Organic catalyst

Abstract

The present invention aims to provide a novel organic catalyst. [Solution] A compound represented by general formula (1) and a method for using the compound as an organic catalyst are provided. TIFF2026166000000016.tif32170 (In formula (1), R 1 , and R 2 These are identical or different, each representing an alkyl group or an aryl group, and R 3 (where * represents a hydrogen atom or a silyl protecting group, and * represents a chiral carbon atom.)

Description

[Technical Field]

[0001] This invention relates to an organic catalyst. [Background technology]

[0002] Non-Patent Document 1 discloses the preparation of β,β-diaryl β-Hydroxy-α-Amino Acids and the evaluation of their organocatalytic activity. Non-Patent Document 1 discloses the synthesis of β,β-diaryl β-hydroxy-α-amino acids by Parikh-Doering oxidation and subsequent Pinnick oxidation, starting from oxazolidine esters and Grignard reagents, and further discloses the evaluation of the organocatalytic activity of β,β-diaryl β-hydroxy-α-amino acids in relation to the enantioselectivity of the asymmetric fluorination of 2-phenylpropionaldehyde.

[0003] Non-patent document 2 discloses the development and optimization of the chemical reaction of LY503430, a potential therapeutic agent for Parkinson's disease, and its subsequent preparation under GMP. Non-patent document 2 discloses the replacement of chiral chromatography with a diastereomeric salt resolution and the preferred orientation of LY503430 that complicates XRPD analysis.

[0004] Non-patent document 3 discloses that N,N-dialkyl-β-amino alcohols were enantiospecifically and regioselectively rearranged using N,N-diethylaminosulfur trifluoride (DAST) to prepare optically active β-fluoroamines. Non-patent document 3 also discloses that this rearrangement was applied to the enantioselective synthesis of LY503430, a potential therapeutic agent for Parkinson's disease. [Prior art documents] [Non-patent literature]

[0005] Non-Patent Document 1 Asian J. Org. Chem. 2020, 9, 238-241 Non-Patent Document 2 Organic Process Research & Development 2005, 9, 621-628 Non-Patent Document 3 ORGANIC LETTERS 2010, Vol. 12, No. 20, 4620-4623 Summary of the Invention Problem to be Solved by the Invention

[0006] An object of the present invention is to newly provide an organic catalyst. Means for Solving the Problem

[0007] The present inventors have newly developed organic catalysts. Based on such findings, the present inventors have further conducted extensive research and have finally completed the present invention.

[0008] The present invention encompasses the following organic catalysts.

[0009] Item 1. A compound represented by General Formula (1). [Chemical Formula] In Formula (1), R 1 and R 2 are identical or different, and each independently represents an alkyl group or an aryl group. In Formula (1), R 3 represents a hydrogen atom or a silyl-based protecting group. In Formula (1), * represents an asymmetric carbon atom.

[0010] Item 2. In the aforementioned General Formula (1), R 1 , and R 2 They are the same or different, each being, Alkyl alkyl groups selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or 1-ethylpropyl; or An aryl group selected from the group consisting of phenyl, biphenyl, and / or naphthyl, wherein the aryl group may have one or more substituents (alkyl, alkoxy, etc.); R 3 teeth, Hydrogen atom; or, A silyl protecting group selected from the group consisting of trimethylsilyl group (TMS), triethylsilyl group (TES), tert-butyldimethylsilyl group (TBS), triisopropylsilyl group (TIPS), and tert-butyldiphenylsilyl group (TBDPS); The compound described in item 1 above.

[0011] Section 3. A method for using the compound represented by general formula (1) described in item 1 or 2 above as an organic catalyst.

[0012] Section 4. The method of use according to item 3, wherein the organic catalyst is an organic catalyst used in a fluorination reaction of the α-position of a 2-arylpropionaldehyde compound and / or a 2-arylpropionic acid compound using a fluorinating agent.

[0013] Section 5. A method for producing a fluorinated 2-arylpropionaldehyde compound and / or a fluorinated 2-arylpropionic acid compound by using a compound represented by general formula (1) as described in item 1 or 2 above, and a fluorinating agent to carry out a fluorination reaction at the α-position of the 2-arylpropionaldehyde compound and / or a 2-arylpropionic acid compound.

[0014] A method for producing a fluorinated alcohol compound or an amine compound by subjecting a fluorinated 2-arylpropionaldehyde compound and / or a fluorinated 2-arylpropionic acid compound obtained by the manufacturing method described in item 5 above to a reduction reaction or an amination reaction.

[0015] The organocatalyst of the present invention can be used to introduce fluorine at the α-position of, for example, 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds with high enantioselectivity (fluorination reaction of the α-position of 2-arylpropionic acid). The organocatalyst of the present invention can be used to prepare compounds in which the α-position of, for example, 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds is fluorinated with high enantioselectivity. [Effects of the Invention]

[0016] This invention can provide a novel organic catalyst. [Brief explanation of the drawing]

[0017] [Figure 1] Figure 1 shows the NMR spectrum of the intermediate in the production of the compound (organocatalyst) represented by general formula (1). [Figure 2] Figure 2 shows the NMR spectrum of intermediate 4 in the production of the compound (organocatalyst) represented by general formula (1). [Figure 3] Figure 3 shows the NMR spectrum of the organic catalyst (C9) produced during the manufacturing of the compound represented by general formula (1). [Modes for carrying out the invention]

[0018] The present invention will be described in detail below. The embodiments illustrating the present invention are intended to provide a better understanding of the spirit of the invention and do not limit the scope of the invention unless otherwise specified.

[0019] In the present specification, "include" and "contain" are concepts that encompass all of "comprise", "consist essentially of", and "consist of".

[0020] In the present specification, when a numerical range is indicated as "A to B", it means a numerical range of "A or more and B or less".

[0021] In the present specification, when indications such as "part" and "%" are generally used, these represent mass parts, weight parts, mass% (mass%), or weight% (wt%).

[0022] [1] Organic catalyst The compound of the present invention is represented by general formula (1).

Chemical Formula

[0023] In formula (1), * represents an asymmetric carbon atom.

[0024] In formula (1), R 1 and R 2 are identical or different, and each independently represents an alkyl group or an aryl group.

[0025] In formula (1), R 1 and R 2 are identical or different, and each independently preferably represents an alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and 1-ethylpropyl.

[0026] In formula (1), R 1 and R 2 are identical or different, and each independently preferably represents an aryl group selected from the group consisting of phenyl, biphenyl, and naphthyl. The aryl group may have one or more substituents. The substituent is preferably a substituent such as an alkyl group or an alkoxy group.

[0027] In formula (1), R 3 This represents a hydrogen atom or a silyl protecting group.

[0028] In equation (1), R 3 Preferably, this represents a hydrogen atom.

[0029] In equation (1), R 3 Preferably, this represents a silyl protecting group selected from the group consisting of trimethylsilyl group (TMS), triethylsilyl group (TES), tert-butyldimethylsilyl group (TBS), triisopropylsilyl group (TIPS), and tert-butyldiphenylsilyl group (TBDPS).

[0030] Conventional synthesis methods, for example, when introducing fluorine with high enantioselectivity at the α-position of 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds, have limitations on the range of substrates that can be used in the reaction, and require large amounts of catalyst (10 mol%-20 mol% of catalyst relative to the substrate). Therefore, it was necessary to overcome these challenges for practical application.

[0031] The compound represented by general formula (1) of the present invention (organocatalyst) can introduce fluorine into a substrate with high enantioselectivity by using a fluorinating agent in conjunction with it. Using the organic catalyst of the present invention, for example, fluorine can be introduced with high enantioselectivity to the α position of 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds (fluorination reaction of the α position of 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds) (90% ee or higher).

[0032] The organic catalyst of the present invention makes it possible to prepare compounds in which the α-position of, for example, 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds is fluorinated with high enantioselectivity. Using the organic catalyst of the present invention, fluorinated 2-arylpropionic acids corresponding to compounds having the chemical structure formula of 2-arylpropionic acid (specifically, physiologically active substances such as ibuprofen) can be efficiently synthesized with high enantioselectivity using a fluorinating agent.

[0033] The organic catalyst of the present invention is highly reactive, and even with a small amount of catalyst added, such as 1 mol%, it is possible to sufficiently advance the catalytic reaction.

[0034] The organic catalyst of the present invention can greatly contribute to the research and development of novel pharmaceuticals, drug discovery, and other related fields.

[0035] [2] Fluorination reaction using an organic catalyst The compound represented by general formula (1) of the present invention can preferably be used as an organocatalyst.

[0036] By using the compound represented by general formula (1) of the present invention (organocatalyst), a fluorinating agent can also be used to carry out a fluorination reaction at the α-position of the 2-arylpropionaldehyde compound and / or 2-arylpropionic acid compound, thereby producing a fluorinated 2-arylpropionaldehyde compound and / or fluorinated 2-arylpropionic acid compound.

[0037] The compound represented by general formula (1) of the present invention (organocatalyst) can, when used in conjunction with a fluorinating agent, introduce fluorine into a substrate with high enantioselectivity (fluorination reaction at the α-position of 2-arylpropionic acid). Using the organic catalyst of the present invention, for example, fluorine can be introduced at the α-position of 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds with high enantioselectivity (fluorination reaction at the α-position of 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds) (90% ee or higher).

[0038] The organic catalyst of the present invention makes it possible to prepare compounds in which the α-position of, for example, 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds is fluorinated with high enantioselectivity. Using the organic catalyst of the present invention, fluorinated 2-arylpropionic acids corresponding to compounds having the chemical structure formula of 2-arylpropionic acid (specifically, physiologically active substances such as ibuprofen) can be efficiently synthesized with high enantioselectivity using a fluorinating agent.

[0039] [2-1] Raw material compound (substrate) By using the compound represented by general formula (1) of the present invention (organocatalyst), a fluorinating agent can also be used to carry out a fluorination reaction at the α-position of the 2-arylpropionaldehyde compound and / or 2-arylpropionic acid compound (starting compound) to produce a fluorinated 2-arylpropionaldehyde compound and / or fluorinated 2-arylpropionic acid compound.

[0040] In the production method of the present invention, by using the compound represented by the general formula (1) of the present invention (organic catalyst) when carrying out the fluorination reaction, it is possible to produce a compound in which the α-position of the starting compound is fluorinated in high yield and with high enantioselectivity.

[0041] [2-2] Organic solvents (toluene, etc.) The organic solvent is preferably at least one organic solvent selected from the group consisting of nitrile solvents, nitro solvents, alcohol solvents, halogen solvents, ether solvents, amide solvents, ester solvents, hydrocarbon solvents, and aromatic solvents.

[0042] The nitrile solvent is preferably acetonitrile (ACN, MeCN), acrylonitrile, etc.

[0043] The nitro-based solvent is preferably nitromethane, nitroethane, nitropropane, etc.

[0044] The alcohol-based solvent is preferably methanol (MeOH), hexafluoroisopropanol (HFIP), trifluoromethanol, pentafluoroethanol, etc.

[0045] The halogenated solvent is preferably dichloromethane (DCM, CH2Cl2), trichloromethane (CHCl3), etc.

[0046] The ether-based solvents are preferably tetrahydrofuran (THF), diethyl ether (Et2O), methyl tert-butyl ether (t-BuOMe), dioxane, isopropyl ether (IPE), etc.

[0047] The amide solvent is preferably N,N-dimethylformamide (DMF) or the like.

[0048] The ester solvent is preferably ethyl acetate (AcOEt) or the like.

[0049] The hydrocarbon solvent is preferably n-hexane or the like.

[0050] The aromatic solvent is preferably toluene or the like.

[0051] The amount of organic solvent used in the fluorination reaction is adjusted so that the concentration of the substrate compound (M (mol / L)) is preferably 0.005 M to 5 M, more preferably 0.05 M to 2 M.

[0052] In the production method of the present invention, by using the compound represented by the general formula (1) of the present invention (organic catalyst) when carrying out the fluorination reaction, and by using an organic solvent in conjunction, it is possible to produce a compound in which the α-position of the starting compound is fluorinated in high yield and with high enantioselectivity.

[0053] [2-3] Organocatalysts (compounds represented by general formula (1)) In the fluorination reaction, the amount of compound represented by general formula (1) (organocatalyst) used is preferably 1 mol% to 50 mol%, more preferably 10 mol% to 40 mol%, and even more preferably 10 mol% to 25 mol%, in terms of molar ratio relative to the compound in the substrate (when the substrate is 100 mol%).

[0054] In the production method of the present invention, by using the compound represented by the general formula (1) of the present invention (organic catalyst) when carrying out the fluorination reaction, it is possible to produce a compound in which the α-position of the starting compound is fluorinated in high yield and with high enantioselectivity.

[0055] [2-4] Fluorinating agents (NFSI, etc.) The fluorinating agent is preferably at least one fluorinating agent selected from the group consisting of N-fluorobenzenesulfonimide (NFSI), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate) (Selectfluor(R)), 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, 2,6-dichloro-1-fluoropyridinium tetrafluoroborate, and 2,6-dichloro-1-fluoropyridinium triflate, more preferably N-fluorobenzenesulfonimide (NFSI) or 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate), and particularly preferably 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate).

[0056] 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate) (Selectfluor(R)) has the following structure:

[0057] [ka]

[0058] The amount of fluorinating agent used in the fluorination reaction is preferably 0.1 to 20 equivalents, more preferably 0.9 to 5 equivalents, and even more preferably 1 to 3 equivalents, in molar ratio relative to the substrate compound (when the substrate is considered to be 1 equivalent).

[0059] In the production method of the present invention, by using the compound represented by the general formula (1) of the present invention (organic catalyst) when carrying out the fluorination reaction, and by using a fluorinating agent in conjunction with it, it is possible to produce a compound in which the α-position of the compound is fluorinated in high yield and with high enantioselectivity.

[0060] [2-5] Acidic compounds (TFA etc.) The acidic compound is preferably at least one acidic compound selected from the group consisting of trifluoroacetic acid (TFA), trifluoromethanesulfonic acid (TfOH), sulfuric acid (H2SO4), acetic acid (AcOH), and formic acid (HCOOH).

[0061] The amount of acidic compound used in the fluorination reaction is preferably 1 mol% to 100 mol%, more preferably 5 mol% to 50 mol%, and even more preferably 10 mol% to 30 mol%, in terms of molar ratio, as the amount used in the organic solvent (when the total amount of the organic solvent is considered to be 100 mol%).

[0062] In the production method of the present invention, by using a compound represented by the general formula (1) of the present invention (organic catalyst) when carrying out the fluorination reaction, and by using an acidic compound in conjunction, it is possible to produce a compound in which the α-position of the compound is fluorinated in high yield and with high enantioselectivity.

[0063] [2-6] Steps to fluorinate the α-position of the substrate. According to the manufacturing method of the present invention, a compound in which the α-position of a substrate (raw material compound) is fluorinated can be produced from a substrate (raw material compound) with high yield (74% to 99% yield) and high enantioselectivity (75% ee to 95% ee).

[0064] The reaction temperature for the fluorination reaction step is preferably 0°C to 90°C, preferably 0°C to 60°C, and more preferably 10°C to 35°C (room temperature, etc.).

[0065] The reaction time for the fluorination reaction step is preferably 0.5 hours to 70 hours, preferably 10 hours to 60 hours, and more preferably 20 hours to 50 hours.

[0066] [2-7]Target compound Fluorinated compounds can be obtained by the manufacturing method of the present invention.

[0067] The organic catalyst of the present invention, when used in conjunction with a fluorinating agent, can introduce fluorine into a substrate with high enantioselectivity. Using the organic catalyst of the present invention, it is possible to introduce fluorine to the α-position of, for example, 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds with high enantioselectivity (fluorination reaction of the α-position of 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds) with a smaller amount of catalyst (approximately 1 mol% to 3 mol%) compared to conventional organic catalysts (90% ee or higher).

[0068] The organic catalyst of the present invention makes it possible to prepare compounds in which the α-position of, for example, 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds is fluorinated with high enantioselectivity. Using the organic catalyst of the present invention, fluorinated 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds corresponding to compounds having the chemical structural formula of, for example, 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds (specifically, physiologically active substances such as ibuprofen) can be efficiently synthesized with high enantioselectivity using a fluorinating agent.

[0069] [3] Examples of applications of fluorination reactions using organic catalysts The present invention includes a method for producing fluorinated 2-arylpropionaldehyde compounds and / or fluorinated 2-arylpropionic acid compounds by using a compound represented by the general formula (1) of the present invention and a fluorinating agent to carry out a fluorination reaction at the α-position of a 2-arylpropionaldehyde compound and / or 2-arylpropionic acid compound.

[0070] The present invention includes a method for producing a fluorinated alcohol compound or an amine compound by subjecting a fluorinated 2-arylpropionaldehyde compound and / or a fluorinated 2-arylpropionic acid compound obtained by the above-mentioned production method to a reduction reaction or an amination reaction.

[0071] The organic catalyst of the present invention makes it possible to prepare compounds in which the α-position of, for example, 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds is fluorinated with high enantioselectivity. Furthermore, the obtained fluorinated aldehyde compounds can be converted to corresponding alcohol compounds and amine compounds, and through subsequent reactions, they can also be converted to important synthetic intermediates of (R)-4'-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide.

[0072] Although embodiments of the present invention have been described above, the present invention is not limited in any way to these examples. Naturally, the present invention can be implemented in various forms without departing from the spirit of the invention. [Examples]

[0073] The embodiments of the present invention will be described in more detail below based on the examples. The present invention is not limited to these embodiments.

[0074] [1] Example of organocatalyst production (diamine catalyst) [ka]

[0075] (Step 1) Compound 1 was synthesized from L-serine according to the protocol (Asian J. Org. Chem., 2020, 9, 238.). To a solution of Compound 1 (2.41 g, 6.37 mmol, 1.0 equivalent) in dry DCM (25.5 mL, 0.25 M), Et3N (4.44 mL, 31.9 mmol, 5.0 equivalents) and tosyl chloride (2.93 g, 15.4 mmol, 2.4 equivalents) were added under an argon atmosphere at 0°C, and the entire reaction mixture was stirred at room temperature. After confirming that the starting material 1 was completely consumed by TLC, the reaction was cooled to 0°C, stopped with H2O, and extracted with DCM. The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography to obtain Compound 2 in 97% yield.

[0076] White solid. [α] 26 D = -47.0° (c = 0.3, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.63-7.61 (2H, m), 7.42-7.36 (4H, m), 7.30-7.26 (5H, m), 7.24-7.18 (8H, m), 5.38 (1H, d, J = 8.2 Hz), 4.99 (2H, s), 4.86-4.82 (1H, m), 4.17 (2H, d, J = 8.2 Hz), 3.73 (1H, s), 2.40 (3H, s); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 156.3, 144.9, 144.0, 143.6, 136.1, 132.2, 129.8, 128.7, 128.5, 128.4, 128.0, 127.9, 127.6, 127.3, 127.2, 125.3, 124.9, 80.0, 69.7, 66.9, 56.1, 21.6; HRMS (ESI / QTOF) m / z: [M+Na] + Calcd for C 30 H 29O6NNaS 554.1608; Found 554.1604; Melting Point = 136-138 ℃.

[0077] (Step 2) To a solution of compound 2 (1.0 equivalent) in dry dioxane (1.0 M), piperidine (10.0 equivalents) was added at room temperature under an argon atmosphere, and the entire reaction mixture was stirred at 90°C. After confirming that the starting material 2 had been completely consumed by TLC, the reaction was stopped with saturated NaHCO3 and extracted by DCM. The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography to obtain compound 3 in 81% yield.

[0078] Colorless oil. [α] 24 D = -33.1° (c = 0.94, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 7.58-7.56 (2H, m), 7.48-7.46 (2H, m), 7.31-7.27 (6H, m), 7.25-7.13 (5H, m), 5.57 (1H, d, J = 7.9 Hz), 5.05 (2H, q, J = 13.4 Hz), 4.73-4.71 (1H, m), 2.79 (1H, dd, J = 14.2 Hz, J = 2.4 Hz), 2.53-2.49 (3H, m), 2.06-2.00 (2H, m), 1.57-1.52 (5H, m), 1.38 (2H, br); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 156.0, 146.6, 144.9, 136.6, 128.4, 128.2, 127.9, 127.5 (overlapping two carbons), 126.7, 126.6, 125.12, 125.07, 81.0, 66.5, 58.8, 56.3, 54.7, 26.2, 23.6; HRMS (ESI / QTOF) m / z: [M+H] + Calcd for C 28 H33 O3N2445.2486; Found 445.2478.

[0079] (Step 3) To a solution of compound 3 (1.27 g, 2.28 mmol, 1.0 equivalent) in dried CH3CN (4.6 mL, 0.5 M), 2,6-lutidine (1.33 mL, 11.42 mmol, 5.0 equivalents) and tert-butyldimethylsilyltrifluoromethanesulfonate (2.10 mL, 9.14 mmol, 4.0 equivalents) were added at 0°C under an argon atmosphere, and the entire reaction mixture was stirred at room temperature. After confirming that the starting material 3 had been completely consumed by TLC, the reaction was stopped with saturated Na2CO3 and extracted with CHCl3. The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography to obtain compound 4 in 93% yield.

[0080] The NMR analysis of compound 4 is complex due to the presence of rotational isomers in the carbamate moiety. The NMR analysis of compound 4 was performed after deprotection of Cbz.

[0081] (Step 4) To a solution of compound 4 (1.30 g, 2.33 mmol, 1.0 equivalent) in MeOH (11.7 mL, 0.2 M), 10%-Pd / C (116.5 mg, approximately 50 mg per 1.0 mmol of compound 4) was added. The entire mixture was stirred at room temperature under an H2 atmosphere, and TLC confirmed that the starting material 4 was completely consumed. The mixture was passed through Celite, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography (elution at DCM / MeOH = 20 / 1 to 5 / 1) yielded C9 (a compound represented by general formula (1), an organocatalyst) as a white powder in 99% yield.

[0082] [α] 27 D = -36.1° (c = 0.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.49-7.47 (2H, m), 7.36-7.34 (2H, m), 7.31-7.23 (6H, m), 3.69 (1H, dd,J = 1.9 Hz, J = 10.4 Hz), 2.51 (2H, broad s), 2.43 (1H, d, J= 12.4 Hz), 2.18 (2H, m), 1.70-1.46 (7H, m), 1.41-1.36 (2H, m), 0.96 (9H, s), -0.37 (3H, s), -0.38 (3H, s); 13 C{ 1 H} NMR (100 MHz, CDCl3) δ 144.3, 143.8, 128.8, 128.7, 127.7, 127.2, 127.1, 126.9, 83.2, 61.3, 55.3, 54.1, 26.4, 26.2, 24.5, 19.1, -3.1; HRMS (ESI / QTOF) m / z: [M+H] + Calcd for C 26 H 41 N2OSi 425.2983; Found 425.2977; Melting Point = 75-76 ℃.

[0083] [2] Examples of fluorination reactions

Chem.

[0084]

Table 1

[0085] a: Determined by TLC monitoring the consumption of 1a. b: Determined by 19 F NMR of the crude reaction mixture using fluorobenzene as an internal standard. c: Determined by HPLC equipped with Daicel Chiralpak, IA-3, after the reduction to the alcohol. d: at 0℃. e: The value in the parentheses is the isolated yield of the alcohol.

[0086] By using the organic catalyst of the example, it was possible to introduce fluorine at the α-position of the 2-arylpropionaldehyde compound with high enantioselectivity (fluorination reaction of the α-position of the 2-arylpropionaldehyde compound).

[0087] [3] Examples of substrates for fluorination reactions [ka]

[0088] a: The reaction time was determined by TLC monitoring the consumption of 1. b: The values ​​in the parentheses are the isolated yield of the corresponding alcohol 3 after reduction. c: C9 (2.0 mol%) and A2 (2.2 mol%) were used. d: CH3CN (1.0 M) was used. e: C9 (3.0 mol%) and A2 (3.3 mol%) were used.

[0089] By using the organic catalyst of the example, it was possible to introduce fluorine at the α-position of the 2-arylpropionaldehyde compound with high enantioselectivity (fluorination reaction of the α-position of the 2-arylpropionaldehyde compound).

[0090] [4] Examples of solvents for fluorination reactions [ka]

[0091] [Table 2]

[0092] a: The reaction time was determined by monitoring the consumption of 1a by TLC. b: Determined by 19F NMR of the crude reaction mixture using fluorobenzene as an internal standard, and the values ​​in the parentheses are the isolated yield. c: Determined by HPLC equipped with Daicel Chiralpak, IA-3, after the reduction to the alcohol 3a.

[0093] By using the organic catalyst of the example, it was possible to introduce fluorine at the α-position of the 2-arylpropionaldehyde compound with high enantioselectivity (fluorination reaction of the α-position of the 2-arylpropionaldehyde compound).

[0094] [5] Examples of acids in fluorination reactions [ka]

[0095] [Table 3]

[0096] a: The reaction time was determined by monitoring the consumption of 1a by TLC. b: Determined by 19F NMR of the crude reaction mixture using fluorobenzene as an internal standard, and the values ​​in the parentheses are the isolated yield. c: Determined by HPLC equipped with Daicel Chiralpak, IA-3, after the reduction to the alcohol 3a.

[0097] By using the organic catalyst of the example, it was possible to introduce fluorine at the α-position of the 2-arylpropionaldehyde compound with high enantioselectivity (fluorination reaction of the α-position of the 2-arylpropionaldehyde compound).

[0098] [6] Synthesis of fluorinated NSAIDs (Fluorination of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)) [ka]

[0099] a: the values ​​in the parentheses are 19 F NMR yield of 2. b: The values ​​of ee were determined after 4 was converted to the amide 5. c: ent-C9 (2.0 mol%), A2 (2.2 mol%). (d) isolated as the Et3N complex.

[0100] Fluorinated NSAIDs (2-arylpropionaldehyde compounds) were fluorinated, followed by Pinnick oxidation (oxidation of aldehydes to carboxylic acids under mild conditions) to produce fluorinated NSAIDs.

[0101] By using the organic catalyst described in the example, it was possible to introduce fluorine to the α-position of NSAIDs with high enantioselectivity (fluorination reaction of the α-position of 2-arylpropionaldehyde compounds).

[0102] [7] Synthesis of fluorinated repalixin (Fluorination of reparixin) [ka]

[0103] Fluorinated reparixin (F-reparixin) was produced by fluorinating aldehyde 1t (a 2-arylpropionaldehyde compound) and then reacting it with a sulfonamide via Pinick oxidation.

[0104] By using the organic catalyst of the example, it was possible to introduce fluorine at the α-position of reparixin with high enantioselectivity (fluorination reaction of the α-position of the 2-arylpropionaldehyde compound).

[0105] Formal synthesis of [8](R)-4'-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide [ka]

[0106] (Step 1) In the presence of catalyst C9, aldehyde 1e (2-arylpropionaldehyde compound) was fluorinated, and then (Step 2) the fluorinated aldehyde was reduced by reaction with NaBH4 to the corresponding fluorinated alcohol 3e.

[0107] By using the organic catalyst described in the example, it was possible to introduce fluorine at the α-position of aldehyde 1e with high enantioselectivity (fluorination reaction of the α-position of 2-arylpropionaldehyde compounds).

[0108] Next, fluorinated alcohol 3e was converted to tosylated compound 5 of 3e by reaction with tosyl chloride. Subsequently, tosylated compound 5 was converted to compound 6 by reaction with potassium phthalimide. Subsequently, compound 6 was converted to an amino group by (step 1) reaction with methylamine, and (step 2) reaction with isopropylsulfonyl chloride to produce an important synthetic intermediate 7 of (R)-4'-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide (LY503430).

[0109] This intermediate 7 can be used to produce (R)-4'-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide (LY503430) according to the protocol (Org. Process Res. Dev. 2005, 9, 621-628). By using the organocatalyst in the examples, the important synthetic intermediate 7 of (R)-4'-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide (LY503430) was synthesized with high enantioselectivity. [Industrial applicability]

[0110] The present invention provides a method for enantioselectively introducing fluorine using an organic molecular catalyst and a fluorinating agent. The organic catalyst of the present invention, when used in conjunction with a fluorinating agent, can introduce fluorine into a substrate with high enantioselectivity. Using the organic catalyst of the present invention, it is possible to introduce fluorine with high enantioselectivity to the α position of, for example, 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds (fluorination reaction of the α position of 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds) with a smaller amount of catalyst (approximately 1 mol% to 3 mol%) compared to conventional organic catalysts (90% ee or higher).

[0111] The organic catalyst of the present invention makes it possible to prepare compounds in which the α-position of, for example, 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds is fluorinated with high enantioselectivity. Using the organic catalyst of the present invention, fluorinated 2-arylpropionic acids corresponding to compounds having the chemical structure formula of 2-arylpropionic acid (specifically, physiologically active substances such as ibuprofen) can be efficiently synthesized with high enantioselectivity using a fluorinating agent.

[0112] The organic catalyst of the present invention makes it possible to prepare compounds in which the α-position of, for example, 2-arylpropionaldehyde compounds and / or 2-arylpropionic acid compounds is fluorinated with high enantioselectivity. Furthermore, the obtained fluorinated aldehyde compounds can be converted to corresponding alcohol compounds and amine compounds, and through subsequent reactions, they can also be converted to important synthetic intermediates of (R)-4'-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide.

Claims

1. A compound represented by general formula (1). 【Chemistry 1】 (In formula (1), R 1 , and R 2 These represent, either identically or differently, an alkyl group or an aryl group, respectively. In formula (1), R 3 This represents a hydrogen atom or a silyl protecting group. In formula (1), * represents a chiral carbon atom.

2. In the above general formula (1), R 1 , and R 2 They are the same or different, each being, Alkyl alkyl groups selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or 1-ethylpropyl; or, An aryl group selected from the group consisting of phenyl, biphenyl, and / or naphthyl, wherein the aryl group may have one or more substituents; R 3 teeth, Hydrogen atom; or, A silyl protecting group selected from the group consisting of trimethylsilyl group (TMS), triethylsilyl group (TES), tert-butyldimethylsilyl group (TBS), triisopropylsilyl group (TIPS), and tert-butyldiphenylsilyl group (TBDPS); The compound according to claim 1.

3. A method for using the compound represented by general formula (1) as an organic catalyst, as described in claim 1 or 2.

4. The method of use according to claim 3, wherein the organic catalyst is an organic catalyst used in a fluorination reaction of the α-position of a 2-arylpropionaldehyde compound and / or a 2-arylpropionic acid compound using a fluorinating agent.

5. A method for producing a fluorinated 2-arylpropionaldehyde compound and / or a fluorinated 2-arylpropionic acid compound by carrying out a fluorination reaction at the α-position of a 2-arylpropionaldehyde compound and / or a fluorinated 2-arylpropionic acid compound using a compound represented by general formula (1) as described in claim 1 or 2 and a fluorinating agent.

6. A method for producing a fluorinated alcohol compound or an amine compound by subjecting a fluorinated 2-arylpropionaldehyde compound and / or a fluorinated 2-arylpropionic acid compound obtained by the manufacturing method described in claim 5 to a reduction reaction or an amination reaction.

Images