Crystalline alcohol adduct of 2, 2 ''-bis [1-(diphenylphosphino) ethyl]-1, 1''-diferrocene and method for producing same

Abstract

The present invention relates to a product form of 2, 2 "-bis [1-(diphenylphosphino) ethyl]-1, 1"-diferrocene (Ph-TRAP) having excellent crystallinity and air stability, which is useful as an aromatic asymmetric hydrogenation ligand but is difficult to synthesize and / or separate and purify, and to a method for efficiently producing the same, and more particularly, to a method for producing 2, 2 "-bis [1-(diphenylphosphino) ethyl]-1, 1"-diferrocene (Ph-TRAP) having excellent crystallinity and air stability. The present invention provides: a crystalline alcohol adduct comprising Ph-TRAP and an alcohol; and a method for producing the crystalline alcohol adduct, said method comprising reacting Ph-TRAP (BH3) 2 represented by general formula (1) (BH3) 2 with an alcohol.

Description

Technical Field

[0001] This invention relates to a novel crystalline alcoholic compound of 2,2”-bis[1-(diphenylphosphino)ethyl]-1,1”-biferrocene (Ph-TRAP) and an efficient method for its production. The 2,2”-bis[1-(diphenylphosphino)ethyl]-1,1”-biferrocene (Ph-TRAP) is a diphosphine compound useful as an aromatic asymmetric hydrogenation ligand, but difficult to synthesize and / or isolate and purify. Background Technology

[0002] Optically active cyclic compounds are extremely important as pharmaceuticals, pesticides, functional materials, fragrances, and synthetic intermediates; therefore, research and development on their manufacturing methods are actively underway. Among these methods, the catalytic asymmetric hydrogenation of aromatic and heteroaromatic compounds—specifically, aromatic asymmetric hydrogenation—offers advantages such as extremely high atomic efficiency and significant waste reduction, in addition to simultaneously introducing multiple carbon centers asymmetrically into the target molecule. Therefore, aromatic asymmetric hydrogenation is not only useful as a method for manufacturing optically active cyclic compounds, but also, from the perspective of the currently popular SDGs and green chemistry, has become one of the most important catalytic reactions.

[0003] For the practical application of this aromatic asymmetric hydrogenation, an asymmetric ligand with excellent catalytic activity, asymmetric induction ability, substrate universality, and air stability is indispensable, in addition to ease of manufacture. Therefore, it has been developed intensively over the years. Among them, Kuwano et al. discovered in 2000 that 2,2”-bis[1-(diphenylphosphino)ethyl]-1,1”-bidiferrocene (commonly known as Ph-TRAP, Patent Document 1 and Non-Patent Document 1), a rare trans-chelate type diphosphine compound developed by Ito and Sawamura et al. in 1991, functions as an aromatic asymmetric hydrogenation ligand with particularly excellent substrate universality (Non-Patent Document 2).

[0004] For example, by using Ph-TRAP as an asymmetric ligand, various aromatic and heteroaromatic compounds such as naphthalenes, pyrroles, imidazoles, oxazoles, indoles, azaindoles, quinolines, and isoquinolines can be catalytically hydrogenated, thereby enabling the extremely efficient synthesis of optically active cyclic compounds (Non-Patent Literature 3-4). Against this backdrop, extensive research has been conducted on methods for synthesizing Ph-TRAP, and various methods have been reported to date (Non-Patent Literature 5-7) (For reference, the stereostructure of a typical optically active form of Ph-TRAP is shown in Equation 1 below, and a schematic diagram of the asymmetric hydrogenation of aromatic compounds using Ph-TRAP as an asymmetric ligand is shown in Equation 2 below).

[0005]

[0006] Existing technical documents

[0007] Patent documents

[0008] Patent Document 1: Japanese Patent Application Publication No. 4-283596

[0009] Non-patent literature

[0010] Non-patent document 1: Masaya Sawamura, Hitoshi Hamashima, and Yoshihiko Ito, Tetrahedron Asymmetry, 1991, 7(2), 593-596.

[0011] Non-patent document 2: Ryoichi Kuwano, Koji Sato, Takashi Kurokawa, Daisuke Karube, and Yoshihiko Ito, J.Am.Chem.Soc., 2000, 122(31), 7614-7615.

[0012] Non-patent literature 3: Ryoichi Kuwano, J.Synth.Org.Chem., Jpn., 2007, 65(2), 109-118.

[0013] Non-patent literature 4: Ryoichi Kuwano, J.Synth.Org.Chem., Jpn., 2021, 79(12), 1125-1135.

[0014] Non-patent document 5: Masaya Sawamura, Hitoshi Hamashima, Masanobu Sugawara, Ryoichi Kuwano, and Yoshihiko Ito, Organometallics, 1995, 14(10), 4549-4558.

[0015] Non-patent document 6: Ryoichi Kuwano, and Masaya Sawamura, Catalysts for FineChemical Synthesis: Vol. 5, Regio-and Stereo-Controlled Oxidations and Reductions, Wiley, Chichester, 2007, 73-86.

[0016] Non-patent literature 7: Michael A. Schmidt, Eric M. Simmons, Carolyn S. Wei, Hyunsoo Park, and Martin D. Eastgate, J. Org. Chem., 2018, 83(7), 3928-3940. Summary of the Invention

[0017] The problem the invention aims to solve

[0018] As mentioned above, Ph-TRAP is a diphosphine compound useful as an aromatic asymmetric hydrogenation ligand, and therefore, various application studies are underway. On the other hand, conventional synthetic methods (non-patent literature 5-7), as shown in Formula 3 below, have various problems. Specifically, conventional methods are indispensable for various reagents and / or solvents that are difficult to use industrially, such as mutagenic iodomethane (step 2), the preparation of complex and unstable lithium diphenylphosphine (step 3), various heavy metals such as copper, nickel, and zinc (step 4), complex treatment and / or post-treatment of trichlorosilane, and highly carcinogenic benzene (step 5). Moreover, in order to remove the by-product impurities in step 5, Ph-TRAP synthesized by this method must be purified by column chromatography based on alumina / benzene systems and recrystallization based on benzene / ethanol systems (step 6). Furthermore, its product morphology is also characterized by unstable amorphous or highly toxic benzene compounds, making it extremely difficult to manufacture Ph-TRAP industrially using conventional synthetic methods.

[0019]

[0020] This invention was made in view of the above circumstances. Specifically, from the viewpoint of the practical application and further efficiency improvement of aromatic asymmetric hydrogenation, this invention provides a novel product form of Ph-TRAP and an efficient manufacturing method thereof. More preferably, this invention provides a Ph-TRAP product form and an efficient manufacturing method thereof with the following advantages: 1) it can be easily manufactured using industrially readily available reagents and / or solvents; 2) it possesses both excellent crystallinity and air stability; 3) it is easy to separate, purify, and / or store for long periods.

[0021] Solution for solving the problem

[0022] When the inventors conceived the idea to solve the aforementioned problems, they focused on the well-known phenomenon of forming crystalline phosphine-borane complexes with excellent air stability through the reaction of phosphine compounds with borane sources. That is, if Ph-TRAP, a difficult-to-process diphosphine compound, could be derived into the unknown Ph-TRAP·(BH3)2 as a diphosphine-diborane complex, a significant improvement in its various properties could be expected. However, as shown in Formula 4 below, even if Ph-TRAP·(BH3)2 is formed by reacting the already difficult-to-synthesize Ph-TRAP with a borane source, the synthetic problems of conventional methods are not fully resolved. Therefore, at least to the knowledge of the inventors, no such attempt has been reported to date.

[0023]

[0024] In light of this background, the inventors established the following method: a method for directly producing Ph-TRAP·(BH3)2 as its diborane complex from commercially available N,N-dimethyl-1-diferroceneethylamine (commonly known as Ugiamine), without relying on the difficult-to-synthesize Ph-TRAP itself. It is also clear that in this manufacturing method, reagents and / or solvents that are difficult to use industrially, such as iodomethane, lithium diphenylphosphine, various heavy metals, trichlorosilanes, and benzene, which were problematic in conventional synthesis methods, are no longer needed. Furthermore, the novel Ph-TRAP·(BH3)2 obtained by this method exhibits excellent crystallinity and / or air stability, as anticipated, and can be easily separated and purified (for reference, a summary of the method for producing optically active Ph-TRAP·(BH3)2 is shown in Formula 5 below, but the present invention is not limited to this summary at all).

[0025]

[0026] Based on the above insights, the inventors conducted repeated and in-depth research and unexpectedly discovered that: 1) Ph-TRAP·(BH3)2 can be rapidly converted into Ph-TRAP by heating and stirring in n-butanol (n-BuOH), and 2) Ph-TRAP precipitates out as crystals simply by cooling the resulting reaction solution. Therefore, upon examining the crystals obtained from the reaction solution, a surprising discovery was made: 3) the crystals are a novel alcohol compound, Ph-TRAP·n-BuOH, which is extremely stable to air. Based on this fundamental insight, the inventors further conducted research and thus completed the present invention (for reference, a summary of the method for producing Ph-TRAP·n-BuOH is shown in Formula 6 below, but the present invention is not limited to this summary at all).

[0027] Formula 6

[0028]

[0029] That is, the present invention includes the following [1] to [9].

[0030] [1] A crystalline alcohol compound formed from 2,2”-bis[1-(diphenylphosphino)ethyl]-1,1”-biferrocene (Ph-TRAP) as shown in the following planar structural formula (1) and an alcohol as shown in the following general formula (A).

[0031]

[0032] [In the formula,

[0033] Solid lines represent single keys;

[0034] H represents a hydrogen atom, C represents a carbon atom, and P represents a phosphorus atom;

[0035] Me represents methyl, and Ph represents phenyl;

[0036] Fe represents a divalent iron ion, the pentagon containing the circle represents a cyclopentadienyl anion, and the thick line indicates that the cyclopentadienyl anion donates 6 electrons to Fe.

[0037]

[0038] [In the formula,

[0039] Solid lines represent single keys;

[0040] H represents a hydrogen atom, and O represents an oxygen atom;

[0041] R A Indicates a hydrocarbon group.

[0042] [2] According to the crystalline alcohol compound described above [1], Ph-TRAP is an optically active compound.

[0043] [3] According to the crystalline alcohol compound described in [1] or [2] above, wherein R A The group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms is selected.

[0044] [4] The crystalline alcohol compound according to any one of [1] to [3] above, wherein R A Choose the group consisting of n-propyl and n-butyl groups.

[0045] [5] The crystalline alcohol compound according to any one of [1] to [4] above, wherein the content of the alcohol represented by general formula (A) relative to the amount of substance of Ph-TRAP is selected from the range of 30 to 100 mol%.

[0046] [6] A method for manufacturing the crystalline alcohol compound described in any one of [1] to [5] above, comprising: reacting the {μ-[2,2”-bis[1-(diphenylphosphino-κP)ethyl]-1,1”-diferrocene]} hexahydrodiboron (Ph-TRAP·(BH3)2) shown in the following planar structural formula (1·(BH3)2) with the alcohol shown in the following general formula (A).

[0047]

[0048] [In the formula,

[0049] Solid lines represent single bonds, and dashed lines represent coordinate bonds;

[0050] H represents a hydrogen atom, B represents a boron atom, C represents a carbon atom, and P represents a phosphorus atom;

[0051] Me represents methyl, and Ph represents phenyl;

[0052] Fe represents a divalent iron ion, the pentagon containing the circle represents a cyclopentadienyl anion, and the thick line indicates that the cyclopentadienyl anion donates 6 electrons to Fe.

[0053]

[0054] [In the formula,

[0055] Solid lines represent single keys;

[0056] H represents a hydrogen atom, and O represents an oxygen atom;

[0057] R A Indicates a hydrocarbon group.

[0058] [7] The manufacturing method described above [6] is wherein Ph-TRAP·(BH3)2 is an optically active material.

[0059] [8] According to the manufacturing method described in [6] or [7] above, wherein R A The group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms is selected.

[0060] [9] The manufacturing method according to any one of [6] to [8] above, wherein R A Choose the group consisting of n-propyl and n-butyl groups.

[0061] The effects of the invention

[0062] Ph-TRAP (hereinafter referred to as Ph-TRAP(1)) represented by the aforementioned planar structural formula (1) and alcohols (hereinafter referred to as R) represented by the aforementioned general formula (A) AA novel crystalline alcoholy compound (hereinafter referred to as Ph-TRAP·R) is formed by OH(A) A OH(1·A)) does not undergo the difficult-to-synthesize Ph-TRAP(1) itself, but can be synthesized by reacting Ph-TRAP·(BH3)2 (hereinafter referred to as Ph-TRAP·(BH3)2(1·(BH3)2)) with R, as shown in the aforementioned planar structural formula (1·(BH3)2). A It is readily produced by reacting OH(A). Furthermore, according to a preferred embodiment of the invention, Ph-TRAP·R A OH(1·A) has completely different physical properties from Ph-TRAP(1), and has the advantages of excellent crystallinity and / or air stability, easy separation and purification and / or long-term storage. Therefore, it can help to facilitate the practical application and / or further efficiency of useful catalytic reactions in the manufacture of optically active cyclic compounds, namely aromatic asymmetric hydrogenation. Attached Figure Description

[0063] Figure 1 It is manufactured in Example 2 below (S) C ,S C ,R P ,R P Single-crystal X-ray structural analysis results of )-Ph-TRAP·n-PrOH (thermal vibration ellipsoid diagram; atomic presence probability of 50%).

[0064] Figure 2 It is manufactured in Example 3 below (S) C ,S C ,R P ,R P Single-crystal X-ray structural analysis results of )-Ph-TRAP·n-BuOH (thermal vibration ellipsoid diagram; atomic presence probability of 50%).

[0065] Figure 3 It is manufactured in Example 4 below (R) C ,R C ,S P ,S P Single-crystal X-ray structural analysis results of )-Ph-TRAP·n-BuOH (thermal vibration ellipsoid diagram; atomic presence probability of 50%).

[0066] Figure 4 This indicates that the (S) produced in large quantities in Example 6 below C ,S C ,R P ,R P A portion of )-Ph-TRAP·n-BuOH was measured in deuterated chloroform after being left in air at room temperature for 3 months. 1 H NMR (left side) and31 The mass spectrum of the P NMR results (right side). Detailed Implementation

[0067] Hereinafter, Ph-TRAP·R, which forms the basis of this invention, will be discussed. A Ph-TRAP(1) and R of OH(1·A) A OH(A) will be explained in detail in turn. First, as Ph-TRAP(1), the compound shown in the aforementioned planar structural formula (1) can be listed, namely 2,2”-bis[1-(diphenylphosphino)ethyl]-1,1”-diferrocene. It should be noted that in the aforementioned planar structural formula (1), the solid lines are single bonds, H is a hydrogen atom, C is a carbon atom, P is a phosphorus atom, Me is a methyl group, Ph is a phenyl group, Fe is a divalent iron ion, the pentagon containing the circle is a cyclopentadienyl anion, and the thick line indicates that the cyclopentadienyl anion donates 6 electrons to Fe.

[0068] Ph-TRAP(1) in this invention has two asymmetric carbon centers in its structure (hereinafter referred to as R). C and S C (representing the absolute configuration of these carbon center asymmetries) and two planar asymmetries (hereinafter referred to as R) P and S P (representing the absolute configuration of these planar asymmetries), therefore, it can be a mixture of stereoisomers resulting from these asymmetries, or a single stereoisomer, especially from the viewpoint of its application in aromatic asymmetric hydrogenation, a single stereoisomer, i.e., an optically active one, is preferred. As a preferred form of optically active Ph-TRAP(1), based on its structural requirements, specifically, the stereostructure shown in the following formula 7 (S) can be listed. C ,S C ,R P ,R P )-Ph-TRAP and (R C ,R C ,S P ,S P Ph-TRAP (It should be noted that, by convention, the carbon atom C and the hydrogen atom H on the carbon atom are omitted in the three-dimensional structural diagrams in this specification. In addition, wedge-shaped solid lines represent carbon-carbon bonds facing the front of the paper, and wedge-shaped dashed lines represent carbon-carbon bonds facing the back of the paper).

[0069]

[0070] Next, as R in this invention AOH(A) can be used to list alcohols represented by the aforementioned general formula (A). It should be noted that in the aforementioned general formula (A), solid lines represent single bonds, H represents a hydrogen atom, O represents an oxygen atom, and R... A Indicates a hydrocarbon group. As R... A The hydrocarbon group in R can typically be listed as a straight-chain, branched, or cyclic hydrocarbon group, and preferably as a group selected from the group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms, and more preferably as an alkyl group having 3 to 4 carbon atoms. A Preferred specific examples of the hydrocarbon group in the form include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, from Ph-TRAP·R A From the viewpoint of the crystallinity of OH(I·A), n-propyl and n-butyl are particularly preferred examples. As R in this invention... A Specific examples of particularly preferred OH(A) include n-propanol (n-PrOH) and n-butanol (n-BuOH).

[0071] Ph-TRAP·R in this invention A The preferred method for OH(1·A), from the same viewpoint as Ph-TRAP(1) that forms this alcohol, specifically, can be listed as (S C ,S C ,R P ,R P )-Ph-TRAP·R A OH and (R) C ,R C ,S P ,S P )-Ph-TRAP·R A OH.

[0072] It should be noted that Ph-TRAP·R A R in OH(1·A) A The content of OH(A) depends on R. A Chemical structure of OH(A) and Ph-TRAP·R A The separation and purification method of OH(1·A) is used, but the amount of Ph-TRAP(1) is usually appropriately selected from the range of 10 to 200 mol%, preferably from 20 to 150 mol%, and more preferably from 30 to 100 mol%.

[0073] Ph-TRAP·R in this invention A A particularly preferred example of OH(1·A) is, specifically, that which is shown in the three-dimensional structural formula in the following formula 8 (S C,S C ,R P ,R P )-Ph-TRAP·n-PrOH、(R C ,R C ,S P ,S P )-Ph-TRAP·n-PrOH、(S C ,S C ,R P ,R P )-Ph-TRAP·n-BuOH and (R C ,R C ,S P ,S P )-Ph-TRAP·n-BuOH.

[0074]

[0075] Next, regarding Ph-TRAP·R in this invention... A The method for manufacturing OH(I·A) (hereinafter referred to as the manufacturing method of the present invention) will be described. Ph-TRAP·R A In principle, OH(1·A) can be produced by reacting Ph-TRAP(1) with R. A Ph-TRAP(1) is generated by mixing OH(A), but since Ph-TRAP(1) itself is difficult to synthesize, it is preferred in practical applications to synthesize it by mixing Ph-TRAP·(BH3)2(1·(BH3)2) with R. A It is produced by the reaction of OH(A), and the specific method is explained in detail below.

[0076] Ph-TRAP·(BH3)2(1·(BH3)2) in the manufacturing method of the present invention can be exemplified by the compound shown in the aforementioned planar structural formula (1·(BH3)2), namely {μ-[2,2”-bis[1-(diphenylphosphino-κP)ethyl]-1,1”-ferrocene]}hexahydrodiboron. It should be noted that in the aforementioned planar structural formula (1·(BH3)2), solid lines represent single bonds, dashed lines represent coordinate bonds, H represents a hydrogen atom, B represents a boron atom, C represents a carbon atom, P represents a phosphorus atom, Me represents a methyl group, Ph represents a phenyl group, Fe represents a divalent iron ion, the pentagon containing the circle represents a cyclopentadienyl anion, and the thick line indicates that the cyclopentadienyl anion donates 6 electrons to Fe.

[0077] Compared with the aforementioned Ph-TRAP·R ASimilarly, especially from the viewpoint of its application in aromatic asymmetric hydrogenation, Ph-TRAP·(BH3)2(1·(BH3)2) in the manufacturing method of the present invention is preferably a single stereoisomer, i.e., an optically active one. As a particularly preferred form of the optically active Ph-TRAP·(BH3)2(1·(BH3)2), from the perspective of its structural requirements, specifically, examples of stereoisomers shown in Formula 9 (S) can be listed. C ,S C ,R P ,R P )-Ph-TRAP·(BH3)2 and (R C ,R C ,S P ,S P Ph-TRAP·(BH3)2. In the manufacturing method of the present invention, by using these optically active Ph-TRAP·(BH3)2 (1·(BH3)2) as initial raw materials, it is possible to easily distinguish and manufacture Ph-TRAP·R as an optically active material. A The preferred method of OH(1·A) described above (S) C ,S C ,R P ,R P )-Ph-TRAP·R A OH and (R) C ,R C ,S P ,S P )-Ph-TRAP·R A OH.

[0078] Formula 9

[0079]

[0080] The synthesis method of Ph-TRAP·(BH3)2(1·(BH3)2) used in the manufacturing method of the present invention is not particularly limited, but in practical terms, a method that does not involve the difficult-to-synthesize Ph-TRAP(1) itself is preferred, specifically exemplified in the following Formula 10. That is, Ph-TRAP·(BH3)2(1·(BH3)2) can be easily synthesized with good reproducibility by using commercially available N,N-dimethyl-1-diferroceneethylamine (commonly known as: Ugiamine) as a starting material, and by lithiumization and bromination (step 1), phosphation (step 2), reaction with a borane source (step 3), reaction with a magnesium source (step 4), reaction with an oxidant (step 5), and, as needed, reacting the borane source. In addition, in this synthesis method, by using Ugiamine as an optically active agent, it is possible to easily distinguish the foregoing (S) of the particularly preferred method for manufacturing the optically active Ph-TRAP·(BH3)2(1·(BH3)2). C ,S C ,R P ,R P )-Ph-TRAP·(BH3)2 and (R C ,R C ,S P ,S P )-Ph-TRAP·(BH3)2.

[0081] Formula 10

[0082]

[0083] The reaction solution obtained in step 5 of the aforementioned synthesis method can be post-processed as needed to separate Ph-TRAP·(BH3)2(1·(BH3)2) from the reaction solution and further purified. Specifically, post-processing methods include washing the reaction solution, extraction of the aqueous layer, and drying / filtration / concentration of the organic layer; these methods can be performed individually or in combination. Separation methods include crystallization of the reaction solution and filtration / washing / drying of crude crystals; these methods can be performed individually or in combination. Purification methods include dissolution of crude crystals, adsorbent-based decolorization, column chromatography, recrystallization, and filtration / washing / drying of purified crystals; these methods can be performed individually or in combination.

[0084] Furthermore, when using Ph-TRAP·(BH3)2(1·(BH3)2) in the manufacturing method of the present invention, the reaction solution obtained by step 5 of the aforementioned synthesis method can be used directly, or it can be used after the aforementioned post-processing, separation, and purification as needed. On the other hand, in order to more efficiently manufacture the target Ph-TRAP·R APreferably, the reaction solution obtained by step 5 of the aforementioned synthesis method is used in the manufacturing method of the present invention without separating and purifying Ph-TRAP·(BH3)2(1·(BH3)2) after post-treatment as needed.

[0085] Next, R, used as the manufacturing method of the present invention A OH(A) can be used to list alcohols represented by the aforementioned general formula (A). It should be noted that in the aforementioned general formula (A), solid lines represent single bonds, H represents a hydrogen atom, O represents an oxygen atom, and R... A Indicates a hydrocarbon group. As R... A The hydrocarbon group in R can typically be listed as a straight-chain, branched, or cyclic hydrocarbon group, and preferably as a group selected from the group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms, and more preferably as an alkyl group having 3 to 4 carbon atoms. A Preferred specific examples of the hydrocarbon group in Ph-TRAP·R include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, from which Ph-TRAP·R is targeted. A From the viewpoint of the crystallinity of OH(I·A), n-propyl and n-butyl are particularly preferred examples. R is used in the manufacturing method of this invention. A Specific examples of particularly preferred OH(A) include n-propanol (n-PrOH) and n-butanol (n-BuOH).

[0086] Hereinafter, in order to explain the manufacturing method of the present invention in more detail, Ph-TRAP·(BH3)2(1·(BH3)2) and R A The reaction mechanism of OH(A) is shown in Equation 11 below.

[0087]

[0088] Based on this reaction mechanism, it can be known that R used in the manufacturing method of this invention... A Theoretically, OH(A) must be at least 7 equivalents relative to Ph-TRAP·(BH3)2(1·(BH3)2), therefore, it is preferable to use it not only as a reactant but also as a solvent. R as the solvent... A Although the amount of OH(A) depends on its chemical structure, it is usually appropriately selected from 1 to 200 times the weight of Ph-TRAP·(BH3)2, preferably from 2 to 100 times the weight, and more preferably from 3 to 50 times the weight.

[0089] In addition, Ph-TRAP·(BH3)2(1·(BH3)2) was reacted with R without purification. AWhen OH(A) reacts, the solvent in the reaction solution prepared by step 5 of the aforementioned synthesis method or the residual solvent contained in the crude product of Ph-TRAP·(BH3)2(1·(BH3)2) can coexist. As such a coexisting solvent, it is acceptable as long as it does not impair the reaction between Ph-TRAP·(BH3)2(1·(BH3)2) and R... A The reaction of OH(A) and R A OH(A) does not have any particular limitation on the solvation of Ph-TRAP(1) generated by this reaction. Chloroform, tetrahydrofuran, toluene and water are particularly preferred coexisting solvents.

[0090] To suppress the oxidative decomposition of Ph-TRAP(1) in solution at high temperatures, the manufacturing method of the present invention is preferably carried out under an inert gas atmosphere. Specifically, argon and nitrogen are examples of inert gases, with nitrogen being a preferred example. The reaction temperature is typically selected within a range of 0°C to 220°C, preferably from 40°C to 180°C, and more preferably from 80°C to 140°C. To control the reaction temperature, the manufacturing method of the present invention can be carried out under any conditions, including reduced pressure, normal pressure, or pressurized pressure; however, due to its ease of operation, it is preferred to be carried out under normal pressure. The reaction time depends on R, which acts as both a reactant and a solvent. A The chemical structure and amount of OH(A), reaction temperature and pressure, are typically selected within a range of 5 minutes to 48 hours, preferably from 10 minutes to 24 hours, and more preferably from 15 minutes to 12 hours.

[0091] The reaction solution obtained by the manufacturing method of the present invention can be post-processed as needed, and the target Ph-TRAP·R can be separated from the reaction solution. A OH(1·A) is reacted and further purified. Post-treatment methods include washing the reaction solution, extraction of the aqueous layer, and drying / filtration / concentration of the organic layer; these methods can be performed individually or in combination. Separation methods include crystallization of the reaction solution and filtration / washing / drying of crude crystals; these methods can be performed individually or in combination. Purification methods include dissolution of crude crystals, adsorbent-based decolorization, column chromatography, recrystallization, and filtration / washing / drying of purified crystals; these methods can be performed individually or in combination.

[0092] Additionally, when using Ph-TRAP·R AWhen OH(I·A) is used as an aromatic asymmetric hydrogenation ligand, the reaction solution obtained by the manufacturing method of the present invention can be used directly, or it can be used after the aforementioned post-treatment, separation, and purification as needed. On the other hand, according to a preferred embodiment of the present invention, Ph-TRAP·R... A OH(1·A) has excellent crystallinity and air stability, and can be stored for a long time. Therefore, from the viewpoint of making full use of these properties, it is preferable to separate it from the reaction solution in the form of crystals and then use it as an aromatic asymmetric hydrogenation ligand.

[0093] Through this invention, Ph-TRAP(1), which is difficult to synthesize and / or isolate and purify, can be synthesized as an alcoholysis with excellent crystallinity and / or air stability, namely Ph-TRAP·R A The OH(1·A) form is easily prepared, and therefore, it is expected to be useful in the production of optically active cyclic compounds, namely the practical application and further efficiency of aromatic asymmetric hydrogenation.

[0094] Example

[0095] Hereinafter, Ph-TRAP·R in this invention will be discussed. A The manufacture of OH(I·A) and its various stability tests are described in detail with specific examples, but the present invention is not limited to these examples at all. Furthermore, unless otherwise specified, the addition of substrates and solvents, etc., is carried out under a nitrogen gas flow, the reaction is carried out under a nitrogen atmosphere, and post-treatment, separation, and purification are carried out in air. It should be noted that, in the examples, the apparatus used for property determination and the determination / analysis conditions are as follows.

[0096] 1) Proton nuclear magnetic resonance spectroscopy ( 1 H NMR): 400MR DD2 type device (resonance frequency 400MHz; manufactured by Agilent Technologies)

[0097] 2) Carbon-13 nuclear magnetic resonance spectroscopy ( 13 C NMR): 400MR DD2 type device (resonance frequency 100MHz; manufactured by Agilent Technologies)

[0098] 3) Phosphorus-31 nuclear magnetic resonance spectroscopy ( 31 P NMR): 400MR DD2 type device (resonance frequency 161MHz; manufactured by Agilent Technologies)

[0099] 4) Single-crystal X-ray structural analysis: XtaLAB Synergy-S type device (manufactured by Rigaku Oxford Diffraction)

[0100] [Measurement / Analysis Conditions] X-ray source: CuKα rays; Device control program: CrysAlis PRO Structural analysis software: Olex 2 1.3-ac4, Structural analysis program: SHELXS·SHELXL-2018 / 3, Drawing software: Mercury 4.3.0.

[0101] [Example 1] (S) C ,S C ,R P ,R P Manufacturing of Ph-TRAP (BH3)2 (Formula 12)

[0102]

[0103] Step 1: (S) C ,R P )-1-bromo-2-[1-(dimethylamino)ethyl]ferrocene ((S C ,R P Synthesis of Br-Ugiamine

[0104] [Feeding / Reaction] Add (S) to a 200mL four-necked round-bottom flask. C )-N,N-dimethyl-1-diferroceneethylamine((S C 8.7 g (33.9 mmol, 1.0 equivalent) of 1-Ugiamine was added to the flask. A magnetic stir bar, dropping funnel, thermometer, and three-way stopcock were installed, and the flask was purged with nitrogen. Anhydrous cyclopentyl methyl ether (CPME; 51 mL) was added to the flask, and the resulting orange-red solution was stirred while cooling to -20°C using a dry ice-acetone bath. Next, a pentane solution of tert-butyllithium (t-BuLi) (1.70 mol / L, 21.9 mL, 37.3 mmol, 1.1 equivalent) was added dropwise over 30 minutes at a rate maintained below -15°C. The resulting orange slurry was stirred at -20°C for 2 hours, and then anhydrous tetrahydrofuran (THF; 10 mL) was added. Next, 1,2-dibromoethane (DBE; 3.4 mL, 39.5 mmol, 1.17 equivalent) and dehydrated THF (7 mL) were added to the dropping funnel in sequence. The reaction mixture was stirred while the addition was carried out dropwise over 30 minutes at an internal temperature maintained below -15°C. The mixture was then stirred at -20°C for 1 hour.

[0105] [Post-processing] The resulting orange-yellow reaction solution was heated to room temperature, tap water (20 mL) was added and stirred, and then allowed to stand to separate the aqueous layer. Next, the organic layer was washed twice with tap water (20 mL), and then concentrated and dried using a rotary evaporator under reduced pressure, thus obtaining 11.3 g of the target (S) as a dark brown solid. C ,R P Crude product of )-Br-Ugi amine. Purity: 90.1 mol%. It should be noted that the target analyte contains (S) as a major impurity. C ,S P )-Br-Ugi amine and unreacted (S C It was obtained as a crude product of )-Ugiamine, but it was not further purified and was used directly in subsequent processes.

[0106] 1 H NMR (400MHz, CDCl3): δ=4.46 (dd, J=1.6, 2.4Hz, 1H), 4.16 (s, 5H), 4.14 (dt, J=0.4, 2.8Hz, 1H) ,4.10(ddd,J=0.4,1.6,2.8Hz,1H),3.75(q,J=7.2Hz,1H),2.13(s,6H),1.52(d,J=7.2Hz,3H).

[0107] 13 C NMR (100MHz, CDCl3): δ=87.38, 79.80, 71.21, 69.82, 65.68, 65.19, 56.07, 41.15, 16.80.

[0108] Step 2: (S) C ,R P )-1-bromo-2-[1-(diphenylphosphino)ethyl]ferrocene ((S C ,R P Synthesis of )-Ph-PEF-Br)

[0109] [Feeding / Reaction] Add all of the (S) synthesized in step 1 to a 200 mL four-necked round-bottom flask. C ,R PCrude Br-Ugi amine (purity: 90.1 mol%, 11.3 g, <33.9 mmol, 1.0 equivalent) was prepared by equipping the flask with a magnetic stir bar, a Demroth condenser, a thermometer, and a three-way stopcock, and purging the interior with nitrogen. Degassed toluene (14 mL), degassed acetic acid (13.6 mL, 237.3 mmol, 7.0 equivalent), and diphenylphosphine (Ph2PH; 5.9 mL, 33.9 mmol, 1.0 equivalent) were added sequentially to the flask. The resulting dark brown solution was heated in an oil bath at 130 °C while stirring under reflux for 6 hours.

[0110] [Post-processing] After cooling the obtained reaction solution to 40°C, degassed toluene (70 mL) and degassed water (28 mL) were added sequentially. The mixture was stirred at 40°C for 30 minutes, then allowed to stand. The aqueous layer was removed under a nitrogen atmosphere. Next, the organic layer was washed twice with degassed water (56 mL) at 40°C under a nitrogen atmosphere. A Kjeldahl distillation apparatus was installed in the reaction vessel, and the organic layer was concentrated and dried while stirring at 60°C and slowly reducing the pressure to 15 Torr. Subsequently, by using nitrogen to bring the internal pressure of the apparatus to atmospheric pressure, the target (S) was obtained in a dark brown amorphous form. C ,R P The crude product of )-Ph-PEF-Br (<33.9 mmol). This compound decomposes slowly in air, therefore, it is not removed from the reaction vessel under a nitrogen atmosphere, but is used directly as a crude product in subsequent processes.

[0111] 31 P NMR [161MHz, CDCl3]: δ = 7.55 (s, 1P).

[0112] Step 3: {(S C ,R P )-1-bromo-2-[1-(diphenylphosphino-κP)ethyl]ferrocene}trihydroboron((S C ,R P Synthesis of )-Ph-PEF-Br·BH3

[0113] [Feeding / Reaction] In this step, the Kreutz distillation apparatus is removed from the reaction vessel used in step 2 and replaced with a dropping funnel. First, the (S) in the reaction vessel synthesized in step 2 is... C ,R PThe crude product of )-Ph-PEF-Br (<33.9 mmol, 1.0 equivalent) was added sequentially with dehydrated THF (34 mL) and sodium borohydride (NaBH4; 1.54 g, 40.7 mmol, 1.2 equivalent). Next, degassed acetic acid (2.3 mL, 40.7 mmol, 1.2 equivalent) and dehydrated THF (9.2 mL) were added sequentially to a dropping funnel while stirring the suspension in the reaction vessel. The addition was carried out dropwise over 5 minutes at a rate maintained below 40°C (bubbling was observed during the addition). The resulting reaction solution was stirred at 40°C for 30 minutes, and then heated in an oil bath at 80°C while stirring under reflux for 3 hours.

[0114] [Post-treatment / Separation / Purification] After the obtained reaction solution was naturally cooled to room temperature while stirring, a mixed solvent of methanol (68 mL) and tap water (34 mL) was added to a dropping funnel over 15 minutes (vigorous bubbling was observed at the beginning of the addition). The resulting orange slurry was cooled to 0°C in an ice-water bath and filtered using a Kiriyama funnel. The filtered crude crystals were washed with a mixed solvent of methanol (34 mL) and tap water (8.5 mL). Toluene (90 mL) and tap water (45 mL) were added sequentially to the wet crude crystals (approximately 18 g), and the mixture was stirred at 40°C. The organic and aqueous layers were filtered together using a Kiriyama funnel and then allowed to stand to separate the aqueous layer. After dehydrating / decolorizing the organic layer with silica gel, it was concentrated and dried under reduced pressure using a rotary evaporator. The resulting residue was recrystallized from toluene and n-heptane, thereby yielding 12.9 g of the target (S) as an air-stable orange powder. C ,R P )-Ph-PEF-Br·BH3. From (S C The overall yield, starting with )-Ugi amine, was 77.5%. It should be noted that in this reaction, (S)-Ugi amine, used in step 2, was generated. C ,R P Impurities in )-Br-Ugi amine can cause various byproducts, but all of them can be easily removed by recrystallization.

[0115] 1H NMR (400MHz, CDCl3): δ=8.02-7.93(m,2H),7.63-7.53(m,3H),7.33-7.27(m,1H),7.17-7.03(m,4H),4.49(t,J=1.6Hz,1H),4.28(dd,J=1 .6,2.4Hz,1H),4.21(dt,J=0.4,2.4Hz,1H),4.18(s,5H),3.68(dq,J=16.4,7.2Hz,1H),1.66(dd,J=7.2,16.4Hz,3H),1.42-0.30(br,3H).

[0116] 13 C NMR (100MHz, CDCl3): δ=133.46(d,J P-C =8.4Hz), 133.06(d,J P-C =8.5Hz), 131.61(d,J P-C =2.5Hz), 130.64(d,J P-C =2.5Hz), 128.91(d,J P-C =9.3Hz), 128.15(d,J P-C =54.0Hz), 127.70(d,J P-C =10.2Hz), 127.00(d,J P-C =51.5Hz), 86.81(d,J P-C =4.2Hz),80.86(s),70.99(s),68.96(s),66.44(s),66.23(s),29.22(d,J P-C =30.4Hz), 17.39(d,J P-C =5.1Hz).

[0117] 31 P NMR (161MHz, CDCl3): δ = 26.37 (br, 1P).

[0118] Step 4 / Step 5: Preparation of Grignard reagent / (S C ,S C ,R P ,R P Synthesis of )-Ph-TRAP·(BH3)2

[0119] [Feeding / Reaction] Magnesium (109 mg, 4.48 mmol, 1.1 equivalence) was added to a 50 mL four-necked round-bottom flask. A magnetic stir bar, dropping funnel, Demrod condenser, and three-way stopcock were installed, and the flask was purged with nitrogen. Dehydrated THF (550 μL) and iodine (5.2 mg, 0.5 mol%) were added sequentially to the flask, and the mixture was stirred gently at room temperature for 15 minutes. The resulting white suspension was then supplemented with the (S) synthesized in step 3. C ,R P After adding 8 mL of dehydrated THF solution of α-Ph-PEF-Br·BH3 (2.0 g, 4.07 mmol, 1.0 equivalent), the mixture was heated in an oil bath at 80 °C and stirred under reflux for 1 hour to obtain a THF solution of the target Grignard reagent (<4.07 mmol) as a deep red liquid. Next, 15 mL of dehydrated toluene solution of ferric acetylacetone (Fe(acac)3; 1.51 g, 4.27 mmol, 1.05 equivalent) was added dropwise to a dropping funnel under reflux for 2 minutes while stirring the reaction mixture. Then, the mixture was heated in an oil bath at 100 °C and stirred under reflux for 30 minutes.

[0120] [Post-treatment / Separation / Purification] After cooling the reaction solution to room temperature, a THF solution of the borane-tetrahydrofuran complex (BH3·THF; 1.10 mol / L, 925 μL, 1.02 mmol, 0.25 equivalents) was added under a nitrogen atmosphere, and the mixture was stirred for 5 minutes at room temperature. Next, hydrochloric acid (20 mL, 20.0 mmol, 4.9 equivalents) was added, and the mixture was stirred at room temperature and allowed to stand to separate the aqueous layer. The resulting organic layer was washed twice with tap water (10 mL), dehydrated / decolorized using silica gel, and concentrated and dried under reduced pressure using a rotary evaporator. The residue was recrystallized from chloroform and n-hexane, thereby yielding 1.49 g of the target (S) as an air-stable orange powder. C ,S C ,R P ,R P Ph-TRAP (BH3)2. Purity: 85.7% by weight (main impurity is chloroform), from (S) C ,R P Overall yield starting from Ph-PEF-Br·BH3: 76.3%.

[0121] 1H NMR (400MHz, CD2Cl2): δ=7.86-7.76(m,4H),7.61-7.54(m,2H),7.53-7.46(m,4H),7.41-7.34(m,2H),7.32(s,1.15H[CHCl3]),7.28-7.13(m,8H), 4.42-4.36(m,2H),4.34(s,10H),4.09(t,J=2.4Hz,2H),4.07-3.91(br,2 H),3.90-3.72(br,2H),1.74(dd,J=7.2,16.4Hz,6H),1.50-0.40(br,6H).

[0122] 13 C NMR (100MHz, CD2Cl2): δ=134.07(d,J P-C =8.4Hz), 132.63(d,J P-C =8.5Hz), 131.58(d,J P-C =2.5Hz), 130.62(d,J P-C =1.6Hz), 129.61(d,J P-C =51.4Hz), 128.81(d,J P-C =9.3Hz), 128.45(d,J P-C =9.2Hz), 128.00(d,J P-C =51.4Hz), 90.09(s), 84.24(d,J) P-C =4.2Hz),77.60(s[CHCl3]),71.41(s),69.71(s),68.63(s),65.90(s),28.91(d,J P-C =31.2Hz), 20.88(d,J P-C =3.4Hz).

[0123] 31 P NMR (161MHz, CD2Cl2): δ = 25.73 (br, 2P).

[0124] [Example 2] (S) C ,S C ,R P ,R P Preparation of )-Ph-TRAP·n-PrOH (Formula 13)

[0125] Formula 13

[0126]

[0127] [Feeding / Reaction] Add the (S) prepared in Example 1 to a 50 mL two-necked round-bottom flask. C ,S C ,R P ,R P Ph-TRAP·(BH3)2 (purity: 85.7 wt%, 1.14 g, 1.19 mmol, 1.0 equivalent) was prepared, and a magnetic stir bar, a Demroth condenser, and a three-way stopcock were installed. The interior was purged with nitrogen. Anhydrous n-propanol (n-PrOH; bp. 97 °C, 34 mL, 30 times the volume) was added to the flask as an alcohol. The resulting mixture was heated in an oil bath at 110 °C while stirring under reflux for 3 hours.

[0128] [Post-processing / Separation] The reaction solution was cooled to 60°C and stirred for 30 minutes under a nitrogen atmosphere. The resulting orange slurry was cooled to 0°C in an ice-water bath and then filtered using a Kiriyama funnel. The filtered crystals were washed once with dehydrated n-PrOH (11 mL), heated to 60°C under reduced pressure of 1 Torr, and dried for 1 hour. This yielded 912 mg of the target (S) as an air-stable orange powder. C ,S C ,R P ,R P Ph-TRAP·n-PrOH. Purity based on Ph-TRAP: 96.8 wt%, n-PrOH content relative to Ph-TRAP: 44 mol%, separation yield: 93.4%. It should be noted that (S... C ,S C ,R P ,R P Single crystals of )-Ph-TRAP·n-PrOH can be prepared by a cooling method using n-PrOH as a solvent.

[0129] 1 H NMR (400MHz, CD2Cl2): δ=7.32-7.13(m,20H),4.59(dd,J=1.2,2.4Hz,2H),4.30(s,10H),4.17(t,J=2.4Hz,2H),3.81(dd,J=1.2,2.4Hz,2H),3.55(t ,J=6.4Hz,0.88H[n-PrOH]),3.52(q,J=7.2Hz,2H),1.51(sextet,J=7.2Hz,0.88H[n-PrOH]),1.39-1.31(m,6H),0.92(t,J=7.2Hz,1.32H[n-PrOH]).

[0130] 31P NMR (161MHz, CD2Cl2): δ = 0.72 (s, 2P).

[0131] The (S) manufactured in Example 2 C ,S C ,R P ,R P The single-crystal X-ray structural analysis results (thermal vibration ellipsoid diagram; atomic presence probability of 50%) of )-Ph-TRAP·n-PrOH are shown below. Figure 1 Based on this result, it can be clearly stated that: 1) the absolute configuration of this alcohol is indeed (S... C ,S C ,R P ,R P ), 2) In single crystals, relative to Ph-TRAP, there is 1 molecule, or 100 mol%, of n-PrOH solvated. Additionally, the main parameters ensuring the accuracy of this analytical result are shown below; Chemical formula: C 51 H 52 Fe2OP2, crystal system: cubic, space group: P212121(#19), lattice constant: α=β=γ=90°, Reliability factor (R1): 0.0402, Weighted reliability factor (wR2): 0.0873, Goodness of fit (GOF): 1.052, Flack parameter: -0.016(3).

[0132] [Example 3] (S) C ,S C ,R P ,R P Preparation of )-Ph-TRAP·n-BuOH (Formula 14)

[0133] Formula 14

[0134]

[0135] [Feeding / Reaction] Add the separately synthesized (S) according to the steps described in Example 1 to a 50 mL two-necked round-bottom flask. C ,S C ,R P ,R PPh-TRAP·(BH3)2 (purity: 86.8% by weight, 2.50 g, 2.64 mmol, 1.0 equivalent) was prepared, and a magnetic stir bar, a Demroth condenser, and a three-way stopcock were installed. The interior was purged with nitrogen. Dehydrated n-butanol (n-BuOH; bp. 117 °C, 25 mL, 10 times the volume) was added to the flask as an alcohol. The resulting mixture was heated in an oil bath at 130 °C while stirring under reflux for 2 hours.

[0136] [Separation] The reaction solution was cooled to 80°C and stirred for 30 minutes under a nitrogen atmosphere. The resulting orange slurry was cooled to 0°C in an ice-water bath and then filtered using a Kiriyama funnel. The filtered crystals were washed three times with dehydrating n-BuOH (5 mL) and dried at room temperature for 1 hour under a gentle nitrogen flow. Thus, 2.13 g of the target (S) was obtained as an air-stable orange powder. C ,S C ,R P ,R P Ph-TRAP·n-BuOH. Purity based on Ph-TRAP: 92.9 wt%, n-BuOH content relative to Ph-TRAP: 82 mol%, separation yield: 94.3%. It should be noted that (S... C ,S C ,R P ,R P Single crystals of )-Ph-TRAP·n-BuOH can be prepared by a cooling method using n-BuOH as a solvent.

[0137] 1 H NMR (400MHz, CDCl3): δ = 7.32-7.09 (m, 20H), 4.56 (dd, J = 1.2, 2.4Hz, 2H), 4.30 (s, 10H), 4.12 (t, J = 2.4Hz, 2H), 3.79 (br, 2H), 3.65 (t, J = 6.4Hz, 1.6 4H[n-BuOH]), 3.49(q,J=7.2Hz,2H), 1.60-1.52(m,1.64H[n-BuOH]), 1.45-1.31(m,7.64H[Ph-TRAP+n-BuOH]), 0.94(t,J=7.2Hz, 2.46H[n-BuOH]).

[0138] 31 P NMR (161MHz, CDCl3): δ=1.34 (s, 2P).

[0139] The (S) manufactured in Example 3 C ,S C ,R P,R P The single-crystal X-ray structural analysis results (thermal vibration ellipsoid diagram; atomic presence probability of 50%) of )-Ph-TRAP·n-BuOH are shown below. Figure 2 Based on this result, it can be clearly stated that: 1) the absolute configuration of this alcohol is indeed (S... C ,S C ,R P ,R P ), 2) In single crystals, relative to Ph-TRAP, there is 1 molecule, or 100 mol%, of n-BuOH solvated. Additionally, the main parameters ensuring the accuracy of this analytical result are shown below; Chemical formula: C 52 H 54 Fe2OP2, crystal system: cubic, space group: P212121(#19), lattice constant: α=β=γ=90°, R1: 0.0492, wR2: 0.1022, GOF: 1.048, Flack parameter: -0.009(3).

[0140] [Example 4] (R) C ,R C ,S P ,S P Preparation of )-Ph-TRAP·n-BuOH (Formula 15)

[0141] Formula 15

[0142]

[0143] By using (Rc)-Ugiamine as a starting material and following the steps described in Example 1, 2.29 g of the target (R)-Ugiamine was obtained as an air-stable orange powder. C ,R C ,S P ,S P Ph-TRAP (BH3)2. Purity: 86.7% by weight (main impurity is chloroform). 2.0g of this product was reacted with n-BuOH according to the steps described in Example 3, followed by crystallization. The filtered crystals were heated to 60°C under reduced pressure of 1 Torr and dried for 1 hour, thereby obtaining 1.60g of the target (R) as an air-stable orange powder. C ,R P ,S P ,S PPh-TRAP·n-BuOH. Purity based on Ph-TRAP: 93.8 wt%, n-BuOH content relative to Ph-TRAP: 71 mol%, separation yield: 89.6%. It should be noted that the NMR analysis results of this ethanol compound, except for the difference in n-BuOH content, are similar to those of the (S) compound prepared in Example 3. C ,S C ,R P ,R P The analytical results for )-Ph-TRAP·n-BuOH were equivalent. Furthermore, (R C ,R C ,S P ,S P Single crystals of )-Ph-TRAP·n-BuOH can be prepared by a cooling method using n-BuOH as a solvent.

[0144] The (R) manufactured in Example 4 C ,R C ,S P ,S P The single-crystal X-ray structural analysis results (thermal vibration ellipsoid diagram; atomic presence probability of 50%) of )-Ph-TRAP·n-BuOH are shown below. Figure 3 Based on this result, it can be clearly stated that this alcohol compound is similar to the one prepared in Example 3 (S). C ,S C ,R P ,R P The mirror image of )-Ph-TRAP·n-BuOH is indistinguishable. Furthermore, the key parameters ensuring the accuracy of this analytical result are shown below; Chemical formula: C 52 H 54 Fe2OP2, crystal system: cubic, space group: P212121(#19), lattice constant: α=β=γ=90°, R1: 0.0453, wR2: 0.0911, GOF: 1.045, Flack parameter: -0.013(3).

[0145] Based on the results of Examples 3 and 4, it is clear that the optically active R in this invention... P -TRAP·R A The preferred method for OH(1·A), namely (S C ,S C ,R P ,R P )-Ph-TRAP·R A OH and (R) C ,R C ,S P ,S P)-Ph-TRAP·R A OH can be easily differentiated and manufactured using Ph-TRAP·(BH3)2(1·(BH3)2) synthesized from optically active Ugiamine as a starting material.

[0146] [Example 5] (S) C ,S C ,R P ,R P Thermal stability test of )-Ph-TRAP·n-BuOH

[0147] The (S) manufactured in Example 3 C ,S C ,R P ,R P Ph-TRAP·n-BuOH (n-BuOH content: 82 mol% relative to Ph-TRAP) were measured in approximately 100 mg portions into Schlenk tubes, heated for 1 hour at specified temperature and pressure, cooled to room temperature, and the appearance was checked. Then, the mixture was subjected to deuterated chloroform. 1 The content of n-BuOH was determined by ¹H NMR. The results are summarized in Table 1 below (it should be noted that, for reference, (S... C ,S C ,R P ,R P The content of n-BuOH in single crystals of )-Ph-TRAP·n-BuOH is set as entry No.1 and recorded together.

[0148] [Table 1]

[0149]

[0150] Based on the results summarized in Table 1, it can be clearly stated that: 1)(S C ,S C ,R P ,R P 1) Ph-TRAP·n-BuOH is a crystalline alcohol compound with efflorescence properties (entries No. 1-2); 2) By heating under reduced pressure, efflorescence is promoted, and n-BuOH is lost from crystallization (entries No. 3-10); 3) If efflorescence continues and the content of n-BuOH decreases to less than 20 mol%, the crystal system is destroyed and amorphization occurs (entry No. 10); 4) On the other hand, the content of n-BuOH relative to (S C ,S C ,R P ,R P Ph-TRAP exists stably in crystalline form when the amount of substance is at least 34 to 100 mol%. (Nos. 1 to 9)

[0151] [Example 6] Using (S) C ,S C ,R P ,R P To produce (S) from a crude product solution of )-Ph-TRAP·(BH3)2. C ,S C ,R P ,R P )-Ph-TRAP·n-BuOH (Equation 16)

[0152] Formula 16

[0153]

[0154] [Feeding / Reaction (1)] This process is carried out by setting the reaction scale to 5 times according to the steps described in steps 4-5 of Example 1. That is, magnesium metal (520 mg, 21.4 mmol, 1.05 mol) is added to a 300 mL four-necked round-bottom flask, a magnetic stir bar, a dropping funnel, a Demorothal condenser, and a three-way stopcock are installed, and the interior is purged with nitrogen. Dehydrated THF (2.6 mL) and iodine (26 mg, 0.5 mol%) are added to the flask in sequence, and the mixture is slowly stirred at room temperature for 15 minutes. The resulting white suspension is then mixed with (S) prepared separately according to the steps described in steps 1-3 of Example 1. C ,R P After adding 40 mL of dehydrated THF to a solution of 10.0 g, 20.4 mmol, and 1.0 equivalent of Fe(acac)3-Ph-PEF-Br·BH3, the mixture was stirred under reflux for 1 hour while heated in an oil bath at 80 °C, thus obtaining a solution of the target Grignard reagent (<20.4 mmol) as a deep red liquid. Next, 76 mL of dehydrated toluene to a dropping funnel was added dropwise over 2 minutes while stirring the reaction mixture under reflux, followed by stirring under reflux for 30 minutes while heated in an oil bath at 100 °C.

[0155] [Post-processing] The resulting reaction solution was cooled to 40°C, and then degassed hydrochloric acid (51 mL, 102.0 mmol, 5.0 equivalents) was added. The mixture was stirred at 40°C for 15 minutes, allowed to stand, and the aqueous layer was removed under a nitrogen atmosphere. Next, the organic layer was washed twice with degassed water (50 mL) to obtain the target (S) as a red liquid. C ,S C ,R P ,R PA crude product solution of )-Ph-TRAP·(BH3)2 (<10.2 mmol) was obtained. This crude product solution contained, as a byproduct, (S) as a diphosphine-monoborane complex. C ,S C ,R P ,R P Ph-TRAP·BH3 is used directly in subsequent processes instead of being removed from the reaction vessel under a nitrogen atmosphere.

[0156] [Feeding / Reaction (2)] relative to (S) C ,S C ,R P ,R P A crude product solution of )-Ph-TRAP·(BH3)2 (<10.2 mmol, 1.0 equivalent) was added to a degassed n-BuOH (80 mL) as an alcohol, and a Kjeldahl distillation apparatus was installed in the reaction vessel. The reaction mixture was then heated in an oil bath at 130 °C under a nitrogen atmosphere and distilled at atmospheric pressure to recover approximately 150 mL of solvent. The resulting concentrated reaction mixture was then heated in an oil bath at 130 °C under reflux and stirred for 1 hour.

[0157] [Post-processing / Separation / Purification] The reaction concentrate was cooled to 80°C and stirred for 30 minutes under a nitrogen atmosphere. The resulting orange slurry was cooled to 0°C in an ice-water bath and then filtered using a Kiriyama funnel under a nitrogen flow. The filtered crystals were washed four times with degassed n-BuOH (10 mL) cooled to 0°C, then heated to 60°C under reduced pressure of 1 Torr and dried for 3 hours. This yielded 6.70 g of the target (S) as an air-stable orange powder. C ,S C ,R P ,R P Ph-TRAP·n-BuOH. Purity as Ph-TRAP: 92.8 wt%, n-BuOH content relative to Ph-TRAP: 73 mol%, (S) C ,R P The overall yield, starting with )-Ph-PEF-Br·BH3, is 76.7%. It should be noted that the yield of (S) produced by this method... C ,S C ,R P ,R P The NMR analysis results of )-Ph-TRAP·n-BuOH were identical to those obtained in Example 3, except for the difference in the content of n-BuOH.

[0158] The (S) mass-produced in Example 6 C ,SC ,R P ,R P Approximately 10 mg of )-Ph-TRAP·n-BuOH was measured into a glass tube, sealed with cotton, and left in air at room temperature for 3 months. Visual inspection and NMR analysis results were obtained, and both yielded results equivalent to those immediately after manufacturing. It should be noted that the following... Figure 4 The figure shows the concentration of Ph-TRAP·n-BuOH in deuterated chloroform after being exposed to air at room temperature for 3 months. 1 H NMR (left side) and 31 p NMR mass spectrum (right side).

[0159] The results of Example 6 clearly demonstrate that: the optically active Ph-TRAP·R A A particularly preferred mode for OH(1·A), namely (S C ,S C ,R P ,R P )-Ph-TRAP·n-BuOH can be obtained by using (S) as a precursor. C ,S C ,R P ,R P It is efficiently manufactured by reacting n-BuOH with )-Ph-TRAP·(BH3)2 for separation and purification, and it does not decompose even when left in air at room temperature for a long time, making it an extremely stable crystalline alcohol.

[0160] Industrial availability

[0161] Ph-TRAP·R in this invention A OH(1·A) is produced without the difficult-to-synthesize and / or isolate and purify Ph-TRAP(1) itself, by reacting Ph-TRAP·(BH3)2(1·(BH3)2) with R. A It can be easily produced by reacting OH(A). Furthermore, according to a preferred embodiment of the invention, Ph-TRAP·R A OH(1·A) has the advantages of excellent crystallinity and / or air stability, easy separation and purification and / or long-term storage, and therefore can help to facilitate the practical application and / or further efficiency of useful catalytic reactions in the manufacture of optically active cyclic compounds, namely aromatic asymmetric hydrogenation.

Claims

1. A crystalline alcohol compound formed from 2,2”-bis[1-(diphenylphosphino)ethyl]-1,1”-ferrocene (Ph-TRAP) as shown in the following planar structural formula (1) and an alcohol as shown in the following general formula (A), In equation (1), Solid lines represent single keys; H represents a hydrogen atom, C represents a carbon atom, and P represents a phosphorus atom; Me represents methyl, and Ph represents phenyl; Fe represents a divalent iron ion, the pentagon containing the circle represents a cyclopentadienyl anion, and the thick line indicates that the cyclopentadienyl anion donates 6 electrons to Fe. In formula (A), Solid lines represent single keys; H represents a hydrogen atom, and O represents an oxygen atom; R A It indicates a hydrocarbon group.

2. The crystalline alcohol compound according to claim 1, wherein, Ph-TRAP is an optically active organism.

3. The crystalline alcohol compound according to claim 2, wherein, R A The group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms is selected.

4. The crystalline alcohol compound according to claim 3, wherein, R A Choose the group consisting of n-propyl and n-butyl groups.

5. The crystalline alcohol compound according to claim 4, wherein, The alcohol content represented by the general formula (A) is selected from the range of 30 to 100 mol% relative to Ph-TRAP.

6. A method for producing the crystalline alcohol compound according to any one of claims 1 to 5, comprising: The planar structural formula (1·(BH3)2) shown below, {μ-[2,2”-bis[1-(diphenylphosphino-κP)ethyl]-1,1”-ferrocene]} hexahydrodiboron (Ph-TRAP·(BH3)2), is reacted with an alcohol shown below, which is represented by the general formula (A). In formula (1·(BH3)2), Solid lines represent single bonds, and dashed lines represent coordinate bonds; H represents a hydrogen atom, B represents a boron atom, C represents a carbon atom, and P represents a phosphorus atom; Me represents methyl, and Ph represents phenyl; Fe represents a divalent iron ion, the pentagon containing the circle represents a cyclopentadienyl anion, and the thick line indicates that the cyclopentadienyl anion donates 6 electrons to Fe. In formula (A), Solid lines represent single keys; H represents a hydrogen atom, and O represents an oxygen atom; R A It indicates a hydrocarbon group.

7. The manufacturing method according to claim 6, wherein, Ph-TRAP·(BH3)2 is an optically active form.

8. The manufacturing method according to claim 7, wherein, R A The group consisting of alkyl groups having 1 to 6 carbon atoms and cycloalkyl groups having 3 to 6 carbon atoms is selected.

9. The manufacturing method according to claim 8, wherein, R A Choose the group consisting of n-propyl and n-butyl groups.

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