from N-methylpyrrolidone (NMP), dimethylacetamide (DMA), and N,N-dimethylformamide (DMF).

43. The composition according to claim 39, wherein the amide solvent is N-methylpyrrolidone.

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