Chiral sulfonamide carboxylic acid compounds, methods of synthesis and use thereof

Abstract

This invention relates to a chiral sulfinamide carboxylic acid compound, its synthesis method, and its applications. The chiral sulfinamide carboxylic acid compound has the structure of formula (1), and its main structural feature is the simultaneous presence of a carboxylic acid and a chiral sulfinamide substituent at the ortho position of a heteroaromatic ring. The substituent in the chiral sulfinamide can be aryl or alkyl, while the heteroaromatic ring can be a mono- or poly-substituted benzene ring, a mono- or poly-substituted naphthalene ring, a thiophene ring, or a furan ring and a pyridine ring. The synthesis of this chiral sulfinamide is simple, using inexpensive and readily available raw materials, with mild reaction conditions and easy operation. This chiral carboxylic acid is a novel protonic acid chiral catalyst. It is particularly suitable for transition metal-catalyzed asymmetric reactions, producing products with high yields and enantioselectivity.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a novel chiral sulfinamide carboxylic acid, its synthetic method, and its application in the palladium-catalyzed oxime ether-guided asymmetric synthesis of diaryl methanol derivatives. Background Technology

[0002] Transition metal-catalyzed asymmetric C-H bond activation reactions are of great significance, enabling the one-step functionalization of widely existing C-H bonds in organic compounds to construct diverse chiral frameworks. Compared with traditional asymmetric synthesis, this method is simpler and more efficient, and has great potential application value, making it a cutting-edge and hotly debated area in asymmetric catalysis research. Among transition metal catalysts, palladium has attracted much attention because it is not only suitable for various directing groups but also capable of constructing different types of bonds, such as CO, CN, CX, and CC bonds. In 2008, Yu Jinquan's research group first achieved palladium-catalyzed enantioselective CH activation using mononitrogen protected amino acids (MPAAs) as chiral ligands (Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 4882-4886). Since then, various mononitrogen-protected amino acid derivatives, chiral phosphate derivatives, and chiral binaphthol derivatives have been developed as chiral ligands, exhibiting good reactivity in palladium-catalyzed asymmetric C-H bond activation reactions (Shao, Q.; Wu, K.; Zhuang, Z.; Qian, S.; Yu, J.-Q. Acc. Chem. Res. 2020, 53, 833-851; Yan, S.-B.; Zhang, S.; Duan, W.-L. Org. Lett., 2015, 17, 2458–2461; Han, Y.-Q.; Ding, Y.; Zhou, T.; Yan, S.-Y.; Song, H.; Shi, B.-FJAm. Chem. Soc., 2019, 141, 4558–4563). The development of chiral ligands plays a crucial role in asymmetric reactions. However, in the current state of palladium-catalyzed asymmetric C-H bond activation, the variety of chiral ligands is relatively limited. Among these, palladium-catalyzed oxime-ether-directed asymmetric C-H bond activation has not been fully explored. The main reason is the poor compatibility of chiral ligands with this type of reaction system, making effective chiral control difficult.

[0003] This invention synthesizes novel chiral sulfinamide carboxylic acids using optically active chiral sulfinamides as starting materials. The synthesized chiral sulfinamide carboxylic acids are then used as chiral ligands in the palladium-catalyzed asymmetric reaction of oxime ether-directed diaryl methanol derivatives with alkynyl bromide to prepare chiral 2-alkynyldiaryl methanol derivatives. Summary of the Invention

[0004] One of the objectives of this invention is to provide a carboxylic acid having a chiral sulfinamide structure.

[0005] The second objective of this invention is to provide a method for preparing the above-mentioned chiral sulfinamide carboxylic acid.

[0006] A third objective of this invention is to provide the application of the above-mentioned chiral sulfinamide carboxylic acid in the preparation of chiral diaryl methanol derivatives by reacting palladium-catalyzed oxime ether-directed reactions of diaryl methanol derivatives with alkynyl bromide derivatives.

[0007] The chiral sulfinamide carboxylic acid compound of the present invention is an optically active compound having the structural formula (I), (II), (III) or (IV):

[0008]

[0009] In formulas (I), (II), (III), or (IV): R is independently selected from aryl or substituted aryl or alkyl, wherein the substituent on the aryl group is selected from alkyl or alkoxy. 1 Selected from one or more of H, alkyl, alkoxy, alkanoyloxy, alkoxycarbonyl, cyano, nitro, and halogen. R 2 The substituent is independently selected from H, alkyl, halogen, alkoxy, cyano, nitro, alkanoyloxy, alkoxycarbonyl, aryl, or substituted aryl, wherein the substituent on the aryl group is selected from alkyl or alkoxy. In (III), X is independently selected from S and O, wherein the carboxylic acid substituent (-COOH) and the sulfinamide substituent [RS(O)NH-] can be located at the 2,3- or 3,4-position of the heterocycle. In (IV), the carboxylic acid substituent and the sulfinamide substituent can be located at the 2,3- or 3,4-position of the pyridine ring.

[0010] Preferably, R is independently selected from C1 to C4 alkyl, substituted or unsubstituted phenyl, wherein the substituent on the phenyl is selected from one or more C1 to C4 alkyl groups;

[0011] R 1 Selected from one or more of H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkanoyloxy, C1-C4 alkoxycarbonyl, cyano, nitro and halogen (or R when there are more). 1 (Representing multiple substituents);

[0012] R 2The substituents are independently selected from H, C1-C4 alkyl, halogen, C1-C4 alkoxy, cyano, nitro, C1-C4 alkanoyloxy, C1-C4 alkoxycarbonyl, substituted silyl, phenyl, or substituted phenyl, wherein the substituent on the phenyl group is selected from C1-C4 alkyl. (III) X is independently selected from S and O, wherein the carboxylic acid substituent and the sulfinamide substituent can be located at the 2,3- or 3,4-position of the heterocycle. (IV) The carboxylic acid substituent and the sulfinamide substituent can be located at the 2,3- or 3,4-position of the pyridine ring.

[0013] As a further preferred option, R is independently selected from phenyl, 4-methyl-substituted phenyl, 2,4,6-trimethyl-substituted phenyl or tert-butyl;

[0014] R 1 It is selected from one or more of H, methyl, tert-butyl, methoxy, formoxy, methoxycarbonyl, cyano, nitro, F, or Cl;

[0015] R 2 The phenyl group is independently selected from H, methyl, tert-butyl, halogen, methoxy, cyano, nitro, formyloxy, methoxycarbonyl, phenyl or substituted phenyl, wherein the substituent on the phenyl group is selected from methyl.

[0016] As a further preferred embodiment, the chiral sulfinamide carboxylic acid compound is one of the following compounds:

[0017]

[0018] The aforementioned chiral sulfinamide carboxylic acid can be either a levorotatory or dextrorotatory form with the same general chemical formula.

[0019] This invention further provides a method for preparing the above-mentioned chiral sulfinamide carboxylic acid, the synthetic steps of which are as follows:

[0020] In the first step, palladium acetate (0.01–0.06 equivalents), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.02–0.12 equivalents), chiral sulfinamide (1.1–1.6 equivalents), and cesium carbonate (1.3–2.6 equivalents) were placed in a 50 mL Shrek tube. The Shrek tube was evacuated and then purged with nitrogen, repeated 2–3 times. Under nitrogen protection, methyl (or ethyl) o-bromo- or o-iodoaryl (naphthyl or heteroaryl) formate (1.0 equivalent) and 10–20 mL of dioxane were added. The reaction mixture was then stirred at 80–120 °C (oil bath) until the starting material was consumed. After cooling to room temperature, water was added, and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. Purification by column chromatography yielded the corresponding compound A.

[0021] In the second step, product A obtained in the first step was dissolved in a tetrahydrofuran / water (1:1 to 3:1) mixed solvent at 0–20 °C, and lithium hydroxide (2–6 equivalents) was added in batches. After the reaction was complete, ethyl acetate and a 1.0 M hydrochloric acid aqueous solution were added to the system. The aqueous layer was then extracted twice with ethyl acetate. The combined organic layers were washed successively with water and brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was recrystallized from ethyl acetate to give the corresponding chiral sulfinamide carboxylic acid compound B.

[0022] The general reaction formula for the preparation of chiral sulfinamide carboxylic acid is as follows:

[0023]

[0024] In the formula: R, R' and R 1 The definition is as described above.

[0025] This invention further provides the application of the chiral sulfinamide carboxylic acid B, wherein the chiral sulfinamide carboxylic acid compound is used as a chiral ligand for the palladium-catalyzed oxime ether-directed asymmetric reaction of diaryl methanol derivative 1 with alkynyl bromide 2 to prepare chiral 2-alkynyldiaryl methanol derivative 3, the reaction formula being:

[0026]

[0027] Where: R 3 It is a methyl group or two R groups. 3 Connecting two R 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 4,4-dimethylcyclohexyl, 3,3-5,5-tetramethylcyclohexyl, or adamantyl are formed by the cyclic combination of carbon atoms. 4 It is one or more of methyl, ethyl, isopropyl, tert-butyl, phenyl, tert-butyldimethylsiloxy, triisopropylsiloxy, hydroxymethyl, methoxy, benzyloxy, hydroxy, acetyl, F, Cl, Br. 5 It is tert-butyldimethylsilyl, triethylsilyl, or triisopropylsilyl.

[0028] The application of the chiral sulfinamide carboxylic acid B in an asymmetric catalytic reaction process is as follows: the diaryl methanol derivative 1 is mixed with alkynyl bromide 2, palladium catalyst, silver carbonate, and chiral sulfinamide carboxylic acid B in a molar equivalent ratio of 1:1.0-3.0:0.05-0.15:1.0-3.0:0.1-0.2 in a mixed solvent of tetrahydrofuran and chloroform. The reaction is carried out at 25-40°C for 24-72 hours. After the reaction is completed, the mixture is filtered and purified by column chromatography to obtain chiral 2-alkynyldiaryl methanol derivative 3.

[0029] This invention provides a method for synthesizing a novel chiral carboxylic acid with a sulfinamide substituent. This chiral sulfinamide carboxylic acid is a novel protic acid-based chiral catalyst. The method involves reacting a palladium-catalyzed diaryl methanol derivative with an alkyne bromide to prepare a chiral 2-alkynyldiaryl methanol derivative, with the product exhibiting high yield and enantioselectivity. Detailed Implementation

[0030] The following examples will help to understand the present invention, but are not limited to the scope of protection of the present invention.

[0031] Example 1: Preparation of (R)-2-((tert-butylsulfinyl)amino)benzoic acid:

[0032]

[0033] In the first step, 0.09 mmol of palladium acetate, 0.18 mmol of 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene), 3.6 mmol of 2-methylpropane-2-sulfinamide, and 6.0 mmol of cesium carbonate were placed in a 50 mL Shrek tube. The Shrek tube was evacuated and then purged with nitrogen, repeated 2–3 times. Under nitrogen protection, 3.0 mmol of methyl o-bromobenzoate and 15 mL of dioxane were added, and the reaction mixture was then stirred at 100 °C (oil bath) until the starting materials were consumed. After cooling to room temperature, water was added, and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. Purification by column chromatography yielded the corresponding compound A.

[0034] In the second step, the product obtained in the first step (1.0 mmol A) was dissolved in 4 mL of a tetrahydrofuran / water (1:1) mixed solvent at 0°C, and 2.0 mmol lithium hydroxide was added in batches. After the reaction was complete, ethyl acetate and a 1.0 M hydrochloric acid aqueous solution were added to the system. The aqueous layer was then extracted twice with ethyl acetate. The combined organic layers were washed successively with water and brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was recrystallized from ethyl acetate to give 314 mg of the corresponding chiral sulfinamide carboxylic acid compound. MP: 135.2-137.0 °C; 1 H NMR (400MHz, CDCl3) δ10.03 (s, 1H), 7.94 (d, J = 8.0Hz, 1H), 7.51–7.45 (m, 2H), 7.00–6.94 (m, 1H), 1.46 (s, 9H); 13 C NMR(101MHz, CDCl3)δ170.8,146.1,134.8,132.3,120.9,115.8,114.9,57.2,22.9; HRMS(ESI)m / z:[M+Na]+ Calcd for C 11 H 15 NNaO3S264.0665; found:264.0663.

[0035] Example 2: Preparation of various other chiral sulfinamide carboxylic acids

[0036] The preparation process is the same as in Example 1, except that the o-bromo (or iodo) aryl carboxylate added in the first step is replaced by other corresponding substituted aryl groups or the chiral sulfinamide R substituent is different. The data of the corresponding chiral sulfinamide carboxylic acids are as follows:

[0037] (R)-2-((tris(methyltrimethylsulfinyl)amino)benzoic acid

[0038]

[0039] MP: 206.8-208.5℃; 1 H NMR (400MHz, CDCl3) δ8.42 (d, J = 7.9Hz,

[0040] 1H),8.05(d,J=7.6Hz,1H),7.79(t,J=7.3Hz,1H),7.57(t,J=7.1Hz,1H),6.74(s,2H),2.27(s,6H),2.19(s,3H); 13 C NMR(101MHz, CDCl3)δ168.2,146.7,141.8,140.2,137.2,132.9,131.8,130.8,130.0,128.4,127.8,21.2,20.0; HRMS(ESI)m / z:[M+Na] + Calcdfor C 16 H 17 NNaO3S 326.0824; found:326.0826.

[0041] (R)-3-((tert-butylsulfinyl)amino)-2-naphthoic acid

[0042]

[0043] MP: 165.1-167.0℃; 1 H NMR (400MHz, CDCl3) δ9.93(s,1H),8.43(s,1H),7.72–7.67(m,3H),7.50(t,J=7.5Hz,1H),7.31(t,J=7.6Hz,1H),1.50(s,9H); 13C NMR(101MHz, CDCl3)δ170.0,141.1,136.7,134.4,129.4,129.4,128.1,126.5,124.8,116.6,111.9,57.2,23.0; HRMS(ESI)m / z:[M+Na] + Calcd for C 15 H 17 NNaO3S 314.0821; found:314.0823.

[0044] (R)-3-((tert-butylsulfinyl)amino)thiophene-2-carboxylic acid

[0045]

[0046] MP: 154.1-155.8℃; 1 H NMR (400MHz, CDCl3) δ8.79 (s, 1H), 7.48 (d, J = 5.4Hz, 1H), 7.11 (d, J = 5.4Hz, 1H), 1.37 (s, 9H); 13 C NMR(101MHz, CDCl3)δ167.9,150.1,133.5,118.4,107.6,57.5,22.6; HRMS(ESI)m / z:[M+Na] + Calcd for C9H 13 NO3S2Na 270.0229; found:270.0228.

[0047] (R)-2-((tert-butylsulfinyl)amino)-6-methylbenzoic acid

[0048]

[0049] 1 H NMR (400MHz, CDCl3) δ9.22(s,1H),7.30–7.25(m,1H),7.19(d,J=8.2Hz,1H),6.86(d,J=7.4Hz,1H),2.47(s,3H),1.42(s,9H); 13 C NMR(101MHz, CDCl3)δ171.7,144.1,141.2,132.0,125.4,119.8,115.3,57.1,23.1,22.8; HRMS(ESI)m / z:[M+Na] + Calcd forC 12 H 17NNaO3S278.0821; found:278.0819.

[0050] (R)-2-((tert-butylsulfinyl)amino)-5-methylbenzoic acid

[0051]

[0052] MP: 126.4-128.1℃; 1 H NMR (400MHz, CDCl3) δ9.75 (s, 1H), 7.63 (s, 1H), 7.25 (d, J = 8.5Hz, 1H), 7.20–7.18 (m, 1H), 2.18 (s, 3H), 1.33 (s, 9H); 13 C NMR(101MHz, CDCl3)δ170.8,143.7,135.7,132.2,130.4,116.1,114.9,57.1,22.8,20.5; HRMS(ESI)m / z:[M+Na] + Calcdfor C 12 H 17 NNaO3S278.0821; found:278.0823.

[0053] (R)-2-((tert-butylsulfinyl)amino)-4-methylbenzoic acid

[0054]

[0055] MP: 134.2-136.0℃; 1 H NMR (400MHz, CDCl3) δ9.89 (s, 1H), 7.82 (d, J = 8.1Hz, 1H), 7.26 (s, 1H), 6.75 (dd, J = 8.2, 1.6Hz, 1H), 2.36 (s, 3H), 1.42 (s, 9H); 13 C NMR(101MHz, CDCl3)δ171.2,146.3,146.2,132.3,122.1,116.2,112.0,57.0,22.9,22.1; HRMS(ESI)m / z:[M+Na] + Calcd for C 12 H 17 NNaO3S278.0821; found:278.0822.

[0056] (R)-2-((tert-butylsulfinyl)amino)-3-fluorobenzoic acid

[0057]

[0058] MP: 143.3-145.1℃; 1 H NMR (400MHz, DMSO-d6) δ9.55 (s, 1H), 7.79 (d, J = 7.9Hz, 1H), 7.56–7.51 (m, 1H), 7.14–7.08 (m, 1H), 1.27 (s, 9H); 13 C NMR(101MHz,DMSO-d6)δ169.2(d,J C-F =3.7Hz), 153.4(d,J C-F =245.0Hz), 133.6(d,J) C-F =11.0Hz), 127.2(d,J C-F =3.3Hz), 122.2(d,J C-F =7.7Hz), 121.3(d,J C-F =19.6Hz), 120.2, 56.6, 21.7; 19 F NMR(376MHz,DMSO-d6)δ-134.58; HRMS(ESI)m / z:[M+Na] + Calcd for C 11 H 14 FNNaO3S282.0571; found:282.0575.

[0059] (R)-2-(tert-butylsulfinyl)amino)-6-fluorobenzoic acid

[0060]

[0061] MP: 115.5-116.8℃; 1 H NMR (400MHz, CDCl3) δ9.90(s,1H),7.35(td,J=8.4,5.8Hz,1H),7.16(d,J=8.4Hz,1H),6.67(td,J=9.4,7.9,2.5Hz,1H),1.42(s,9H); 13 C NMR(101MHz,CDCl3)δ168.4,163.2(d,J C-F =259.6Hz), 146.9(d,J) C-F =3.8Hz), 134.4(d,J C-F =11.8Hz), 111.7(d,J C-F =3.5Hz), 109.3(d,J C-F=24.0Hz), 106.1(d,J C-F =14.4Hz), 57.6, 22.8; 19 FNMR (376MHz, CDCl3) δ-103.70; HRMS (ESI) m / z: [M+Na] + Calcd forC 11 H 14 FNNaO3S282.0571; found:282.0570.

[0062] (R)-6-((tert-butylsulfinyl)amino)-2-fluoro-3-methylbenzoic acid

[0063]

[0064] MP: 123.7-125.2℃; 1 H NMR (400MHz, CDCl3) δ9.66 (s, 1H), 7.25 (d, J = 8.1Hz, 1H), 7.10 (d, J = 8.4Hz, 1H), 2.22 (s, 3H), 1.44 (s, 9H); 13 CNMR (101MHz, CDCl3) δ 168.4 (d, J C-F =2.3Hz), 161.0(d,J C-F =257.9Hz), 144.6(d,J) C-F =3.3Hz), 136.0(d,J C-F =8.1Hz), 118.5(d,J C-F =19.2Hz), 111.7(d,J C-F =3.7Hz), 106.2(d,J C-F =14.8Hz), 57.4, 22.8, 14.2; 19 FNMR (376MHz, CDCl3) δ-107.68; HRMS (ESI) m / z: [M+Na] + Calcd for C 12 H 16 FNNaO3S296.0727; found:296.0726.

[0065] (R)-6-((tert-butylsulfinyl)amino)-3-chloro-2-fluorobenzoic acid

[0066]

[0067] MP: 183.5-185.1℃; 1H NMR (400MHz, CDCl3) δ9.80 (s, 1H), 7.42 (dd, J = 9.0, 7.6Hz, 1H), 7.13 (dd, J = 9.1, 1.6Hz, 1H), 1.42 (s, 9H); 13 CNMR (101MHz, CDCl3) δ 167.5 (d, J C-F =3.4Hz), 158.4(d,J C-F =261.9Hz), 145.3(d,J) C-F =3.1Hz), 134.7(d,J C-F =2.2Hz), 114.5(d,J C-F =20.2Hz), 112.2(d,J C-F =4.3Hz), 107.5(d,J) C-F =14.4Hz), 57.8, 22.8; 19 F NMR (376MHz, CDCl3) δ-104.56; HRMS (ESI) m / z: [M+Na] + Calcd for C 11 H 13 ClFNNaO3S 316.0181; found:316.0181.

[0068] (S)-6-((tert-butylsulfinyl)amino)-2,3-difluorobenzoic acid

[0069]

[0070] MP: 131.2-132.8℃; 1 H NMR (400MHz, CDCl3) δ9.62(s,1H),7.29–7.22(m,1H),7.09–7.05(m,1H),1.43(s,9H); 13 C NMR(101MHz,CDCl3)δ167.2(d,J C-F =3.2Hz), 150.9(dd,J C-F =262.1,14.0Hz),145.9(dd,J C-F =243.7,14.0Hz),141.7,121.8(dd,J C-F =18.6,2.5Hz),111.7(t,J) C-F =5.1Hz), 108.5(d,J C-F =10.9Hz), 57.6, 22.8; 19F NMR(376MHz,CDCl3)δ-129.34(d,J F-F =21.6Hz), -144.91(d,J F-F =21.6Hz); HRMS(ESI)m / z:[M+Na] + Calcdfor C 11 H 13 F2NNaO3S 300.0476; found:300.0475.

[0071] Example 3: A chiral sulfinamide carboxylic acid compound was used as a chiral ligand for the palladium-catalyzed asymmetric reaction of an oxime ether-directed diaryl methanol derivative 1a with alkynyl bromide 2 to prepare a chiral 2-alkynyldiaryl methanol derivative 3a.

[0072] 0.1 mmol of diarylmethanol derivative 1a, 0.01 mmol of dichloro(acetonitrile)palladium(II), 0.1 mmol of silver carbonate, and 0.02 mmol of (R)-6-((tert-butylsulfinyl)amino)-3-chloro-2-fluorobenzoic acid were placed in a 10 mL Shrek tube. The Shrek tube was evacuated and then purged with nitrogen, a process repeated three times. Under a nitrogen atmosphere, 4 mL of a tetrahydrofuran / chloroform mixed solvent (v / v = 3 / 1) and 0.3 mmol of alkynyl bromide 2 were added via syringe, and the reaction mixture was then stirred at 30 °C (aluminum heat transfer module) for 48 h. The mixture was then diluted with dichloromethane and filtered through diatomaceous earth. After concentration, the residue was subjected to thin-layer silica gel chromatography to obtain the target product 3a.

[0073]

[0074] Characterization of typical product 3a:

[0075] (S)-Cyclopentanone O-(phenyl(2-((triisopropylsilyl)ethynyl)phenyl)methyl)oxime

[0076]

[0077] The yield was 79%, and the ee value was 92%. HPLC [AD-H] (n-hexane / isopropanol = 98 / 2, 0.6 mL / min) λ = 254 nm, tr = 10.4 min (major product), 11.5 min (minor product). 1HNMR (400MHz, CDCl3) δ7.55(d,J=7.6Hz,1H),7.46(d,J=7.8Hz,3H),7.35(q,J=8.1,7.7Hz,3H),7.30–7 .20(m,2H),6.77(s,1H),2.61(t,J=7.0Hz,2H),2.39(t,J=6.9Hz,2H),1.85–1.74(m,4H),1.17(s,21H); 13 CNMR (100MHz, CDCl3) δ167.1,144.0,141.3,133.3,128.5,128.1,127.6,127.4,127.0,1 26.8,122.5,105.2,95.9,83.5,31.1,28.3,25.3,24.8,18.8,11.4; HRMS(ESI)m / z:[M+H] + Calcd for C 29 H 40 NOSi 446.2874; found:446.2874.

[0078] Example 4: Results of the reaction between other diaryl methanol derivative 1 and acetylacetonate 2 in chiral sulfinamide carboxylic acids (R)-6-((tert-butylsulfinyl)amino)-3-chloro-2-fluorobenzoic acid and (S)-6-((tert-butylsulfinyl)amino)-2,3-difluorobenzoic acid:

[0079]

Claims

1. A chiral sulfinamide carboxylic acid compound, characterized in that, Optically active compounds with structures as shown in formula (I): ； In formula (I): R is selected from tert-butyl; R 1 It is selected from one or more of H, C1~C4 alkyl, C1~C4 alkoxy, C1~C4 alkanoyloxy, C1~C4 alkoxycarbonyl, cyano, nitro and halogen.

2. The chiral sulfinamide carboxylic acid compound according to claim 1, characterized in that, R 1 It is selected from one or more of H, methyl, tert-butyl, methoxy, formoxy, methoxycarbonyl, cyano, nitro, F or Cl.

3. The chiral sulfinamide carboxylic acid compound according to claim 1, characterized in that, It is one of the following compounds: 。 4. A method for synthesizing the chiral sulfinamide carboxylic acid compound as described in any one of claims 1 to 3, characterized in that, Includes the following steps: ； (1) Palladium acetate, 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene, chiral sulfinamide and cesium carbonate are placed in a reactor, the reactor is evacuated and then purged with nitrogen. This process is repeated 2 to 3 times. Under nitrogen protection, methyl or ethyl o-bromo- or o-iodoarylcarbamate and dioxane are added. The reaction mixture is then stirred at 80 to 120 °C until the raw materials are consumed. After post-treatment, the corresponding compound A is obtained. (2) The compound A obtained in the first step was dissolved in a mixed solvent of tetrahydrofuran and water at 0~20℃. Lithium hydroxide was added in batches. After the reaction was completed, ethyl acetate and hydrochloric acid aqueous solution were added to the system to quench the reaction. Then, post-treatment was performed to obtain the corresponding chiral sulfinamide carboxylic acid compound B.

5. The application of the chiral sulfinamide carboxylic acid compound as described in any one of claims 1 to 3, characterized in that, The chiral sulfinamide carboxylic acid compound was used as a chiral ligand for the palladium-catalyzed oxime ether-directed asymmetric reaction of diaryl methanol derivative 1 with alkynyl bromide 2 to prepare chiral 2-alkynyldiaryl methanol derivative 3. ； Where: R 3 Independently selected from C1-C3 alkyl groups or two R groups 3 Connecting two R 3 The carbon atoms together form a C3-C ring. 10 cycloalkyl or C3-C with substituents 10 cycloalkyl, the C3-C 10 The substituents on the cycloalkyl group are C1-C4 alkyl groups; R 4 It is one or more of C1-C4 alkyl, aryl, silanoxy, hydroxymethyl, alkoxy, hydroxy, acetyl, F, Cl, and Br; R 5 It is a sterically hindered silane.

6. The application of the chiral sulfinamide carboxylic acid compound according to claim 5, characterized in that, R 3 It is a methyl group or two R groups. 3 Connecting two R 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 4,4-dimethylcyclohexyl, 3,3-5,5-tetramethylcyclohexyl or adamantyl are formed by the cyclic combination of carbon atoms.

7. The application of the chiral sulfinamide carboxylic acid compound according to claim 5, characterized in that, R 4 It is one or more of methyl, ethyl, isopropyl, tert-butyl, phenyl, tert-butyldimethylsiloxy, triisopropylsiloxy, hydroxymethyl, methoxy, benzyloxy, hydroxy, acetyl, F, Cl, and Br.

8. The application of the chiral sulfinamide carboxylic acid compound according to claim 5, characterized in that, R 5 It is tert-butyldimethylsilyl, triethylsilyl, or triisopropylsilyl.

9. The application of the chiral sulfinamide carboxylic acid compound according to claim 5, characterized in that, The reaction process is as follows: the diaryl methanol derivative 1, alkynyl bromine 2, palladium catalyst, silver carbonate, and chiral sulfinamide carboxylic acid compound are mixed in a molar equivalent ratio of 1:1.0~3.0:0.05~0.15:1.0~3.0:0.1~0.2 in a mixed solvent of tetrahydrofuran and chloroform, and reacted at 25~40℃ for 24~72 hours. After the reaction is completed, the mixture is filtered and purified by column chromatography to obtain chiral 2-alkynyldiaryl methanol derivative 3.

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