Synthesis and application of chiral isothiourea catalyst

Abstract

The invention discloses synthesis and application of a chiral isothiourea catalyst, and relates to the technical field of chiral chemistry and asymmetric catalytic synthesis. The method comprises the following steps: S1, starting from amino-substituted racemic cyclophane 1a, reacting with thiophosgene under the action of alkali to generate an intermediate 1b; s2, condensing the intermediate 1b with chiral amino alcohol to generate an intermediate 1c; s3, carrying out ring closing under the condition of bromine to generate an intermediate 1d; and S4: carrying out ring closing on 1d under the conditions of alkali and a carboxyl activation reagent to generate an isothiourea catalyst 1, and finally, carrying out conventional column chromatography separation to obtain chiral isothiourea catalysts with different configurations. According to the invention, planar chirality in cyclosimulation and central chirality in amino alcohol are fused to develop a series of isothiourea catalysts with dual chiral elements of planar chirality and central chirality, and the isothiourea catalysts are applied to alpha-site asymmetric fluorination of high-stability carboxylic acid compounds; the rapid and effective synthesis of the alpha-fluorocarboxylic ester compound with optical activity is realized.

Description

Technical Field

[0001] The present invention relates to the technical fields of chiral chemistry and asymmetric catalytic synthesis, and specifically to the synthesis and application of a chiral isothiourea catalyst. Background Technique

[0002] Chiral drugs have become the strategic direction and research hotspot of new drug development in the world today. They are not only widely used in the pharmaceutical field, but also commonly found in the fields of chiral material preparation, chiral pesticides, etc. In 2001 and 2021, the Nobel Prize in Chemistry was awarded to the contributors of chiral catalysis to recognize their contributions in the field of asymmetric catalysis. According to statistics, in the late 1990s of the 20th century, chiral drugs accounted for about 20% of the global best-selling drugs. With the rapid growth of the chiral drug market in recent years, as of now, the total number of drugs in the global market exceeds thousands, and the proportion of chiral drugs exceeds 50%. The market prospect of chiral drugs continues to be promising, with the annual sales growth rate of chiral drugs globally greater than 15%, and the market share in China alone exceeding 100 billion yuan.

[0003] The preparation methods of chiral drugs include extraction from natural products, resolution of racemates, and asymmetric synthesis. Among them, asymmetric synthesis is the main means to obtain chiral drugs at present. By designing and implementing asymmetric synthesis reactions, single enantiomers of chiral drugs can be directly synthesized. This method has the advantages of high efficiency and low cost, and has become the mainstream technology for chiral drug production. The most core issue in asymmetric synthesis is the development of chiral ligands and catalysts. New chiral ligands or catalysts often have high catalytic effects in asymmetric reactions. Therefore, developing new chiral ligands and catalysts using economically feasible synthetic routes can effectively expand the synthetic means of chiral drugs. In particular, isothiourea catalysts can efficiently combine with acyl compounds to form highly active intermediates and then transform into various highly enantioselective organic compounds, and have extensive applications in asymmetric synthesis chemistry.

[0004] Summarizing the isothiourea catalysts developed by chemists in recent years, they often organically combine different chiral amino alcohols and benzotetrazoles. Although the types have reached dozens, the chiral elements they contain are relatively single, usually with one or two central chiralities. When small molecule catalysts carry multiple chiral elements, better selectivity will be produced when different chiral elements match than single chiral elements. Therefore, it is necessary to develop isothiourea catalysts with multiple chiral elements.

[0005] Therefore, we propose the synthesis and application of a chiral isothiourea catalyst to solve the problems raised above.

[0006] The above information disclosed in this background technology is only used to enhance the understanding of the background technology of the present invention. Therefore, it may include prior art that is not known to those of ordinary skill in the art. Summary of the Invention

[0007] The object of the present invention is to provide a synthesis and application of a chiral isothiourea catalyst to solve the problems raised in the above background technology.

[0008] To achieve the above object, the present invention provides the following technical solution: A chiral isothiourea catalyst, the catalyst is an isothiourea catalyst containing planar chirality and central chirality, and the structure is as shown in Formula 1:

[0009]

[0010] Among them, the chirality marked with "*" is in the R configuration, S configuration or racemic, and R is independently selected from phenyl, benzyl or isopropyl respectively.

[0011] A synthesis method of a chiral isothiourea catalyst, comprising the following steps:

[0012] S1: Starting from amino-substituted racemic cyclophane 1a, reacting with thiophosgene under the action of a base to generate intermediate 1b;

[0013] S2: Intermediate 1b is further condensed with chiral amino alcohol to generate intermediate 1c;

[0014] S3: Then cyclize under the condition of bromine to generate intermediate 1d;

[0015] S4: 1d undergoes cyclization under the conditions of a base and a carboxyl activating reagent to generate the isothiourea catalyst 1, and finally different configurations of chiral isothiourea catalysts are obtained through conventional column chromatography separation.

[0016] Preferably, in S1 and S4, the base includes one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylamine, diisopropylethylamine, tetramethylethylenediamine, N,N-dimethylaniline, N,N-diethylaniline, 1,4-diazabicyclooctane (DABCO), 1,5-diazabicycloundecene (DBU).

[0017] Preferably, in S4, the carboxyl activating reagent includes one or more of p-toluenesulfonyl chloride, methanesulfonyl chloride, pivaloyl chloride, benzoyl chloride, chloroacetyl chloride, terephthaloyl chloride, isophthaloyl chloride.

[0018] Preferably, in the synthesis method, the solvents used include one or more of toluene, diethyl ether, acetonitrile, ethylene glycol dimethyl ether, tetrahydrofuran (THF), chloroform, dichloromethane (DCM), methanol, isopropanol, ethanol, tert-butanol, N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide or 1,4-dioxane.

[0019] The application of a chiral isothiourea catalyst as described above includes applying the chiral isothiourea catalyst to the asymmetric fluorination reaction at the α-position of carboxylic acid compounds, specifically including:

[0020]

[0021] Mix the carboxylic acid shown in Formula 2 and diphenylmethanol shown in Formula 3, and carry out an asymmetric fluorination reaction under the action of catalyst 1, a basic reagent, an activating reagent, and a fluorine reagent to obtain an α-fluorinated carboxylic acid ester, that is, a fluorinated carboxylic acid ester shown in Formula 4;

[0022] In Formula 2, R is respectively an aryl group (phenyl, naphthyl, thiophene, furan), an alkenyl group.

[0023] Preferably, the amount of diphenylmethanol used is 1.2 - 1.5 times the molar amount of Formula 2; the basic reagent includes one of Cs2CO3, Na2CO3, K2CO3, DBU, DIPEA, and the amount used is 2.5 - 3.0 times the molar amount of Formula 2.

[0024] Preferably, the activating reagent is one of pivaloyl chloride, p-toluenesulfonyl chloride, and the amount used is 1.5 - 2.0 times the molar amount of Formula 2; the fluorine reagent is one of N-fluorobenzenesulfonimide (NFSI), a selective fluorine reagent, and the amount used is 1.5 - 2.0 times the molar amount of Formula 2.

[0025] Preferably, in the asymmetric fluorination reaction, the solvents used are one or more of dichloromethane, 1,2-dichloroethane, toluene, acetonitrile, ethyl acetate.

[0026] Preferably, in the asymmetric fluorination reaction, the reactants are stirred, the reaction temperature is room temperature, and the reaction time is 12 - 24 h.

[0027] Compared with the prior art, the beneficial effects of the present invention are:

[0028] (1) By integrating planar chirality in cyclohexane and central chirality in amino alcohol, the present invention has developed a series of isothiourea catalysts with both planar chirality and central chirality dual chiral elements, and applied them to the asymmetric fluorination at the α-position of highly stable carboxylic acid compounds, realizing the rapid and effective synthesis of optically active α-fluorinated carboxylic acid ester compounds.

[0029] (2) The chiral isothiourea catalyst in the present invention can be obtained from racemic amino-substituted cyclic imines. The reaction conditions are mild, easy to scale up, and can be prepared on a large scale.

[0030] (3) The chiral isothiourea catalyst in the present invention catalyzes the fluorination reaction at the α-position of carboxylic acids. The reaction conditions are mild, insensitive to water and air, the reaction is simple and easy to operate, and the product has a very high ee value. It is a new and effective method for preparing α-fluorocarboxylic acid esters. Therefore, the present invention has good application value.

[0031] The above summary is only for the purpose of the specification and is not intended to be limiting in any way. In addition to the illustrative aspects, embodiments, and features described above, further aspects, embodiments, and features of the present invention will be readily apparent by reference to the drawings and the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 It is a synthetic route diagram of the chiral isothiourea-type catalyst of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0033] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0034] Example 1: Synthesis of Compound 1b

[0035]

[0036] Dissolve compound rac-1a (4.46 g, 20 mmol) and triethylamine (4.04 g, 40 mmol) in freshly distilled DCM (50.0 mL). Slowly add CSCl2 (2.30 g, 20 mmol) to the reaction system at 0 °C. After stirring at 0 °C for 2 hours, rotary evaporate the solvent to dryness on a rotary evaporator to obtain a light yellow solid.

[0037] Example 2: Synthesis of Compound 1c

[0038]

[0039] Dissolve compound 1b (5.30 g, 20 mmol) in ether (120.0 mL), add amino alcohol (1.2 eq), and continue to stir at room temperature for 12 hours. After rotary evaporating the ether to dryness on a rotary evaporator, purify the crude product 1c by column chromatography.

[0040] Example 3: Synthesis of Compound 1d

[0041]

[0042] Dissolve Compound 1c (10 mmol, 1.0 eq) in CCl4 (20.0 mL). Slowly add a solution of bromine (22 mmol, 1.1 eq) in CCl4 (10.0 mL) dropwise to the reaction system. After the addition is complete, continue stirring at room temperature for 12 h, and then quench with saturated NaHCO3 (40.0 mL) aqueous solution. Subsequently, the resulting product mixture is extracted with DCM (30.0 mL × 3), the organic phases are combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated to obtain crude product 1d.

[0043] Example 4: Synthesis of Catalyst 1

[0044]

[0045] Dissolve Compound 1d (5.0 mmol, 1.0 eq) in DCM (50.0 mL), add NEt3 (15.0 mmol, 3.0 eq), and slowly add MsCl (7.5 mmol, 1.5 eq) dropwise at 0 °C. After stirring for 1 h, add MeOH (1.0 mL) and NEt3 (5.0 mL). Subsequently, transfer the reaction to 50 °C and continue stirring for 12 h. After the reaction is complete, transfer the reaction to room temperature and add NaOH aqueous solution (1 M) to the system. The resulting product mixture is extracted with DCM (30.0 mL × 3), the organic phases are combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated. The diastereoisomers are separated by column chromatography (ethyl acetate / n-hexane / triethylamine = 1 / 20 / 0.1) to obtain two different configurations of Catalyst 1.

[0046]

[0047] Catalyst (S p ,R)-1A Characterization Data: White solid, mp. 228 - 230 °C, [α] 25 D = +150.0 (c = 1.0, CHCl3); 11H NMR (400 MHz, CDCl3) δ 7.52 - 7.45 (m, 4H), 7.37 - 7.34 (m, 1H), 7.00 - 6.98 (m, 1H), 6.56 - 6.49 (m, 2H), 6.45 - 6.40 (m, 2H), 6.30 (d, J = 8.0 Hz, 1H), 5.65 - 5.69 (m, 1H), 4.22 - 4.17 (m, 1H), 4.04 - 4.01 (m, 1H), 3.15 - 3.04 (m, 3H), 3.00 - 2.83 (m, 3H), 2.76 - 2.68 (m, 1H), 2.46 - 2.40 (m, 1H); 13 13C NMR (100 MHz, CDCl3) δ 167.4, 143.9, 138.4, 137.9, 136.6, 135.5, 133.5, 133.0, 131.8, 130.3, 129.0, 127.7, 126.7, 126.7, 126.3, 126.2, 121.9, 75.3, 54.7, 35.3, 33.4, 33.1, 31.7; HRMS (ESI) m / z: [M + H]+ Calcd for C 25 H 23 N2S 383.1576; found 383.1574.

[0048]

[0049] Catalyst (R p ,R)-1B characterization data: white solid, mp. 185 - 187 °C, [α] 25 D = +222.0 (c = 1.0, CHCl3); 1 1H NMR (400 MHz, CDCl3) δ 7.37 - 7.33 (m, 4H), 7.30 - 7.26 (m, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.43 (d, J = 8.0 Hz, 1H), 6.58 - 6.53 (m, 2H), 6.45 (d, J = 8.0 Hz, 1H), 6.32 (d, J = 8.0 Hz, 1H), 5.72 (t, J = 12.0 Hz, 1H), 4.53 (t, J = 8.0 Hz, 1H), 3.61 (t, J = 8.0 Hz, 1H), 3.23 - 3.06 (m, 3H), 2.96 - 2.72 (m, 5H). 1313C NMR (100 MHz, CDCl3) δ 167.1, 142.8, 138.4, 137.9, 136.7, 135.5, 133.4, 132.8, 131.8, 130.3, 128.7, 127.6, 126.8, 126.7, 126.5, 126.3, 122.5, 75.6, 55.2, 35.0, 33.5, 33.1, 31.8; HRMS (ESI) m / z: [M+H] + Calcd for C 25 H 23 N2S 383.1576; found 383.1574.

[0050]

[0051] Catalyst (R p ,S)-1C characterization data: white solid, mp. 113 - 115 °C, [α] 25 D = –42.0 (c = 1.0, CHCl3); 1 1H NMR (400 MHz, CDCl3) δ 7.43 - 7.37 (m, 4H), 7.27 - 7.23 (m, 1H), 6.82 - 6.80 (m, 1H), 6.52 - 6.46 (m, 2H), 6.37 (d, J = 8.0 Hz, 1H), 6.23 (d, J = 8.0 Hz, 1H), 5.86 - 5.84 (m, 1H), 4.96 - 4.84 (m, 1H), 3.89 - 3.85 (m, 1H), 3.71 (t, J = 8.0 Hz, 1H), 3.22 - 3.01 (m, 5H), 2.95 - 2.76 (m, 4H), 2.54 - 2.47 (m, 1H), 2.90 - 2.70 (m, 4H), 2.67 - 2.52 (m, 2H); 13 13C NMR (100 MHz, CDCl3) δ 166.3, 138.3, 137.8, 137.6, 136.7, 135.3, 133.4, 132.8, 131.6, 130.0, 128.6, 127.0, 126.7, 126.4, 126.1, 121.6, 73.2, 49.9, 42.2, 35.3, 33.1.31.7; HRMS (ESI) m / z: [M+H] + Calcd for C 26 H 25 N2S 397.1733; found 397.1731.

[0052]

[0053] Catalyst (R p ,S)-1D characterization data: white solid, mp. 122 - 124 °C, [α] 25 D = –94.0 (c = 1.0, CHCl3); 1 1H NMR (400 MHz, CDCl3) δ 7.28 - 7.16 (m, 5H), 6.82 (d, J = 8.0 Hz, 1H), 4.91 - 4.83 (m, 3H), 3.99 (t, J = 8.0 Hz, 1H), 3.34 (t, J = 12.0 Hz, 1H), 3.24 (dd, J1 = 8.0 Hz, J2 = 12.0 Hz, 1H), 3.06 - 2.96 (m, 3H), 2.90 - 2.70 (m, 4H), 2.67 - 2.52 (m, 2H); 13 13C NMR (100 MHz, CDCl3) δ 166.3, 138.4, 138.1, 137.9, 136.9, 135.4, 133.3, 132.8, 131.7, 130.1, 129.2, 128.7, 126.7, 126.6, 126.4, 126.2, 122.3, 74.2, 52.1, 42.9, 35.0, 33.4, 33.1, 31.8; HRMS (ESI) m / z: [M+H] + Calcd for C 26 H 25 N2S 396.1733; found 397.1730.

[0054]

[0055] Catalyst (R p ,S)-1E characterization data: white solid, mp. 118 - 120 °C, [α] 25 D = –54.0 (c = 1.0, CHCl3); 1 1H NMR (400 MHz, CDCl3): δ 6.94 - 6.92 (m, 1H), 6.57 - 6.52 (m, 2H), 6.47 - 6.41 (m, 2H), 6.25 (d, J = 8.0 Hz, 1H), 4.47 - 4.41 (m, 1H), 3.87 - 3.75 (m, 2H), 3.23 - 3.16 (m, 3H), 3.09 - 2.61 (m, 5H), 2.06 - 2.01 (m, 1H), 1.17 - 1.13 (q, J = 8.0 Hz, 6H); 1313C NMR (100 MHz, CDCl3) δ 166.3, 138.3, 137.6, 136.7, 135.3, 133.4, 132.8, 131.6, 130.0, 128.6, 127.0, 126.7, 126.4, 126.1, 121.6, 73.2, 49.9, 42.2, 35.3, 33.1, 31.7; HRMS (ESI) m / z: [M+H] + Calcd for C 22 H 25 N2S 349.1733; found 349.1731.

[0056]

[0057] Catalyst (R p ,S)-1F characterization data: white solid, mp. 118 - 120 °C, [α] 25 D = –194.0 (c = 1.0, CHCl3); 1 1H NMR (400 MHz, CDCl3) δ 6.91 - 6.89 (m, 1H), 6.57 - 6.53 (m, 3H), 6.43 (d, J = 8.0 Hz, 1H), 6.28 (d, J = 8.0 Hz, 1H), 4.45 - 4.38 (m, 1H), 4.11 (t, J = 8.0 Hz, 1H), 3.41 - 3.36 (m, 1H), 3.21 - 3.03 (m, 3H), 2.97 - 2.68 (m, 5H), 1.90 - 1.84 (m, 1H), 1.07 (d, J = 8.0 Hz, 3H), 0.95 (d, J = 4.0 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 165.8, 138.4, 137.9, 137.0, 135.4, 133.3, 132.8, 131.7, 130.1, 126.5, 126.4, 126.2, 122.3, 79.3, 50.2, 35.0, 33.6, 33.5, 33.1.31.9, 19.2, 18.5; HRMS (ESI) m / z: [M+H] + Calcd for C 22 H 25 N2S 349.1733; found 349.1731.

[0058] Example 5: Asymmetric synthesis of α-fluorocarboxylate 4a catalyzed by chiral isothiourea catalyst (S p ,R)-1A

[0059]

[0060] Add phenylacetic acid 2a (0.1 mmol, 1.0 eq) and 1.0 mL of dichloromethane to a 10-mL reaction tube. Add the activating reagent p-toluenesulfonyl chloride (0.2 mmol, 2.0 eq) to the reaction tube and add cesium carbonate (0.15 mmol, 1.5 eq). After stirring at this temperature for 0.5 h, add N-fluorobenzenesulfonimide (0.15 mmol, 1.5 eq), cesium carbonate (0.15 mmol, 1.5 eq), and the isothiourea catalyst (Sp,R)-1A (0.02 mmol, 0.2 eq) to the reaction tube, and stir the reaction at room temperature for 24 h. After monitoring the completion of the reaction by TLC, concentrate the reaction solution and purify it by silica gel column chromatography to obtain the target product 4a with a yield of 85%.

[0061] The structure identification data are as follows: colorless oil; [α] 25 D = –43.0 (c = 1.0, CHCl3); 1 1H NMR (400 MHz, CDCl3) δ (ppm): 7.44 - 7.37 (m, 5H), 7.32 - 7.28 (m, 5H), 7.21 - 7.18 (m, 3H), 7.06 - 7.04 (m, 2H), 6.93 (s, 1H), 5.86 (d, J = 48.0 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ (ppm): 167.5 (d, J = 28.0 Hz), 139.2 (d, J = 10.0 Hz), 134.0 (d, J = 20.0 Hz), 129.7 (d, J = 2.0 Hz), 128.7 (d, J = 19.0 Hz), 128.4, 128.2 (d, J = 35.0 Hz), 127.0 (d, J = 75.0 Hz), 126.9 (d, J = 6.0 Hz), 89.4 (d, J = 185.0 Hz), 78.2; 19 19F NMR (376 MHz, CDCl3) δ (ppm): –179.5 (d, J = 48.8 Hz, 1F); HRMS (ESI) m / z: [M + Na] + Calcd for C 21 H 17 FO2Na 343.1105; found 343.1108; HPLC (Chiralpak OJ-H, i-propanol / hexane = 30 / 70, flow rate 1.0 mL / min, λ = 220 nm): tR (major) = 15.3 min, tR (minor) = 16.7 min, ee = 97%.

[0062] Example 6: Asymmetric synthesis of α-fluoro carboxylic acid ester 4b catalyzed by chiral isothiourea catalyst (S p ,R)-1A

[0063]

[0064] Synthesis of compound 4b: Using the same synthesis method as compound 4a in Example 5, replacing compound 2a with compound 2b, the yield was 66%.

[0065] Target product 4b, the structure identification data is as follows: white solid, mp 86 - 88 °C; [α] 25 D = –16.0 (c = 1.0, CHCl3); 1 1H NMR (400 MHz, CDCl3) δ (ppm): 7.71 (d, J = 8.0 Hz, 2H), 7.34 - 7.22 (m, 8H), 7.16 (d, J = 8.0 Hz, 2H), 7.09 - 7.06 (m, 2H), 6.92 (s, 1H), 5.80 (d, J = 48.0 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ (ppm): 167.0 (d, J = 27.0 Hz), 139.0 (d, J = 10.0 Hz), 138.0, 133.7 (d, J = 21.0 Hz), 128.6 (d, J = 15.0 Hz), 128.5 (d, J = 16.0 Hz), 128.2, 126.9 (d, J = 61.0 Hz), 95.8 (d, J = 3.0 Hz), 88.8 (d, J = 186.0 Hz), 78.4; 19 19F NMR (376 MHz, CDCl3) δ (ppm): –181.1 (d, J = 45.1 Hz, 1F); HRMS (ESI) m / z: [M+Na] + Calcd for C 21 H 16 FIO2Na 469.0071; found 469.0079; HPLC (Chiralpak OJ-H, i-propanol / hexane = 20 / 80, flow rate 1.0 mL / min, λ = 220 nm): tR(minor) = 27.0 min, tR(major) = 29.1 min, ee = 99%.

[0066] Example 7: Asymmetric synthesis of α-fluoro carboxylic acid ester 4c catalyzed by chiral isothiourea catalyst (S p ,R)-1A

[0067]

[0068] Synthesis of Compound 4c: Using the same synthetic method as that of Compound 4a in Example 5, replacing Compound 2a with Compound 2c, the yield was 88%.

[0069] The target product 4c, the structure identification data are as follows: light-colored oil; [α] 25 D = -47.0 (c = 0.9, CHCl3); 1 1H NMR (400 MHz, CDCl3) δ (ppm): 8.12 (d, J = 8.0 Hz, 1H), 7.90 (t, J = 8.0 Hz, 2H), 7.55 - 7.42 (m, 4H), 7.32 - 7.23 (m, 5H), 7.14 - 7.10 (m, 1H), 7.05 (t, J = 8.0 Hz, 2H), 6.93 (s, 1H), 6.86 (d, J = 8.0 Hz, 2H), 6.45 (d, J = 48.0 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ (ppm): 167.9 (d, J = 28.0 Hz), 139.2 (d, J = 23.0 Hz), 133.9, 130.7 (d, J = 1.0 Hz), 130.6 (d, J = 2.0 Hz), 130.0 (d, J = 18.0 Hz), 128.8, 128.4 (d, J = 35.0 Hz), 128.1 (d, J = 50.0 Hz), 127.1, 127.1 (d, J = 4.0 Hz), 126.9 (d, J = 94.0 Hz), 126.3, 125.1, 123.8 (d, J = 2.0 Hz), 88.7 (d, J = 185.0 Hz), 78.4; 19 19F NMR (376 MHz, CDCl3) δ (ppm): -178.1 (d, J = 48.8 Hz, 1F); HRMS (ESI) m / z: [M+Na] + Calcd for C 25 H 19 FO2Na 393.1261; found 393.1253; HPLC (Chiralpak OJ-H, i-propanol / hexane = 30 / 70, flow rate 1.0 mL / min, λ = 220 nm): tR(minor) = 20.6 min, tR(major) = 28.2 min, ee = 98%.

[0070] Example 8: Chiral isothiourea catalyst (S pAsymmetric synthesis of α-fluoro carboxylic acid ester 4d catalyzed by (S,R)-1A

[0071]

[0072] Synthesis of compound 4d: Using the same synthesis method as that of compound 4a in Example 5, replacing compound 2a with compound 2d, the yield was 75%.

[0073] Target product 4d, the structure identification data is as follows: yellow oil; [α] 25 D = –13.1 (c = 0.8, CHCl3); 1 1H NMR (400 MHz, CDCl3) δ (ppm): 7.41 - 7.39 (m, 1H), 7.35 - 7.31 (m, 5H), 7.27 - 7.25 (m, 3H), 7.19 - 7.15 (m, 3H), 7.02 - 6.99 (m, 1H), 6.98 (s, 1H), 6.08 (d, J = 48.0 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ (ppm): 166.6 (d, J = 29.0 Hz), 139.0 (d, J = 7.0 Hz), 135.2 (d, J = 23.0 Hz), 128.7 (d, J = 5.0 Hz), 128.6 (d, J = 15.0 Hz), 128.3 (d, J = 3.0 Hz), 128.3 (d, J = 27.0 Hz), 127.1 (d, J = 62.0 Hz), 127.1 (d, J = 2.0 Hz), 84.9 (d, J = 186.0 Hz), 78.6; 19 19F NMR (376 MHz, CDCl3) δ (ppm): –164.6 to –164.7 (m, 1F); HRMS (ESI) m / z: [M+Na] + Calcd for C 19 H 15 FO2SNa 349.0669; found 349.0644; HPLC (Chiralpak IB, i-propanol / hexane = 2 / 98, flow rate 1.0 mL / min, λ = 220 nm): tR (minor) = 7.9 min, tR (major) = 8.4 min, ee = 95%.

[0074] Example 9: Asymmetric synthesis of α-fluoro carboxylic acid ester 4e catalyzed by chiral isothiourea catalyst (S p ,R)-1A

[0075]

[0076] Synthesis of Compound 4e: Using the same synthesis method as that of Compound 4a in Example 5, replacing Compound 2a with Compound 2e, the yield was 52%.

[0077] The target product 4e, the structure identification data are as follows: colorless oil; [α] 25 D = +12.0 (c = 1.0, CHCl3); 1 1H NMR (400 MHz, CDCl3) δ (ppm): 7.38 - 7.25 (m, 15H), 6.99 (s, 1H), 6.85 (dd, J1 = 4.0 Hz, J2 = 16.0 Hz, 1H), 6.33 - 6.24 (m, 1H), 5.61 - 5.47 (m, 1H); 13 13C NMR (100 MHz, CDCl3) δ (ppm): 167.4 (d, J = 27.0 Hz), 139.3 (d, J = 2.0 Hz), 136.1 (d, J = 11.0 Hz), 135.3, 128.9, 128.7, 128.6 (d, J = 5.0 Hz), 128.3 (d, J = 14.0 Hz), 127.0 (d, J = 35.0 Hz), 127.0 (d, J = 1.0 Hz), 120.9 (d, J = 19.0 Hz), 88.6 (d, J = 183.0 Hz), 78.2; 19 19F NMR (376 MHz, CDCl3) δ (ppm): –182.8 to –182.9 (m, 1F); HRMS (ESI) m / z: [M + Na] + Calcd for C 23 H 19 FO2Na 369.1261; found 369.1265; HPLC (Chiralpak IC, i - propanol / hexane = 3 / 97, flow rate 1.0 mL / min, λ = 220 nm): tR (major) = 8.5 min, tR (minor) = 9.5 min, ee = 95%.

[0078] As a very important class of rigid planar chiral units with high stability, cyclophanes are widely used in the fields of medicine, pesticides, materials, etc. In planar chiral catalysts containing cyclophanes, the planar chirality in the structure often plays a decisive role in asymmetric catalytic reactions. In the present invention, by fusing the planar chirality in cyclophanes with the central chirality in amino alcohols, a series of isothiourea catalysts with both planar chirality and central chirality dual chiral elements are developed and applied to the asymmetric fluorination of the α-position of highly stable carboxylic acid compounds, realizing the rapid and effective synthesis of optically active α-fluorinated carboxylic ester compounds.

[0079] In the description of this specification, the description referring to terms such as "one embodiment", "some embodiments", "examples", "specific examples", or "some examples", etc. means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0080] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A chiral isothiourea catalyst, characterized in that: The catalyst is an isothiourea catalyst containing face chirality and center chirality, and its structure is as shown in Formula 1: Among them, the chirality marked with "*" is R configuration, S configuration or racemic, and R is independently selected from phenyl, benzyl or isopropyl.

2. The method for synthesizing a chiral isothiourea catalyst according to claim 1, characterized in that: The steps include: S1: Starting from the amino-substituted racemic cyclopentane 1a, it reacts with thiophosgene under the action of a base to generate intermediate 1b; S2: Intermediate 1b is further condensed with chiral amino alcohol to generate intermediate 1c; S3: Then, the intermediate 1d is generated by ring closure under bromine conditions; S4: 1d undergoes ring closure in the presence of a base and a carboxyl activating agent to generate isothiourea catalyst 1, which is then separated by conventional column chromatography to obtain chiral isothiourea catalysts of different configurations.

3. The synthesis and application of a chiral isothiourea catalyst according to claim 2, characterized in that: In S1 and S4, the base includes one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylamine, diisopropylethylamine, tetramethylethylenediamine, N,N-dimethylaniline, N,N-diethylaniline, 1,4-diazabicyclooctane (DABCO), and diazabicyclododecane (DBU).

4. The method for synthesizing a chiral isothiourea catalyst according to claim 2, characterized in that: In S4, the carboxyl activation reagent includes one or more of p-toluenesulfonyl chloride, methanesulfonyl chloride, pivaloyl chloride, benzoyl chloride, chloroacetyl chloride, terephthaloyl chloride, and isophthaloyl chloride.

5. The method for synthesizing a chiral isothiourea catalyst according to claim 2, characterized in that: In the synthesis method, the solvent used includes one or more of toluene, ether, acetonitrile, ethylene glycol dimethyl ether, tetrahydrofuran (THF), chloroform, dichloromethane (DCM), methanol, isopropanol, ethanol, tert-butanol, N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide or 1,4-dioxane.

6. The use of a chiral isothiourea catalyst according to any one of claims 1 to 5, comprising applying the chiral isothiourea catalyst to an asymmetric fluorination reaction at the α-position of a carboxylic acid compound, specifically comprising: The carboxylic acid represented by Formula 2 and the diphenylmethanol represented by Formula 3 are mixed, and an asymmetric fluorination reaction is carried out under the action of a catalyst 1, an alkaline reagent, an activating reagent, and a fluorine reagent to obtain an α-fluorocarboxylate, i.e., a fluorine-containing carboxylate represented by Formula 4; In formula 2, R is an aryl group (phenyl, naphthyl, thiophene, furan) or an alkenyl group.

7. The use according to claim 6, characterized in that: The amount of the diphenylmethanol used is 1.2-1.5 times the molar amount of the formula 2; the alkaline reagent includes one of Cs2CO3, Na2CO3, K2CO3, DBU, and DIPEA, and the amount used is 2.5-3.0 times the molar amount of the formula 2.

8. The use according to claim 6, characterized in that: The activation reagent is one of pivaloyl chloride and p-toluenesulfonyl chloride, and the amount used is 1.5-2.0 times the molar amount of the formula 2; the fluorine reagent is one of N-fluorobisbenzenesulfonamide (NFSI) and a selective fluorine reagent, and the amount used is 1.5-2.0 times the molar amount of the formula 2.

9. The use according to claim 6, characterized in that: In the asymmetric fluorination reaction, the solvent used is one or more of dichloromethane, 1,2-dichloroethane, toluene, acetonitrile and ethyl acetate.

10. The use according to claim 6, characterized in that: In the asymmetric fluorination reaction, the reactants are stirred, the reaction temperature is room temperature, and the reaction time is 12-24 hours.

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