Preparation method of chiral phthaloyl ester prodrug

Abstract

The invention discloses a preparation method of a chiral phthaloyl ester prodrug, and relates to the technical field of organic chemical synthesis. According to the invention, isothiourea is taken as a Lewis base catalyst, acyl chloride is taken as an acylating agent, and an acylation dynamic kinetic resolution process of racemic 3-hydroxyisobenzofuran-1 (3H)-ketone (hereinafter referred to as phthalide) is realized, so that chiral phthaloyl ester with good to excellent yield and enantioselectivity and a natural product and a medicine containing the structure are formed.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a method for preparing a chiral phthalate prodrug. Background Art

[0002] Phthaloyl esters play a vital role in the anti-inflammatory process. For example, the commercial drug talosalate containing 3-hydroxyisobenzofuran-1(3H)-one (hereinafter referred to as phthalide) fragment is an inhibitor of platelet aggregation; Talniflumate is a phthalate drug with anti-inflammatory activity; and commercialized Talmetacin has anti-inflammatory, analgesic and anti-tumor activities and can be used to treat cardiovascular diseases. Currently, all phthalate drugs containing chiral centers are sold in the form of racemic mixtures. However, different biological activities are observed between R- and S-enantiomers, and the presence of racemic mixtures may affect the efficacy and other properties of the drug. Therefore, the development of a synthetic method to form a single enantiomer of chiral phthalide is of great significance in drug synthesis.

[0003] So far, obtaining optically pure phthalic acid esters through organic catalysts is a common treatment method. In 2019, Chi and his colleagues developed a prodrug strategy that uses o-phthalaldehyde and carboxylic acid as substrates to quickly construct phthalic acid esters (Nat. Commun. 2019, 10 (1), 1675-1682.). Subsequently, based on this, a large number of researchers have developed several organic catalytic dynamic kinetic resolution (DKR) acylation methods for racemic phthalide, such as a carbene-catalyzed asymmetric acylation reaction with dynamic kinetic resolution, which uses benzaldehyde as an acylating agent to react with o-phthalaldehyde to quickly obtain optically pure phthalic acid esters (Angew. Chem. Int. Ed. 2020, 59 (10), 3859-3863.). Zhang's research group disclosed an acylation reaction of racemic 3-hydroxyphthalide catalyzed by a chiral bicyclic imidazole. The reaction was carried out at -80°C through a DKR process, using acyl chloride as an acylating agent to obtain optically pure phthalic acid esters (Angew. Chem. Int. Ed. 2021, 60, 1641-1645.); some researchers also used anhydrides as acylating agents to achieve the organic catalytic acylation dynamic kinetic resolution of racemic phthalide (Org. Lett. 2023, 25 (30), 5585-5590; Angew.). Although the acylation DKR reaction of phthalide has been developed, the previously reported reaction process requires harsh reaction conditions or expensive catalysts. At the same time, the atomic utilization rate is low when anhydrides are used as acylating agents. Therefore, the reaction conditions need to be further optimized in order to prepare optically pure phthalic acid ester compounds under mild reaction conditions and high atom economy. Summary of the invention

[0004] The invention provides a method for preparing a chiral phthalate prodrug, so as to solve the unsatisfactory technical problems of the existing phthalide compound acylation DKR reaction, such as harsh reaction conditions, expensive catalysts and low reaction atom economy.

[0005] The technical solution adopted by the present invention is as follows:

[0006] A method for preparing a chiral phthalate prodrug, wherein the specific preparation process of the preparation method is shown in Formula 1, wherein isothiourea is used as a Lewis base catalyst and acyl chloride is used as an acylating agent to achieve dynamic kinetic resolution of compound 1 in Formula 1:

[0007]

[0008] Furthermore, the general structural formula of the isothiourea is shown in Formula 2:

[0009]

[0010] Furthermore, in Formula 2, R 1 is one of fluorine, bromine, chlorine, methyl and methoxy at any position on the phenyl group, R 2 is hydrogen or phenyl, R 3 It is hydrogen or isopropyl.

[0011] More preferably, R 1 is 8-chloro, R 2 is phenyl, R 3 The isothiourea is hydrogen, and the amount of the isothiourea added is 5%-20% of 1 mol of the compound in Formula 1.

[0012] Furthermore, the base used in Formula 1 is one or more of triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate and 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0013] Furthermore, the base used in Formula 1 is N,N-diisopropylethylamine, and the amount of N,N-diisopropylethylamine used is 150%-250% of 1 mole of the compound.

[0014] Furthermore, the solvent used in Formula 1 is one or more of tetrahydrofuran, chloroform, dichloromethane, toluene and mesitylene, and the volume of the solvent used is 1 mL to 4 mL.

[0015] Furthermore, the solvent used in Formula 1 is mesitylene, and the volume of the solvent used is 2 mL.

[0016] Furthermore, the reaction time in Formula 1 is 12 hours.

[0017] Furthermore, compound 3 / 4 in formula 1 is one of the compounds of the following structures:

[0018]

[0019] In summary, compared with the prior art, the present invention has the following advantages and beneficial effects:

[0020] The invention uses isothiourea as a Lewis base catalyst and acyl chloride as an acylating agent to realize the acylation dynamic kinetic resolution process of racemic 3-hydroxyphthalide under mild reaction conditions, thereby preparing chiral phthalic acid ester compounds with good to excellent yield and enantioselectivity and natural products and drugs containing the fragments. DETAILED DESCRIPTION

[0021] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with various embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention, that is, the embodiments described are only part of the embodiments of the present invention, rather than all of the embodiments.

[0022] The word "embodiment" used here as an "exemplary" does not necessarily mean that any embodiment described is superior to or better than other embodiments. Unless otherwise specified, the performance index tests in the embodiments of this method adopt conventional test methods in the art. The terms described in the present invention are only for describing specific implementation methods and are not intended to limit the content disclosed in the present invention.

[0023] Unless otherwise specified, the technical and scientific terms used herein have the same meanings as commonly understood by ordinary technicians in the technical field to which the invention belongs; other raw materials, reagents, experimental methods and technical means not specifically specified in the present invention refer to the raw materials and reagents commonly used by ordinary technicians in the field, as well as the commonly used experimental methods and technical means.

[0024] The synthetic routes of the following embodiments are as follows:

[0025]

[0026] In the reaction formula, R 1 Preferably 8-chloro, R 2 Preferably, phenyl, R 3 Preferably, hydrogen is used; the amount of isothiourea used is preferably 10% of 1 mol of the compound; the base is preferably N,N-diisopropylethylamine, and its amount is 200% of 1 mol of the compound; the reaction time is preferably 12 h; the structures of the prepared compounds 3 / 4 include 3a to 3x / 4a to 4h as shown below:

[0027]

[0028] Example 1

[0029] In this example, compound 3a was synthesized, and the corresponding synthesis route is as follows:

[0030]

[0031] Specific operation: Add phthalide 1a (0.10mmol), isothiourea catalyst (0.01mmol), and mesitylene (2mL) as solvent to a 4mL dried vial equipped with a magnetic stirrer. Add benzoyl chloride 2a (0.15mmol) and N,N-diisopropylethylamine (0.20mmol) in sequence. The stirring speed should be controlled between 200-300r / min, and the reaction is carried out at room temperature. The reaction is detected by GC-MS. The solvent is removed under reduced pressure, and the mixture is directly purified by column chromatography (petroleum ether / ethyl acetate = 20:1 to 10:1) to obtain the desired pure product 3a.

[0032] The obtained pure product 3a was a white solid with a yield of 92% and a melting point of 61-62°C. D 25 = +84.5 (c = 0.50 in CHCl3).

[0033] The relevant atlas data are as follows:

[0034] 1 H NMR (400MHz, CDCl3)δ:8.08–8.05(m,2H),7.99–7.97(m,1H),7.77(td,J=7.3, 6.9,1.2Hz,1H),7.71–7.67(m,3H),7.64–7.59(m,1H),7.48–7.44(m,2H).

[0035] 13 CNMR (101MHz, CDCl3)δ:167.96,165.11,144.50,134.94,134.12,131.37,130.20(2C),128.65(2C),128.41,126.62,125.88,123.79,93.30.

[0036] HRMS (ESI,m / z)calcd.for C 15 H 10 O4Na[M+Na] + :247.0471,found:277.04759.

[0037] HPLCanalysis :96:4er (IB column, 25℃, hexane / i-propanol=90 / 10, flow rate=0.5mL / min, λ=254nm), R t =17.1min(major),18.4min(minor).

[0038] According to the spectral data, it can be seen that pure product 3a was obtained in this example.

[0039] Example 2

[0040] In this example, compound 3b was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0041] The obtained pure product 3b was a white solid with a yield of 95%, a melting point of 137-138°C, [α] D 25 = +24.0 (c = 0.33 in CHCl3).

[0042] The relevant atlas data are as follows:

[0043] 1 H NMR (400MHz, CDCl3)δ:7.98–7.95(m,1H),7.92(dd,J=8.0,1.5Hz,1H),7.78(td,J=7.3,1.1Hz,1H),7.69(d,J=1.6Hz ,1H),7.68–7.64(m,2H),7.45(td,J=7.5,1.5Hz,1H),7.28(d,J=7.8Hz,1H),7.23(t,J=7.6Hz,1H),2.65(s,3H).

[0044] 13 CNMR (101MHz, CDCl3)δ:168.04,165.47,144.61,141.62,134.91,133.23,132.0 2,131.30,131.19,127.32,126.65,125.94,125.86,123.70,93.07,21.94.

[0045] HRMS (ESI,m / z)calcd.for C 16 H 12 O4Na[M+Na] + :291.0628,found:291.0616.

[0046] HPLCanalysis :94:6er(IB column,25℃,hexane / i-propanol=90 / 10, flow rate=0.5mL / min,λ=254nm),R t =15.7min(major),17.2min(minor).

[0047] According to the spectral data, it can be seen that pure product 3b was obtained in this example.

[0048] Example 3

[0049] In this example, compound 3c was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0050] The obtained pure product 3c was a white solid with a yield of 97% and a melting point of 104-105°C. D 25 = +23.8 (c = 0.40 in CHCl3).

[0051] The relevant atlas data are as follows:

[0052] 1 H NMR (400MHz, CDCl3)δ:7.99–7.97(m,1H),7.87–7.84(m,2H),7.78(td,J=7.4,1.2Hz,1H),7.71 –7.67(m,3H),7.42(ddt,J=7.6,2.0,0.9Hz,1H),7.34(td,J=7.5,1.1Hz,1H),2.39(s,3H).

[0053] 13 CNMR (101MHz, CDCl3)δ:167.99,165.29,144.58,138.55,134.90(2C),131.33 ,130.66,128.54,128.32,127.37,126.66,125.87,123.80,93.30,21.22.

[0054] HRMS (ESI,m / z)calcd.for C 16 H 12 O4Na[M+Na] + :291.0628,found:291.0620.

[0055] HPLC analysis :97:3er(IB column,25℃,hexane / i-propanol=95 / 5,flow rate=0.5

[0056] mL / min, λ=254nm), Rt=19.8min (major), 21.1min (minor).

[0057] According to the spectral data, it can be seen that pure product 3c was obtained in this example.

[0058] Example 4

[0059] In this example, compound 3d was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0060] The obtained pure product 3d was a white solid with a yield of 93% and a melting point of 110-111°C. D 25 = +38.3 (c = 0.20 in CHCl3).

[0061] The relevant atlas data are as follows:

[0062] 1 H NMR (400MHz, CDCl3)δ:8.01–7.98(m,1H),7.96–7.93(m,2H),7.79–7.75(m,1H),7.70–7.66(m,3H),7.28–7.24(m,2H),2.41(s,3H).

[0063] 13 CNMR (101MHz, CDCl3)δ:168.04,165.15,145.11,144.63,134.87,131.30,130.2 5,129.37,129.23,126.67,126.58,125.85,125.64,123.77,93.25,21.78.

[0064] HRMS (ESI,m / z)calcd.for C 16 H 12 O4Na[M+Na] + :291.0628,found:291.0619.

[0065] HPLCanalysis :97:3er(IB column,25℃,hexane / i-propanol=95 / 5, flow rate=0.5mL / min,λ=254nm),R t =21.0min(major),22.8min(minor).

[0066] It can be seen from the spectral data that pure product 3d was obtained in this example.

[0067] Example 5

[0068] In this example, compound 3e was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0069] The obtained pure product 3e was a white solid with a yield of 86% and a melting point of 147-148°C. D 25 = +33.3 (c = 0.20 in CHCl3).

[0070] The relevant atlas data are as follows:

[0071] 1 H NMR (400MHz, CDCl3)δ:7.99(ddd,J=7.3,4.7,2.0Hz,3H),7.79(td,J=7.5,1.2Hz,1H),7.71–7.67(m,3H),7.43(d,J=8.6Hz,2H).

[0072] 13 CNMR (101MHz, CDCl3)δ:167.82,164.29,144.28,140.73,134.99,131.55(2C),131.46,129.06(2C),126.87,126.57,125.93,123.78,93.34.

[0073] HRMS (ESI,m / z)calcd.for C 15 H9ClO4Na[M+Na] + :311.0082,found:311.0072.

[0074] HPLCanalysis :92:8er(IB column,25℃,hexane / i-propanol=90 / 10, flow rate=0.5mL / min,λ=254nm),R t =18.2min(major),19.7min(minor).

[0075] According to the spectral data, it can be seen that pure product 3e was obtained in this example.

[0076] Example 6

[0077] In this example, compound 3f was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0078] The obtained pure product 3f was a white solid with a yield of 89% and a melting point of 137-138°C. D 25 = +29.2 (c = 0.40 in CHCl3).

[0079] The relevant atlas data are as follows:

[0080] 1 H NMR (400MHz, CDCl3)δ:8.10–8.06(m,2H),7.98(dd,J=7.3,1.5Hz,1H),7.79(td,J=7.4,1.2Hz,1H),7.71–7.67(m,3H),7.13(t,J=8.6Hz,2H).

[0081] 13 CNMR (101MHz, CDCl3) δ: 167.86, 166.42 (d, J = 256.4Hz), 164.12, 144.35, 134.97, 132.94, 1 32.84,131.43,126.59,125.91,124.68(d,J=2.9Hz),123.77,116.04,115.82,93.30.

[0082] 19 FNMR (377MHz,CDCl3)δ:-103.26.

[0083] HRMS (ESI,m / z)calcd.for C 15 H9FO4Na[M+Na] + :295.0377,found:295.0372.

[0084] HPLCanalysis :96:4er (IB column, 25℃, hexane / i-propanol=90 / 10, flow rate=0.5mL / min, λ=254nm), R t =17.2min(major),19.0min(minor).

[0085] According to the spectral data, it can be seen that pure product 3f was obtained in this example.

[0086] Example 7

[0087] In this example, compound 3g was synthesized. The corresponding synthesis route and specific operations were referred to Example 1.

[0088] The obtained pure product 3g is a white solid with a yield of 76%, a melting point of 133-134°C, [α]D 25 = +10.6 (c = 0.33 in CHCl3).

[0089] The relevant atlas data are as follows:

[0090] 1 H NMR (400MHz, CDCl3)δ:9.02(d,J=8.7Hz,1H),8.22(dd,J=7.4,1.4Hz,1H),8.06(d,J=8.2Hz,1H),7.97(d,J=7.6Hz,1H),7.89(dd,J= 8.2,1.5Hz,1H),7.79–7.73(m,3H),7.66(tdd,J=8.7,4.9,1.4Hz,2H),7.56(ddd,J=8.1,6.8,1.3Hz,1H),7.45(t,J=7.8Hz,1H).

[0091] 13 CNMR (101MHz, CDCl3)δ:168.07,165.44,144.60,134.96,134.92,133.87,131.62,131.53,13 1.35,128.80,128.48,126.67,126.59,125.89,125.53,124.52,124.43,123.78,93.25.

[0092] HRMS (ESI,m / z)calcd.for C 19 H 12 O4Na[M+Na] + :327.0628,found:327.0619.

[0093] HPLC analysis :92:7er(IB column,25℃,hexane / i-propanol=95 / 5, flow rate=0.5mL / min,λ=254nm),R t =21.7min(major),25.7min(minor).

[0094] According to the spectral data, it can be seen that 3 g of pure product was obtained in this example.

[0095] Example 8

[0096] In this example, compound 3h was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0097] The obtained pure product 3h was a white solid with a yield of 87%, a melting point of 152-153°C, [α] D 25 = +15.6 (c = 0.40 in CHCl3).

[0098] The relevant atlas data are as follows:

[0099] 1 H NMR (400MHz, CDCl3)δ:7.97(dt,J=7.5,1.1Hz,1H),7.78(td,J=7.4,1.1Hz,1H),7.70–7.64(m,4H),7.28(dd,J=3.5,0.8Hz,1H),6.55(dd,J=3.5,1.7Hz,1H).

[0100] 13 CNMR (101MHz, CDCl3)δ:167.76,156.82,147.75,144.13,142.98,134.96,131.45,126.60,125.92,123.81,120.41,112.34,92.94.

[0101] HRMS (ESI,m / z)calcd.for C 13 H8O5Na[M+Na] + :267.0264,found:267.0254.

[0102] HPLCanalysis :94:6er(IB column,25℃,hexane / i-propanol=90 / 10, flow rate=0.5mL / min,λ=254nm),R t =26.4min(major),30.7min(minor).

[0103] According to the spectral data, it can be seen that pure product 3h was obtained in this example.

[0104] Example 9

[0105] In this example, compound 3i was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0106] The obtained pure product 3i was a light yellow solid with a yield of 91% and a melting point of 150-151°C. D 25 = +19.3 (c = 0.20 in CHCl3).

[0107] The relevant atlas data are as follows:

[0108] 1 H NMR (400MHz, CDCl3)δ:7.97(dt,J=7.7,1.1Hz,1H),7.87(dd,J=3.8,1.3Hz,1H),7.78(td,J=7.5,1.1Hz,1H),7.70–7.63(m,4H),7.13(dd,J=5.0,3.8Hz,1H).

[0109] 13 CNMR (101MHz, CDCl3)δ:167.89,160.58,144.11,135.28,134.96,134.40,131.60,131.41,128.18,126.59,125.88,123.79,93.22.

[0110] HRMS (ESI,m / z)calcd.for C 13 H8O4SNa[M+Na] + :283.0036,found:283.0025.

[0111] HPLCanalysis :97:3er(IB column,25℃,hexane / i-propanol=90 / 10, flow rate=0.5mL / min,λ=254nm),R t =23.1min(major),25.1min(minor).

[0112] According to the spectral data, it can be seen that pure product 3i was obtained in this example.

[0113] Example 10

[0114] In this example, compound 3j was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0115] The obtained pure product 3j was a white solid with a yield of 86% and a melting point of 120-121°C. D 25 = +16.8 (c = 0.20 in CHCl3).

[0116] The relevant atlas data are as follows:

[0117] 1 H NMR(400MHz, CDCl3) δ: 8.19 (dd, J=3.0, 1.2Hz, 1H), 7.97 (dd, J=7.6, 1.0Hz, 1H), 7.76 (dd, J=7. 5,1.1Hz,1H),7.70–7.64(m,3H),7.56(dd,J=5.1,1.2Hz,1H),7.34(dd,J=5.1,3.0Hz,1H).

[0118] 13 CNMR (101MHz, CDCl3)δ:167.94,160.88,144.48,134.90,134.80,131.64,131.35,128.04,126.64(2C),125.87,123.75,93.08.

[0119] HRMS (ESI,m / z)calcd.for C 13 H8O4SNa[M+Na] + :283.0036,found:283.0023.

[0120] HPLCanalysis :97:3er(IB column,25℃,hexane / i-propanol=90 / 10, flow rate=0.5mL / min,λ=254nm),R t =23.7min(major),26.3min(minor).

[0121] According to the spectral data, it can be seen that pure product 3j was obtained in this example.

[0122] Embodiment 11

[0123] In this example, compound 3k was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0124] The obtained pure product 3k was a white solid with a yield of 81% and a melting point of 152-153°C. D 25 = +10.0 (c = 0.25 in CHCl3).

[0125] The relevant atlas data are as follows:

[0126] 1 H NMR(400MHz, CDCl3)δ:8.13(d,J=0.8Hz,1H),8.00–7.98(m,1H),7.89–7.85(m,2H),7.82–7.78(m ,1H),7.72–7.67(m,3H),7.49(ddd,J=8.3,7.1,1.3Hz,1H),7.42(ddd,J=8.0,7.1,1.1Hz,1H).

[0127] 13 CNMR (101MHz, CDCl3)δ:167.81,161.31,144.16,142.85,138.49,135.00,132.53,13 1.49,131.35,127.68,126.60,125.95,125.93,125.25,123.82,122.85,93.40.

[0128] HRMS (ESI,m / z)calcd.for C 17 H 10 O4SNa[M+Na] + :333.0192,found:333.0180.

[0129] HPLCanalysis :92:8er(IB column,25℃,hexane / i-propanol=90 / 10, flow rate=0.5mL / min,λ=254nm),R t =31.8min(major),27.4min(minor).

[0130] According to the spectral data, it can be seen that pure product 3k was obtained in this example.

[0131] Example 12

[0132] In this example, compound 31 was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0133] The obtained pure product 31 was a light yellow solid with a yield of 77% and a melting point of 176-177°C. D 25 = -31.7 (c = 0.33 in CHCl3).

[0134] The relevant atlas data are as follows:

[0135] 1 H NMR(400MHz, CDCl3) δ: 7.92 (dd, J=7.5, 1.1Hz, 1H), 7.72 (td, J=7.5, 1.2Hz, 1H), 7.64 (td, J=7.5, 1.0Hz, 1H), 7.47 (d d,J=7.6,0.9Hz,1H),7.42(s,1H),7.32–7.27(m,2H),7.24–7.19(m,3H),3.01(t,J=7.7Hz,2H),2.78–2.74(m,2H)

[0136] 13 CNMR (101MHz, CDCl3)δ:171.45,167.87,144.29,139.75,134.82,131.27,128.6 5(2C),128.35(2C),126.55,126.48,125.80,123.58,92.68,35.63,30.57.

[0137] HRMS (ESI,m / z)calcd.for C 17 H 14 O4Na[M+Na] + :305.0784,found:305.0775.

[0138] HPLCanalysis :96:4er (IB column, 25℃, hexane / i-propanol=90 / 10, flow rate=0.5mL / min, λ=254nm), Rt=22.8min (major), 25.1min (minor).

[0139] According to the spectral data, it can be seen that pure product 31 was obtained in this example.

[0140] Embodiment 13

[0141] In this example, compound 3m was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0142] The obtained pure product 3m was a brown solid with a yield of 80% and a melting point of 118-119°C. D 25 =+46.54(c=0.40in CHCl3).

[0143] The relevant atlas data are as follows:

[0144] 1 H NMR(400MHz, CDCl3)δ:7.96(dd,J=7.5,1.3Hz,1H),7.83–7.75(m,2H),7.67(td,J=8.1,7.5 ,1.2Hz,2H),7.59(s,1H),7.54–7.52(m,2H),7.42–7.39(m,3H),6.46(d,J=16.0Hz,1H).

[0145] 13 CNMR (101MHz, CDCl3)δ:167.97,165.23,147.74,144.53,134.87,133.82,131.30 ,131.07,129.06(2C),128.43(2C),126.61,125.83,123.73,116.04,92.97.

[0146] HRMS (ESI,m / z)calcd.for C 17 H 12 O4Na[M+Na] + :303.0628,found:303.0616.

[0147] HPLCanalysis :97:3er(IB column,25℃,hexane / i-propanol=70 / 30, flow rate=0.5mL / min,λ=254nm),R t =26.8min(major),19.3min(minor).

[0148] According to the spectral data, it can be seen that pure product 3m was obtained in this example.

[0149] Embodiment 14

[0150] In this example, compound 3n was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0151] The obtained pure product 3n was a yellow oil with a yield of 97%. D 25 = +27.6 (c = 0.33 in CHCl3).

[0152] The relevant atlas data are as follows:

[0153] 1 H NMR(400MHz, CDCl3)δ:7.93(d,J=7.6Hz,1H),7.77(d,J=1.1Hz,1H),7.67–7.67(m,1H) ,7.61(d,J=7.6Hz,1H),7.46(s,1H),2.46(t,J=7.5Hz,2H),1.21(t,J=7.5Hz,3H).

[0154] 13 CNMR (101MHz, CDCl3)δ:172.97,167.94,144.38,134.86,131.25,126.47,125.73,123.57,92.62,27.39,8.66.

[0155] HRMS (ESI,m / z)calcd.for C 11 H 10 O4Na[M+Na] + :229.0471,found:229.0460.

[0156] HPLCanalysis :97:3er (IB column, 25℃, hexane / i-propanol=90 / 10, flow rate=0.5mL / min, λ=254nm), R t =15.2min(major),17.5min(minor).

[0157] According to the spectral data, it can be seen that pure product 3n was obtained in this example.

[0158] Embodiment 15

[0159] In this example, compound 3o was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0160] The pure product 3o was obtained as a colorless oil with a yield of 75%. D 25 = +13.1 (c = 0.33 in CHCl3).

[0161] The relevant atlas data are as follows:

[0162] 1H NMR(400MHz, CDCl3)δ:7.93(d,J=7.6Hz,1H),7.76(td,J=7.5,1.1Hz,1H),7.66(t,J=7.5Hz,1H),7.60(d,J=7.6Hz,1H ),7.45(s,1H),2.43(t,J=7.5Hz,2H),1.67(q,J=7.4Hz,2H),1.29(dp,J=8.8,4.6,4.0Hz,10H),0.87(d,J=7.0Hz,3H).

[0163] 13 C NMR(101MHz, CDCl3)δ:172.32,167.95,144.43,134.83,131.22,126.48,125 .74,123.54,92.60,34.00,31.74,29.11,29.04,28.94,24.51,22.60,14.05.

[0164] HRMS (ESI, m / z) calculation for C 17 H 22 O4Na[M+Na] + :313.1410,found:313.1397.

[0165] HPLC analysis: 96:4er (IB column, 25℃, hexane / i-propanol=90 / 10, flowrate=0.5mL / min, λ=254nm), R t =12.1min(major),13.7min(minor).

[0166] According to the spectral data, it can be seen that pure product 3o was obtained in this example.

[0167] Example 16

[0168] In this example, compound 3p was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0169] The obtained pure product 3p was a white solid with a yield of 74% and a melting point of 63-64°C. D 25 = +18.2 (c = 0.25 in CHCl3).

[0170] The relevant atlas data are as follows:

[0171] 1H NMR(400MHz, CDCl3)δ:7.86(dt,J=7.6,1.0Hz,1H),7.68(td,J=7.5,1.1Hz,1H),7.60–7.52(m,2H), 7.43(s,1H),7.07(dq,J=15.6,6.9Hz,1H),5.82(dq,J=15.5,1.7Hz,1H),1.85(dd,J=7.0,1.7Hz,3H)

[0172] 13 C NMR (101MHz, CDCl3) δ: 166.96, 163.55, 147.44, 143.53, 133.76, 130.18, 125.55, 124.74, 122.60, 120.06, 91.72, 17.27.

[0173] HRMS (ESI, m / z) calculation for C 12 H 10 O4Na[M+Na] + :241.0471,found:241.0464.

[0174] HPLC analysis: 97:3er (IB column, 25℃, hexane / i-propanol=90 / 10, flowrate=0.5mL / min, λ=254nm), R t =16.8min(major),18.7min(minor).

[0175] It can be seen from the spectral data that pure product 3p was obtained in this example.

[0176] Embodiment 17

[0177] In this example, compound 3q was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0178] The obtained pure product 3q was a white solid with a yield of 67%, a melting point of 133-134°C, [α] D 25 = +4.4 (c = 0.33 in CHCl3).

[0179] The relevant atlas data are as follows:

[0180] 1H NMR (400MHz, CDCl3) δ: 7.93 (dt, J = 7.5, 1.1 Hz, 1H), 7.75 (td, J = 7.5, 1.1 Hz, 1H), 7.66 (td, J = 7.5, 1. 0Hz,1H),7.55–7.51(m,2H),7.32–7.28(m,2H),7.04–7.00(m,1H),6.92–6.89(m,2H),4.74(s,2H).

[0181] 13 C NMR(101MHz, CDCl3)δ:167.88,167.61,157.50,143.76,135.03,131.57,129.72(2C),126.33,125.92,123.70,122.19,114.76(2C),92.98,65.06.

[0182] HRMS (ESI, m / z) calculation for C 16 H 12 O5Na[M+Na] + :307.0577,found:307.0566.

[0183] HPLC analysis: 90:10er (IA column, 25℃, hexane / i-propanol=80 / 20, flowrate=0.5mL / min, λ=254nm), R t =21.5min(major),27.8min(minor).

[0184] According to the spectral data, it can be seen that pure product 3q was obtained in this example.

[0185] Embodiment 18

[0186] In this example, compound 3r was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0187] The obtained pure product 3r was a white solid with a yield of 71% and a melting point of 64-65°C. D 25 = +14.0 (c = 0.40 in CHCl3).

[0188] The relevant atlas data are as follows:

[0189] 1H NMR(400MHz, CDCl3)δ:7.86(dt,J=7.6,1.0Hz,1H),7.67(td,J=7.5,1.1Hz,1H),7.58(td,J=7.5,1.0Hz,1H),7.51–7.49(m, 1H),7.37(s,1H),2.33(tt,J=11.2,3.7Hz,1H),1.91–1.84(m,2H),1.73–1.54(m,4H),1.48–1.38(m,2H),1.27–1.11(m,4H).

[0190] 13 C NMR (101MHz, CDCl3) δ: 173.48, 166.98, 143.56, 133.78, 130.17, 125.53, 124.77, 122.42, 91.57, 41.87, 27.66, 27.60, 24.54, 24.19, 24.16.

[0191] HRMS (ESI, m / z) calculation for C 15 H 16 O4Na[M+Na] + :283.0941,found:283.0929.

[0192] HPLC analysis: 99:1er (IB column, 25℃, hexane / i-propanol=90 / 10, flowrate=0.5mL / min, λ=254nm), R t =13.0min(major),14.0min(minor).

[0193] According to the spectral data, it can be seen that pure product 3r was obtained in this example.

[0194] Embodiment 19

[0195] In this example, compound 3s was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0196] The obtained pure product 3s was a white solid with a yield of 93% and a melting point of 89-90°C. D 25 = +59.6 (c = 0.33 in CHCl3).

[0197] The relevant atlas data are as follows:

[0198] 1H NMR(400MHz, CDCl3)δ:8.37–8.33(m,2H),8.05(ddd,J=8.0,6.8,1.2Hz,3H),7.73(s,1H),7.65–7.61(m,1H),7.49–7.45(m,2H),3.99(s,3H).

[0199] 13 C NMR(101MHz, CDCl3)δ:166.92,165.34,164.92,144.59,136.30,134.26,132. 67,130.26(2C),130.23,128.69(2C),128.16,125.96,125.04,93.05,52.93.

[0200] HRMS (ESI, m / z) calculation for C 17 H 12 O6Na[M+Na] + :335.0526,found:335.0518.

[0201] HPLC analysis: 97:3er (IA column, 25℃, hexane / i-propanol=80 / 20, flowrate=0.5mL / min, λ=254nm), R t =21.6min(major),23.1min(minor).

[0202] According to the spectral data, it can be seen that pure product 3s was obtained in this example.

[0203] Embodiment 20

[0204] In this example, compound 3t was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0205] The obtained pure product 3t was a white solid with a yield of 85%, a melting point of 148-149°C, [α] D 25 =+150.5(c=0.33in CHCl3).

[0206] The relevant atlas data are as follows:

[0207] 1 H NMR(400MHz, CDCl3)δ:8.08–8.05(m,2H),7.84(dt,J=10.8,1.1Hz,3H),7.65–7.61(m,2H),7.49–7.45(m,2H).

[0208] 13 C NMR (101MHz, CDCl3) δ: 166.94, 164.94, 146.22, 134.97, 134.29, 130.26 (2C), 130.16, 128.71, 128.13 (2C), 127.31, 127.11, 125.55, 92.60.

[0209] HRMS (ESI, m / z) calculation for C 15 H9BrO4Na[M+Na] + :354.9576,found:354.9561.

[0210] HPLC analysis: 98:2er (IB column, 25℃, hexane / i-propanol=95 / 5, flow rate=0.5mL / min, λ=254nm), R t =22.9min(major),25.0min(minor).

[0211] According to the spectral data, it can be seen that pure product 3t was obtained in this example.

[0212] Embodiment 21

[0213] In this example, compound 3u was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0214] The obtained pure product 3u was a white solid with a yield of 80% and a melting point of 135-136°C. D 25 = +24.9 (c = 0.33 in CHCl3).

[0215] The relevant atlas data are as follows:

[0216] 1 H NMR(400MHz, CDCl3)δ:8.79(d,J=2.0Hz,1H),8.65(dd,J=8.3,2.0Hz,1H),8.15–8.01 (m,2H),7.92(d,J=8.3Hz,1H),7.77(s,1H),7.67–7.63(m,1H),7.48(t,J=7.9Hz,2H).

[0217] 13C NMR (101MHz, CDCl3) δ: 165.43, 164.69, 150.48, 149.45, 134.53, 130.27 (2C), 129.84, 128.80 (2C), 128.59, 127.77, 125.37, 121.42, 92.83.

[0218] HRMS (ESI, m / z) calculation for C 15 H9NO6Na[M+Na] + :322.0322,found:322.0317.

[0219] HPLC analysis: 90:10er (IB column, 25℃, hexane / i-propanol=80 / 20, flowrate=0.5mL / min, λ=254nm), R t =31.8min(major),37.4min(minor).

[0220] According to the spectral data, it can be seen that pure product 3u was obtained in this example.

[0221] Embodiment 22

[0222] In this example, compound 3v was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0223] The obtained pure product 3v was a light yellow solid with a yield of 73% and a melting point of 82-83°C. D 25 = +5.3 (c = 0.20 in CHCl3).

[0224] The relevant atlas data are as follows:

[0225] 1 H NMR(400MHz, CDCl3)δ:8.07–8.04(m,2H),7.65–7.61(m,1H),7.50–7.46(m,3H),7.26–7.25(m,1H),6.39(dd,J=5.6,1.2Hz,1H).

[0226] 13 C NMR (101MHz, CDCl3) δ: 169.68, 164.58, 149.84, 134.21, 130.18 (2C), 128.69 (2C), 128.17, 125.42, 94.49.

[0227] HRMS (ESI, m / z) calculation for C11 H8O4Na[M+Na] + :227.0315,found:227.0304.

[0228] HPLC analysis: 91:9er (IB column, 25℃, hexane / i-propanol=90 / 10, flowrate=0.5mL / min, λ=254nm), R t =11.5min(major),12.0min(minor).

[0229] According to the spectral data, it can be seen that pure product 3v was obtained in this example.

[0230] Embodiment 23

[0231] In this example, compound 3w was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0232] The obtained pure product 3w was a light yellow solid with a yield of 84% and a melting point of 58-59°C. D 25 =-16.87(c=0.50in CHCl3).

[0233] The relevant atlas data are as follows:

[0234] 1 H NMR (400MHz, CDCl3)δ:8.05–8.03(m,2H),7.62–7.59(m,1H),7.48–7.44(m,2H),7.04–7.03(m,1H),6.02(q,J=1.4Hz,1H),2.14(d,J=1.6Hz,3H).

[0235] 13 C NMR (101MHz, CDCl3) δ: 170.06, 164.84, 163.12, 134.21, 130.14 (2C), 128.71 (2C), 128.24, 119.67, 94.99, 13.35.

[0236] HRMS (ESI, m / z) calculation for C 12 H 10 O4Na[M+Na] + :241.0471,found:241.0472.

[0237] HPLC analysis: 91:9er (IA column, 25℃, hexane / i-propanol=80 / 20, flowrate=0.5mL / min, λ=254nm), R t =12.2min(major),14.0min(minor).

[0238] According to the spectral data, it can be seen that pure product 3w was obtained in this example.

[0239] Embodiment 24

[0240] In this example, compound 3x was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0241] The pure product 3x was obtained as a colorless oil with a yield of 79%. D 25 =-40.3 (c = 0.40 in CHCl3).

[0242] The relevant atlas data are as follows:

[0243] 1 H NMR(400MHz, CDCl3)δ:8.07–8.05(m,2H),7.65–7.61(m,1H),7.50–7.46(m,2H),7.11(d,J=0. 9Hz, 1H), 6.02 (q, J = 0.8Hz, 1H), 2.47–2.35 (m, 2H), 1.75–1.64 (m, 2H), 1.03 (t, J = 7.4Hz, 3H).

[0244] 13 C NMR (101MHz, CDCl3) δ: 170.11, 167.44, 164.82, 134.19, 130.18 (2C), 128.72 (2C), 128.28, 118.59, 94.47, 29.58, 20.09, 13.74.

[0245] HRMS (ESI, m / z) calculation for C 14 H 14 O4Na[M+Na] + :269.0784,found:269.0780.

[0246] HPLC analysis: 92:8er (IA column, 25℃, hexane / i-propanol=80 / 20, flowrate=0.5mL / min, λ=254nm), R t=11.0min(major),12.5min(minor).

[0247] According to the spectral data, it can be seen that the pure product 3x was obtained in this example.

[0248] Embodiment 25

[0249] In this example, compound 4a was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0250] The obtained pure product 4a was a white solid with a yield of 79% and a melting point of 128-129°C. D 25 = +26.2 (c = 0.20 in CHCl3).

[0251] The relevant atlas data are as follows:

[0252] 1 H NMR (400MHz, CDCl3) δ: 7.97 (dt, J=7.8, 1.1Hz, 1H), 7.77 (td, J=7.5, 1.1Hz, 1H) ,7.70–7.65(m,4H),7.46(d,J=1.7Hz,1H),6.84(d,J=8.2Hz,1H),6.05(s,2H).

[0253] 13 C NMR(101MHz, CDCl3)δ:167.97,164.39,152.67,147.99,144.56,134.88,131. 32,126.65,126.49,125.86,123.74,122.20,109.84,108.23,102.09,93.25.

[0254] HRMS (ESI, m / z) calculation for C 16 H 10 O6Na[M+Na] + :321.0370,found:321.0551.

[0255] HPLC analysis: 90:10er (IA column, 25℃, hexane / i-propanol=70 / 30, flowrate=0.5mL / min, λ=254nm), Rt=19.7min (major), 25.4min (minor).

[0256] According to the spectral data, it can be seen that pure product 4a was obtained in this example.

[0257] Embodiment 26

[0258] In this example, compound 4b was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0259] The obtained pure product 4b was a colorless oil with a yield of 79%. D 25 = +18.3 (c = 0.33 in CHCl3).

[0260] The relevant atlas data are as follows:

[0261] 1 H NMR (400MHz, CDCl3) δ: 7.94 (dt, J=7.6, 1.0Hz, 1H), 7.75 (td, J=7.5, 1.1Hz, 1H ),7.65(td,J=7.6,1.0Hz,1H),7.55(dq,J=7.6,0.8Hz,1H),7.47(s,1H),2.47 (tt,J=8.9,5.3Hz,1H),1.65(dddd,J=15.6,8.8,4.9,1.2Hz,2H),1.47(dddd, J=14.8,6.9,4.5,1.9Hz,2H),1.38–1.32(m,4H),0.91(td,J=7.3,2.4Hz,6H).

[0262] 13 C NMR (101MHz, CDCl3) δ: 175.07, 168.02, 144.63, 134.80, 131.19, 126.63, 125.83, 123.37, 92.57, 45.14, 34.29, 34.25, 20.56, 20.51, 13.97, 13.94.

[0263] HRMS (ESI, m / z) calculation for C 16 H 20 O4Na[M+Na] + :299.1254,found:299.1241.

[0264] HPLC analysis: 99:1er (IA column, 25℃, hexane / i-propanol=95 / 5, flow rate=0.5mL / min, λ=254nm), R t =13.2min(major),14.8min(minor).

[0265] According to the spectral data, it can be seen that pure product 4b was obtained in this example.

[0266] Embodiment 27

[0267] In this example, compound 4c was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0268] The obtained pure product 4c was a light yellow oil with a yield of 87%. D 25 =+31.3 (c=0.40inCHCl3).

[0269] The relevant atlas data are as follows:

[0270] 1 H NMR(400MHz, CDCl3)δ:8.19–8.17(m,2H),7.99(d,J=7.5Hz,1H),7.90–7.88(m,2H),7.80(td,J=7.5,1 .1Hz,1H),7.73–7.69(m,3H),3.12–3.08(m,4H),1.54(dd,J=15.2,7.5Hz,4H),0.86(t,J=7.4Hz,6H).

[0271] 13 C NMR(101MHz, CDCl3)δ:167.70,163.88,145.40,144.04,135.08,131.67,13 1.60,130.83,127.18,126.51,126.00,123.80,93.47,49.86,21.87,11.13.

[0272] HRMS (ESI, m / z) calculation for C 21 H 24 NO6S[M+H] + :418.1319,found:418.1301.

[0273] HPLC analysis: 86:14er (IB column, 25℃, hexane / i-propanol=90 / 10, flowrate=0.5mL / min, λ=254nm), R t =36.3min(major),40.1min(minor).

[0274] According to the spectral data, it can be seen that pure product 4c was obtained in this example.

[0275] Embodiment 28

[0276] In this example, compound 4d was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0277] The obtained pure product 4d was a white solid with a yield of 80%, a melting point of 160-161°C, [α] D 25 = +40.6 (c = 0.50 in CHCl3).

[0278] The relevant atlas data are as follows:

[0279] 1 H NMR (400MHz, CDCl3) δ: 8.16 (d, J=2.3Hz, 1H), 8.06 (dd, J=8.9, 2.3Hz, 1H), 7.98 (dt, J=7.5, 1.0Hz, 1H), 7.79 (td, J=7.5, 1.1Hz, 1H), 7.72–7.66(m,2H),7.60(s,1H),7.00(d,J=9.0Hz,1H),3.89(d,J=6.5Hz,2H),2.79(s,3H),2.23–2.16(m,1H),1.08(d,J=6.8Hz,6H).

[0280] 13 C NMR(101MHz, CDCl3)δ:167.77,166.67,162.84,161.78,159.31,142.99,134.00,131.67,131.25,130.49, 125.53,124.97,124.59,122.62,118.46,114.22,111.67,102.09,92.06,74.74,27.12,18.01(2C),16.79.

[0281] HRMS (ESI, m / z) calculation for C 24 H 21 N2O5S[M+H] + :449.1166,found:449.1158.

[0282] HPLC analysis: 94:6er (IB column, 25℃, hexane / i-propanol=80 / 20, flowrate=0.5mL / min, λ=254nm), R t =34.6min(major),41.3min(minor).

[0283] According to the spectral data, it can be seen that pure product 4d was obtained in this example.

[0284] Embodiment 29

[0285] In this example, compound 4e was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0286] The obtained pure product 4e was a white solid with a yield of 72% and a melting point of 149-150°C. D 25 = +13.8 (c = 0.33 in CHCl3).

[0287] The relevant atlas data are as follows:

[0288] 1 H NMR (400MHz, CDCl3) δ: 7.96–7.94 (m, 1H), 7.79–7.76 (m, 2H), 7.74–7.66 (m, 2H), 7.65 (s, 1H), 7.44 (d, J = 8.5Hz, 1H).

[0289] 13 C NMR (101MHz, CDCl3) δ: 166.55, 160.71, 148.23, 144.52, 142.61, 140.38, 134.03, 130.59, 129.62, 127.22, 125.47, 124.91, 122.99, 92.85.

[0290] HRMS (ESI, m / z) calculation for C 14 H7Cl2NO4Na[M+Na] + :345.9644,found:345.9639.

[0291] HPLC analysis: 97:3er (OD-H column, 25℃, hexane / i-propanol=80 / 20, flowrate=0.5mL / min, λ=254nm), R t =20.6min(major),23.0min(minor).

[0292] According to the spectral data, it can be seen that pure product 4e was obtained in this example.

[0293] Embodiment 30

[0294] In this example, compound 4f was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0295] The pure product 4f was obtained as a colorless oil with a yield of 88%. D 25 = +11.5 (c = 0.33 in CHCl3).

[0296] The relevant atlas data are as follows:

[0297] 1 H NMR(400MHz, CDCl3)δ:7.97–7.87(m,3H),7.82(dd,J=6.3,3.3Hz,1H),7.65(dtd,J=15. 3,7.6,6.4Hz,2H),7.57–7.49(m,2H),7.43(q,J=5.1,4.0Hz,3H),4.18(d,J=2.1Hz,2H).

[0298] 13 C NMR(101MHz, CDCl3)δ:170.20,167.85,144.20,134.82,133.89,131.95,131.30,129.17,128 .91,128.58,128.28,126.62,126.47,125.98,125.81,125.53,123.54,123.52,93.06,38.75.

[0299] HRMS (ESI, m / z) calculation for C 20 H 14 O4Na[M+Na] + :341.0784,found:341.0773.

[0300] HPLC analysis:95:5er(IB column,25℃,hexane / i-propanol=95 / 5, flow rate=0.5mL / min,λ=254nm),R t =24.4min(major),38.8min(minor).

[0301] According to the spectral data, it can be seen that pure product 4f was obtained in this example.

[0302] Embodiment 31

[0303] In this example, compound 4g was synthesized. The corresponding synthesis route and specific operations were referred to Example 1.

[0304] The obtained pure product 4g was a light yellow oil with a yield of 97%, [α] D 25=+135.4 (c=0.50inCHCl3).

[0305] The relevant atlas data are as follows:

[0306] 1 H NMR(400MHz, CDCl3)δ:8.00(dd,J=7.9,1.7Hz,1H),7.95–7.93(m,1H),7.78–7.74(m,1H),7.68–7.6 4(m,2H),7.61–7.57(m,2H),7.29(td,J=7.7,1.2Hz,1H),7.12(dd,J=8.1,1.2Hz,1H),2.19(s,3H).

[0307] 13 C NMR(101MHz, CDCl3)δ:169.57,167.82,162.88,151.20,144.25,135.12,135.04, 132.20,131.48,126.43,126.22,125.84,124.17,123.94,121.57,93.19,20.81.

[0308] HRMS (ESI, m / z) calculation for C 17 H 12 O6Na[M+Na] + :335.0526,found:335.0518.

[0309] HPLC analysis: 93:7er (IB column, 25℃, hexane / i-propanol=90 / 10, flowrate=0.5mL / min, λ=254nm), R t =23.1min(major),25.7min(minor).

[0310] According to the spectral data, it can be seen that 4 g of pure product was obtained in this example.

[0311] Embodiment 32

[0312] In this example, compound 4h was synthesized. The corresponding synthesis route and specific operations are shown in Example 1.

[0313] The obtained pure product 4h was a white solid with a yield of 81%, a melting point of 160-161°C, [α] D 25 = +11.5 (c = 0.23 in CHCl3).

[0314] The relevant atlas data are as follows:

[0315] 1 H NMR (400MHz, CDCl3) δ: 7.94 (dt, J=7.3, 1.1Hz, 1H), 7.72 (td, J=7.5, 1.2Hz, 1H), 7.68–7.64 (m, 3H), 7.50–7. 46(m,3H),7.43(s,1H),6.92–6.88(m,2H),6.69(dd,J=9.0,2.5Hz,1H),3.78(d,J=4.5Hz,5H),2.37(s,3H).

[0316] 13 C NMR(101MHz, CDCl3)δ:169.39,168.31,156.12,144.16,139.48,136.34,134.88,133.73,131.39,131.24(2C),13 0.82,130.23,129.21(2C),126.48,125.91,123.55,115.05,112.01,111.22,101.09,93.07,55.70,30.21,13.43.

[0317] HRMS (ESI, m / z) calcd.For C 27 H 21 ClNO6[M+H] + :490.1052,found:490.1046.

[0318] HPLC analysis: 90:10er (IB column, 25℃, hexane / i-propanol=80 / 20, flowrate=0.5mL / min, λ=254nm), R t =36.0min(major),40.2min(minor).

[0319] According to the spectral data, it can be seen that pure product 4h was obtained in this example.

[0320] The above-mentioned embodiments only express the specific implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the protection scope of the present application. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the technical solution concept of the present application, and these all belong to the protection scope of the present application.

Claims

1. A method for preparing a chiral phthalate prodrug, characterized in that: The specific preparation process of the preparation method is shown in Formula 1, using isothiourea as a Lewis base catalyst and acyl chloride as an acylating agent to achieve dynamic kinetic resolution of compound 1 in Formula 1:

2. The method for preparing a chiral phthalate prodrug according to claim 1, characterized in that: The general structural formula of the isothiourea is shown in Formula 2:

3. The method for preparing a chiral phthalate prodrug according to claim 2, characterized in that: In formula 2, R 1 is one of fluorine, bromine, chlorine, methyl and methoxy at any position on the phenyl group, R 2 is hydrogen or phenyl, R 3 It is hydrogen or isopropyl.

4. The method for preparing a chiral phthalate prodrug according to claim 3, characterized in that: R 1 is 8-chloro, R 2 is phenyl, R 3 The isothiourea is hydrogen, and the amount of the isothiourea added is 5%-20% of 1 mol of the compound in Formula 1.

5. The method for preparing a chiral phthalate prodrug according to claim 1, characterized in that: The base used in Formula 1 is one or more of triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate and 1,8-diazabicyclo[5.4.0]undec-7-ene.

6. The method for preparing a chiral phthalate prodrug according to claim 5, characterized in that: The base used in formula 1 is N,N-diisopropylethylamine, and the amount of N,N-diisopropylethylamine used is 150%-250% of the molar amount of the compound.

7. The method for preparing a chiral phthalate prodrug according to claim 1, characterized in that: The solvent used in Formula 1 is one or more of tetrahydrofuran, chloroform, dichloromethane, toluene and mesitylene, and the volume of the solvent used is 1 mL to 4 mL.

8. The method for preparing a chiral phthalate prodrug according to claim 7, characterized in that: The solvent used in Formula 1 is mesitylene, and the volume of the solvent used is 2 mL.

9. The method for preparing a chiral phthalate prodrug according to claim 1, characterized in that: The reaction time in Formula 1 is 12 hours.

10. The method for preparing a chiral phthalate prodrug according to claim 1, characterized in that: In formula 1, compound 3 / 4 is one of the compounds with the following structures:

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