Preparation method of chiral benzyl carboxylic acid

Abstract

The invention discloses a preparation method of chiral benzyl carboxylic acid, which belongs to the technical field of benzyl carboxylic acid synthesis, and comprises the following steps: in an organic solvent, in the presence of a nickel catalyst, a chiral ligand, a reducing agent and an additive, taking water as a hydrogen source, and carrying out hydrocarboxylation reaction on a styrene substrate and carbon dioxide to prepare the chiral benzyl carboxylic acid, the asymmetric hydrocarboxylation reaction is carried out by taking styrene as a substrate, taking a carbon dioxide atmosphere as another substrate and taking water as a hydrogen source, so that the chiral benzyl carboxylic acid is prepared, and the reaction has better substrate universality and functional group compatibility, high yield, good purity and low production cost, and is more suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a method for preparing chiral benzyl carboxylic acid, and belongs to the technical field of benzyl carboxylic acid synthesis. Background Art

[0002] Chiral carboxyl groups are important structural units in natural products and drug molecules. The traditional preparation of chiral carboxylic acids is mainly achieved by asymmetric splitting or asymmetric alkylation reactions induced by chiral auxiliary groups. These methods have many steps and low efficiency, resulting in a huge waste of time, energy and resources.

[0003] Compared with traditional synthesis methods, the direct carboxylation reaction of carbon dioxide catalyzed by transition metals under mild conditions with cheap and readily available allyl compounds and olefins as raw materials can synthesize chiral carboxylic acids in a regio- and stereo-selective manner. It has the advantages of being simple, direct and environmentally friendly, and is the focus of scientists' research. Although the carboxylation reaction of allyl compounds and other substrates has made great progress, however, the research on asymmetric carboxylation reaction is very little.

[0004] Summary of the invention

[0005] The object of the present invention is to provide a method for preparing chiral benzyl carboxylic acid by asymmetric hydrocarboxylation reaction.

[0006] The technical solution adopted by the present invention is as follows:

[0007] A method for preparing a chiral benzyl carboxylic acid comprises the following steps: in an organic solvent, in the presence of a nickel catalyst, a chiral ligand, a reducing agent and an additive, using water as a hydrogen source, subjecting a styrene substrate represented by formula (II) to a hydrogen carboxylation reaction with carbon dioxide to prepare a chiral benzyl carboxylic acid represented by formula (I).

[0008] The reaction equation involved in the present invention is as follows:

[0009]

[0010] Further settings are:

[0011] The styrene substrate represented by formula (II) is marked with a group R, which indicates that it is a substituent directly connected to the benzene ring; preferably, R is selected from H, unsubstituted C1~C 30 Alkyl, substituted C1~C 30 An alkyl group, or a 6-12 membered carbon ring connected by carbon-carbon bonds;

[0012] The substituted C1~C 30 The alkyl group is selected from C6-C 10Aryl, OH, OBz, COOEt, CF3, OMe, OPh, OTBS, halogen, Or one of CN.

[0013] The nickel catalyst is nickel chloride.

[0014] The chiral ligand is a dinitrogen chiral ligand L:

[0015]

[0016] The molar ratio of the chiral ligand to the nickel catalyst is 1.5:1-4:1.

[0017] The hydrocarboxylation reaction is carried out under a carbon dioxide atmosphere.

[0018] The organic solvent is DMF.

[0019] The molar concentration of the styrene substrate of formula (II) in the organic solvent is 0.05-1.0 mol / L.

[0020] The reducing agent is manganese or zinc.

[0021] The additive is an acetate, preferably one or more of lithium acetate, sodium acetate, zinc acetate and manganese acetate.

[0022] The reaction temperature is 30-60°C.

[0023] The reaction time is 10-24h.

[0024] The chiral benzyl carboxylic acid prepared by the invention can be widely used in anti-inflammatory and analgesic drugs, such as ibuprofen, naproxen, ketoprofen and the like.

[0025] The beneficial effects of the present invention are as follows:

[0026] (1) The present invention uses styrene as a substrate, another substrate is a carbon dioxide atmosphere, and water as a hydrogen source to carry out an asymmetric hydrocarboxylation reaction to prepare chiral benzyl carboxylic acid.

[0027] (2) The present invention studies the nickel-catalyzed asymmetric hydrocarboxylation reaction of styrene substrates. The reaction has good substrate universality and functional group compatibility, high yield, good purity, low production cost, and is more suitable for industrial production. Most substrates can give excellent reaction results.

[0028] (3) Chiral organic benzyl carboxylic acid compounds are very important in synthesis and medicinal chemistry. The synthetic method we developed provides a simple and efficient route to synthesize chiral benzyl carboxylic acids.

[0029] The present invention is further described below in conjunction with specific implementation modes. DETAILED DESCRIPTION

[0030] Example 1

[0031] A method for preparing chiral benzyl carboxylic acid, the general operation steps of which are as follows: add a stirrer, NiCl2 (0.025mmol, 10mol%), a ligand (0.0375mmol, 15mol%), Mn (0.5mmol, 2equiv.), H2O (0.25mmol, 1equiv.), and Zn(OAc)2 (0.25mmol, 1equiv.) into a dried sealed tube. Replace the carbon dioxide atmosphere three times, add a styrene substrate (0.25mmol, 1.0equiv.) and anhydrous DMF (2mL), close the sealed tube and react at 40°C for 12 hours. Add 1M HCl to quench the reaction, extract with ethyl acetate three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Silica gel column chromatography to obtain the target product.

[0032] The reaction equations involved are as follows:

[0033]

[0034] Example 2

[0035] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a colorless liquid compound represented by formula (2b) with a yield of 81%.

[0036] Product structure:

[0037]

[0038] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ11.24 (s, 1H), 7.39–7.05 (m, 5H), 3.70 (q, J = 7.1Hz, 1H), 1.48 (d, J = 7.2Hz, 3H). 13 C NMR (101MHz, CDCl3) δ181.09,139.66,128.60,127.52,127.31,45.33,17.98.Enantioselective ratio=87:13,determined by HPLC(Daicel Chiralpak AD-H Column,n-Hexane:i-PrOH=92:8,flow rate0.7mL / min, T=25℃, λ=214nm):t R =8.6min(minor),tR =9.5min(major).

[0039] Replacement Example

[0040] According to the preparation method of Example 2, the reaction conditions were adjusted as shown in Table 1, and their effects on the reaction yield were tested respectively.

[0041] Table 1. Effects of different reaction conditions on asymmetric hydrocarboxylation

[0042]

[0043]

[0044] .

[0045] Example 3

[0046] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a white solid compound represented by formula (2c) with a yield of 73%.

[0047] Product structure:

[0048]

[0049] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.28 (s, 2H), 6.98 (t, J = 7.3Hz, 1H), 6.91 (d, J = 8.4Hz, 1H), 4.11 (q, J = 7.1Hz, 1H), 3.86 (s, 3H), 1.51 (d, J = 7.2Hz, 3H). 13 C NMR (101MHz, CDCl3) δ179.79,156.63,128.66,128.37,127.99,120.84,110.73,55.49,38.98,16.79.

[0050] Example 4

[0051] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a transparent oily compound represented by formula (2d) with a yield of 92%.

[0052] Product structure:

[0053]

[0054] Product Confirmation: 1H NMR (400MHz, CDCl3) δ6.96 (d, J = 6.9Hz, 3H), 3.70 (q, J = 7.1Hz, 1H), 2.34 (s, 6H), 1.52 (d, J = 7.2Hz, 3H). 13 C NMR (101MHz, CDCl3) δ180.94,139.62,138.22,129.07,125.33,45.21,21.26,18.06.

[0055] Example 5

[0056] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a clear oily compound represented by formula (2e) with a yield of 66%.

[0057] Product structure:

[0058]

[0059] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.16–7.02(m,2H),6.77(d,J=8.2Hz,1H),3.81(s,3H),3.65(q,J=7.1Hz,1H),2.20(s,3H),1.47(d,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ181.01,157.03,131.37,129.81,126.87,125.75,109.92,55.31,44.46,18.13,16.26.

[0060] Example 6

[0061] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a yellow oily compound represented by formula (2f) with a yield of 75%.

[0062] Product structure:

[0063]

[0064] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.26(t,J=7.9Hz,1H),6.95–6.87(m,2H),6.82(dd,J=8.2,2.4Hz,1H),3.81(s,3H),3.72(q,J=7.2Hz,1H),1.51(d,J=7.2Hz,3H). 13CNMR(101MHz,CDCl3)δ13C NMR(101MHz,Chloroform-d)δ180.56,159.69,141.23,129.62,119.93,113.41,112.64,55.16,45.33,18.02.

[0065] Example 7

[0066] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a white solid compound represented by formula (2g) with a yield of 81%.

[0067] Product structure:

[0068]

[0069] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.42(d,J=7.2Hz,2H),7.37(t,J=7.5Hz,2H),7.31(t,J=7.0Hz,1H),7.24(dd ,J=8.3,7.5Hz,1H),7.00–6.85(m,3H),5.04(s,2H),3.70(q,J=7.2Hz,1H),1.49(d,J=7.2Hz,3H). 13 CNMR(101MHz, CDCl3)δ180.29,158.97,141.25,136.82,129.67,128.55,127.97,127.57,120.24,114.38,113.48,69.97,45.28,18.04.

[0070] Example 8

[0071] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a yellow oily compound represented by formula (2h) with a yield of 79%.

[0072] Product structure:

[0073]

[0074] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.18(t,J=7.9Hz,1H),6.91(d,J=7.7Hz,1H),6.81(s,1H),6.75(dd, J=8.1,2.0Hz,1H),3.68(q,J=7.1Hz,1H),1.49(d,J=7.2Hz,3H),0.98(s,9H),0.19(s,6H).13 C NMR (101MHz, CDCl3) δ180.65,155.81,141.15,129.50,120.48,119.42,118.97,45.19,25.68,18.12,-4.44.

[0075] Example 9

[0076] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a white solid compound represented by formula (2i) with a yield of 78%.

[0077] Product structure:

[0078]

[0079] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.26(dd,J=14.4,7.0Hz,1H),7.13(dd,J=12.7,7.7Hz,3H),3.73(q,J=7.1Hz,1H),2.37(s,3H),1.53(d,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ180.61,139.66,138.34,128.56,128.29,128.15,124.59,45.24,21.39,18.07.

[0080] Example 10

[0081] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a white solid compound represented by formula (2j) with a yield of 89%.

[0082] Product structure:

[0083]

[0084] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.23 (d, J = 8.6Hz, 2H), 6.85 (d, J = 8.5Hz, 2H), 3.78 (s, 3H), 3.68 (q, J = 7.0Hz, 1H), 1.48 (d, J = 7.2Hz, 3H). 13 CNMR (101MHz, CDCl3) δ180.99,158.81,131.83,128.60,114.02,55.24,44.48,18.13.

[0085] Embodiment 11

[0086] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a white solid compound represented by formula (2k) with a yield of 81%.

[0087] Product structure:

[0088]

[0089] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.32(t,J=7.7Hz,2H),7.27(d,J=8.4Hz,2H),7.09(t,J=7.0Hz,1H), 7.00(d,J=8.5Hz,2H), 6.95(d,J=8.2Hz,2H), 3.72(q,J=7.1Hz,1H), 1.50(d,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ180.71,156.97,156.58,134.37,129.72,128.89,123.35,118.99,118.81,44.62,18.15.

[0090] Example 12

[0091] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a colorless oily compound represented by formula (21) with a yield of 85%.

[0092] Product structure:

[0093]

[0094] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.36–7.10(m,4H),3.87–3.64(m,1H),2.40(d,J=3.8Hz,3H),1.56(t,J=5.6Hz,3H). 13 C NMR (101MHz, CDCl3) δ181.26,136.98,136.74,129.30,127.41,44.94,20.98,18.01.

[0095] Embodiment 13

[0096] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a white solid compound represented by formula (2m) with a yield of 87%.

[0097] Product structure:

[0098]

[0099] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.36 (d, J = 8.4Hz, 2H), 7.27 (d, J = 8.3Hz, 2H), 3.73 (q, J = 7.2Hz, 1H), 1.52 (d, J = 7.2Hz, 3H), 1.32 (s, 9H). 13 CNMR (101MHz, CDCl3) δ180.99,150.22,136.62,127.22,125.58,44.86,34.45,31.33,18.03.

[0100] Embodiment 14

[0101] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a yellow solid compound represented by formula (2n) with a yield of 57%.

[0102] Product structure:

[0103]

[0104] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.55(dd,J=7.0,4.6Hz,4H),7.40(dd,J=15.5,7.7Hz,4H),7.32(t,J=7.2Hz,1H),3.78(q,J=7.0Hz,1H),1.54(d,J=7.1Hz,3H). 13 CNMR (101MHz, CDCl3) δ180.09,140.67,140.38,138.72,128.72,127.99,127.41,127.27,127.06,44.92,18.10.

[0105] Embodiment 15

[0106] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a white solid compound represented by formula (2o) with a yield of 58%.

[0107] Product structure:

[0108]

[0109] Product Confirmation: 1H NMR (400MHz, CDCl3) δ7.98 (d, J = 8.0Hz, 2H), 7.37 (d, J = 8.0Hz, 2H), 3.89 (s, 3H), 3.78 (q, J = 7.0Hz, 1H), 1.51 (d, J = 7.1Hz, 3H). 13 CNMR (101MHz, CDCl3) δ179.56,166.82,144.79,129.96,129.23,127.68,52.12,45.31,17.99.

[0110] Example 16

[0111] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a yellow solid compound represented by formula (2p) with a yield of 61%.

[0112] Product structure:

[0113]

[0114] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.66(d,J=8.2Hz,2H),7.46(d,J=8.3Hz,2H),3.83(q,J=7.2Hz,1H),1.56(d,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ178.71,144.83,132.49,128.54,118.55,111.45,45.29,17.94.

[0115] Embodiment 17

[0116] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a clear oily compound represented by formula (2q) with a yield of 69%.

[0117] Product structure:

[0118]

[0119] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.07 (dd, J=12.2, 2.1Hz, 1H), 7.02 (d, J=8.8Hz, 1H), 6.9 1(t,J=8.5Hz,1H),3.87(s,3H),3.67(q,J=7.1Hz,1H),1.48(d,J=7.2Hz,3H). 13C NMR (101MHz, CDCl3) δ180.26, 152.25 (J=244.8Hz), 146.88 (J=10.6Hz), 132.56 (J=6. 2Hz), 123.34 (J=3.6Hz), 115.36 (J=18.9Hz), 113.38 (J=2.1Hz), 56.27, 44.34, 18.02. 19 F NMR (376MHz,CDCl3)δ-134.63.

[0120] Embodiment 18

[0121] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a transparent oily compound represented by formula (2r) with a yield of 73%.

[0122] Product structure:

[0123]

[0124] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.34–7.28(m,1H),7.20(s,1H),7.10(dd,J=8.2,1.9Hz,1H),3.70(q,J=7.2Hz,1H),2.38(s,3H),1.51(d,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ180.34,138.15,136.32,133.44,130.16,129.24,126.28,44.70,20.09,18.03.

[0125] Embodiment 19

[0126] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a clear oily compound represented by formula (2s) with a yield of 77%.

[0127] Product structure:

[0128]

[0129] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.15 (s, 1H), 7.03 (d, J = 8.2Hz, 1H), 6.72 (d, J = 8.2Hz, 1H), 4.54 (t,J=8.7Hz,2H),3.65(q,J=7.2Hz,1H),3.17(t,J=8.7Hz,2H),1.46(d,J=7.2Hz,3H). 13C NMR (101MHz, CDCl3) δ181.05,159.38,131.78,127.39,124.03,109.23,71.33,44.72,29.67,18.30.

[0130] Embodiment 20

[0131] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a yellow oily compound represented by formula (2s) with a yield of 72%.

[0132] Product structure:

[0133]

[0134] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.87–7.81(m,3H),7.79(s,1H),7.48(ddt,J=8.6,4.3,2.0Hz,3H),3.94(q,J=7.1Hz,1H),1.64(d,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ180.56,137.12,133.37,132.64,128.39,127.79,127.60,126.33,126.19,125.91,125.67,45.43,18.09.

[0135] Embodiment 21

[0136] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a white solid compound represented by formula (2u) with a yield of 77%.

[0137] Product structure:

[0138]

[0139] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ8.35(dd,J=8.3,0.7Hz,1H),8.05(d,J=8.4Hz,1H),7.62–7.55(m,1H),7.52(dd,J=11.1,4. 0Hz, 1H), 7.42 (d, J = 8.0Hz, 1H), 6.82 (d, J = 8.0Hz, 1H), 4.46 (q, J = 7.1Hz, 1H), 4.02 (s, 3H), 1.68 (d, J = 7.1Hz, 3H). 13C NMR (101MHz, CDCl3) δ180.90,154.94,132.15,127.83,126.91,125.90,125.03,124.59,122.83,122.76,103.34,55.47,40.55,17.73.

[0140] Embodiment 22

[0141] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a white solid compound represented by formula (2v) with a yield of 71%.

[0142] Product structure:

[0143]

[0144] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.28–7.23(m,1H),7.11(d,J=8.1Hz,1H),7.05(s,1H),3.68(q,J=7.1Hz,1H),2.91(dd,J=8.8,4.0Hz,2H),2.51(dd,J =18.9,8.5Hz,1H),2.45–2.38(m,1H),2.28(td,J=10.7,4.1Hz,1H),2.22–2.11(m,1H),2.10–1.93(m,3H),1.69–1.42(m,9H),0.90(s,3H). 13 C NMR (101MHz, CDCl3) δ221.11,180.33,138.89,136.82,128.14,128.11,125.69,124.96,124.93,50.4 3,47.97,44.80,44.27,38.01,35.83,31.52,29.37,29.35,26.43,25.59,21.54,18.03,18.02,13.79.

[0145] Embodiment 23

[0146] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a white solid compound represented by formula (2w) with a yield of 81%.

[0147] Product structure:

[0148]

[0149] Product Confirmation: 1H NMR (400MHz, CDCl3) δ7.24(d,J=7.6Hz,2H),7.11(d,J=7.7Hz,2H),3.72(q,J=7.0Hz,1H),2.4 6(d,J=7.1Hz,2H),1.86(dp,J=13.3,6.5Hz,1H),1.51(d,J=7.1Hz,3H),0.91(d,J=6.5Hz,6H). 13 C NMR (101MHz, CDCl3) δ181.26,140.82,136.95,129.37,127.27,45.03,45.01,30.15,22.39,18.08.

[0150] The compound synthesized in this embodiment can be used to prepare ibuprofen, which is a nonsteroidal anti-inflammatory drug (NSAID), mainly used to relieve mild to moderate pain, including headache, toothache, muscle pain and arthralgia. In addition, it is also commonly used to relieve fever and anti-inflammatory.

[0151] Embodiment 24

[0152] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a white solid compound represented by formula (2x) with a yield of 75%.

[0153] Product structure:

[0154]

[0155] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.67(d,J=8.9Hz,3H),7.39(d,J=8.4Hz,1H),7.16–7.04(m,2H),3.94–3.81(m,4H),1.57(d,J=7.1Hz,3H). 13 CNMR (101MHz, CDCl3) δ180.94,157.68,134.84,133.80,129.29,128.88,127.21,126.15,119.01,105.59,55.27,45.28,18.10.

[0156] The compound synthesized in this example can be used to prepare naproxen, which is a non-steroidal anti-inflammatory drug with anti-inflammatory, antipyretic and analgesic effects and is a PG synthase inhibitor.

[0157] Embodiment 25

[0158] According to the preparation method of Example 1, the styrene substrate was adjusted to obtain a white solid compound represented by formula (2y) with a yield of 51%.

[0159] Product structure:

[0160]

[0161] Product Confirmation: 1 H NMR (400MHz, CDCl3) δ7.83–7.74(m,3H),7.69(d,J=7.7Hz,1H),7.63–7.54(m,2H),7.51–7.41(m,3H),3.84(q,J=7.1Hz,1H),1.56(d,J=7.2Hz,3H). 13 CNMR (101MHz, CDCl3) δ196.44,179.17,140.09,137.92,137.39,132.54,131.62,130.08,129.31,129.27,128.59,128.30,45.07,18.14.

[0162] The compound synthesized in this example can be used to prepare ketoprofen, which has analgesic, anti-inflammatory and antipyretic effects and is used for rheumatoid arthritis, rheumatic arthritis, osteoarthritis, ankylosing spondylitis and gout.

Claims

1. A method for preparing a chiral benzyl carboxylic acid, characterized in that: The method comprises the following steps: in an organic solvent, in the presence of a nickel catalyst, a chiral ligand, a reducing agent and an additive, using water as a hydrogen source, subjecting a styrene substrate represented by formula (II) to a hydrogen carboxylation reaction with carbon dioxide to prepare a chiral benzyl carboxylic acid represented by formula (I); Where: The group marked with R indicates that it is a substituent directly connected to the benzene ring; R is selected from H, unsubstituted C1~C 30 Alkyl, substituted C1~C 30 or a 6-12 membered carbon ring connected by carbon-carbon bonds.

2. The method for preparing a chiral benzyl carboxylic acid according to claim 1, characterized in that: The substituted C1~C 30 The alkyl group, whose substituent is selected from C6-C 10 Aryl, OH, OBz, COOEt, CF3, OMe, OPh, OTBS, halogen, Or one of CN.

3. The method for preparing a chiral benzyl carboxylic acid according to claim 1, characterized in that: The nickel catalyst is nickel chloride.

4. The method for preparing a chiral benzyl carboxylic acid according to claim 1, characterized in that: The chiral ligand is a dinitrogen chiral ligand L:

5. The method for preparing a chiral benzyl carboxylic acid according to claim 1, characterized in that: The molar ratio of the chiral ligand to the nickel catalyst is 1.5:1 to 4:

1.

6. The method for preparing a chiral benzyl carboxylic acid according to claim 1, characterized in that: The hydrocarboxylation reaction is carried out under a carbon dioxide atmosphere.

7. The method for preparing a chiral benzyl carboxylic acid according to claim 1, characterized in that: The organic solvent is DMF, and the molar concentration of the styrene substrate in the organic solvent is 0.05-1.0 mol / L.

8. The method for preparing a chiral benzyl carboxylic acid according to claim 1, characterized in that: The reducing agent is manganese or zinc.

9. The method for preparing a chiral benzyl carboxylic acid according to claim 1, characterized in that: The additive is acetate, selected from one or more of lithium acetate, sodium acetate, zinc acetate and manganese acetate.

10. The method for preparing a chiral benzyl carboxylic acid according to claim 1, characterized in that: The reaction temperature is 30-60°C and the reaction time is 10-24h.

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