A method for preparing a chiral phthalate prodrug

Abstract

The application discloses a preparation method of a chiral phthalic ester prodrug and relates to the technical field of organic chemical synthesis. In the application, isothiourea is used as a Lewis base catalyst, and acyl chloride is used as an acylating agent, so that an acylation dynamic kinetic resolution process of racemic 3-hydroxyisobenzofuran-1(3H)-one (hereinafter referred to as phthalide) is realized, thereby forming a chiral phthalic ester with good to excellent yield and enantioselectivity and natural products and drugs containing the structure.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, and specifically to a method for preparing a chiral phthaloyl ester prodrug. Background Technology

[0002] Phthalate drugs play a crucial role in anti-inflammatory processes. For example, talosalate, a commercially available drug containing the 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 commercially available talmetacin has anti-inflammatory, analgesic, and antitumor activities and can be used to treat cardiovascular diseases. Currently, all phthalate drugs containing chiral centers are marketed in the form of racemic mixtures. However, different biological activities have been observed between the R- and S-enantiomers, and the presence of racemic mixtures may affect the efficacy and other properties of the drugs. Therefore, developing synthetic methods to form single enantiomers of chiral phthalides is of great significance in drug synthesis.

[0003] To date, obtaining optically pure phthalates via organic catalysts has been a common approach. In 2019, Chi and colleagues developed a prodrug strategy using phthalaldehyde and carboxylic acid as substrates to rapidly construct phthalate esters (Nat. Commun. 2019, 10(1), 1675-1682.). Subsequently, based on this, numerous researchers have developed several organocatalytic dynamic kinetic resolution (DKR) acylation methods for racemic phthalides, such as a carbene-catalyzed asymmetric acylation reaction with dynamic kinetic resolution, which uses benzaldehyde as an acylating agent to react with phthalaldehyde, and can rapidly obtain optically pure phthalates (Angew. Chem. Int. Ed. 2020, 59(10), 3859-3863.). Zhang's research group disclosed a chiral bicyclic imidazole-catalyzed acylation reaction of racemic 3-hydroxyphthalide, which was carried out at -80 °C via a DKR process, using acyl chloride as the acylation agent to obtain optically pure phthalyl esters (Angew. Chem. Int. Ed. 2021, 60, 1641-1645.). Other researchers have also used acid anhydrides as acylation agents to achieve dynamic kinetic resolution of racemic phthalide via organocatalytic acylation (Org. Lett. 2023, 25(30), 5585-5590; Angew.). Although the DKR reaction for acylation of phthalide has been developed, the previously reported reactions require harsh reaction conditions or expensive catalysts. In addition, the atom utilization rate is low when acid anhydrides are used as acylation agents. Therefore, further optimization of reaction conditions is needed to prepare optically pure phthalyl esters with mild reaction conditions and high atom economy. Summary of the Invention

[0004] This invention provides a method for preparing a chiral phthaloyl ester prodrug to solve the technical problems of the existing acylation of phthalyl compounds to DKR, such as harsh reaction conditions, expensive catalysts, and low atom economy.

[0005] The technical solution adopted in this invention is as follows:

[0006] A method for preparing a chiral phthalic ester prodrug, wherein the specific preparation process 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:

[0007]

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

[0009]

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

[0011] More preferably, R 1 It is 8-chloro, R 2 It is a phenyl group, R 3 The amount of hydrogen is used, and the amount of isothiourea added is 5%-20% of 1 mole 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 Equation 1 is 12 hours.

[0017] Furthermore, compound 3 / 4 in Formula 1 is one of the following compounds with the following structure:

[0018]

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

[0020] This invention uses isothiourea as a Lewis base catalyst and acyl chloride as an acylating agent to achieve the dynamic kinetic resolution process of racemic 3-hydroxyphthalide under mild reaction conditions, thereby preparing chiral phthaloyl ester compounds with good to excellent yields and enantioselectivity, as well as natural products and drugs containing this fragment. Detailed Implementation

[0021] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to various embodiments. It should be understood that the specific embodiments described herein are only for explaining the invention and are not intended to limit the invention; that is, the described embodiments are merely some embodiments of the invention, and not all embodiments.

[0022] The term "embodiment" used herein, as an example, is not necessarily to be construed as superior to or better than other embodiments. Performance testing in these embodiments, unless otherwise specified, employs conventional testing methods in the art. The terminology used in this invention is merely for describing particular implementations and is not intended to limit the scope of the disclosure.

[0023] Unless otherwise stated, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains; other raw materials, reagents, test methods and techniques not specifically mentioned herein refer to raw materials and reagents commonly used by one of ordinary skill in the art, as well as commonly employed test methods and techniques.

[0024] The synthesis routes for the following embodiments are as follows:

[0025]

[0026] In the reaction formula, R in the general formula of isothiourea structure 1 Preferably 8-chloro, R 2 Preferably phenyl, R 3 The preferred form is hydrogen, and the amount of isothiourea added is preferably 10% of 1 mole of the compound; the preferred base is N,N-diisopropylethylamine, which is used in an amount of 200% of 1 mole of the compound; the preferred reaction time is 12 h; the structure of the obtained compound 3 / 4 includes the following: 3a~3x / 4a~4h:

[0027]

[0028] Example 1

[0029] In this embodiment, compound 3a is synthesized via the following synthetic route:

[0030]

[0031] Specific procedures: Add phthalide 1a (0.10 mmol), isothiourea catalyst (0.01 mmol), and mesitylene (2 mL) as solvent to a 4 mL dried vial equipped with a magnetic stirrer. Then add benzoyl chloride 2a (0.15 mmol) and N,N-diisopropylethylamine (0.20 mmol) sequentially. The stirring speed should be controlled between 200-300 rpm, and the reaction should be carried out at room temperature. The reaction should be monitored for completion using GC-MS. Remove the solvent under reduced pressure, and purify the mixture directly 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. [α] D 25 = +84.5 (c = 0.50 in CHCl3).

[0033] The relevant spectral 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] As can be seen from the spectral data, pure product 3a was obtained in this embodiment.

[0039] Example 2

[0040] In this embodiment, compound 3b was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

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

[0042] The relevant spectral 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] As can be seen from the spectral data, pure product 3b was obtained in this embodiment.

[0048] Example 3

[0049] In this embodiment, compound 3c was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

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

[0051] The relevant spectral 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] As can be seen from the spectral data, pure product 3c was obtained in this embodiment.

[0058] Example 4

[0059] In this embodiment, compound 3d was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

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

[0061] The relevant spectral 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] As can be seen from the spectral data, this embodiment obtained the pure product 3d.

[0067] Example 5

[0068] In this embodiment, compound 3e was synthesized. The corresponding synthetic route and specific operations are described 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. [α] D 25 = +33.3 (c = 0.20 in CHCl3).

[0070] The relevant spectral 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] As can be seen from the spectral data, this embodiment obtained the pure product 3e.

[0076] Example 6

[0077] In this embodiment, compound 3f was synthesized. The corresponding synthetic route and specific operations are described 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. [α] D 25 = +29.2 (c = 0.40 in CHCl3).

[0079] The relevant spectral 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] As can be seen from the spectral data, this embodiment obtained the pure product 3f.

[0086] Example 7

[0087] In this embodiment, 3g of compound was synthesized. The corresponding synthetic route and specific operation are described in Example 1.

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

[0089] The relevant spectral 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] As can be seen from the spectral data, 3g of pure product was obtained in this embodiment.

[0095] Example 8

[0096] In this embodiment, the compound was synthesized in 3 hours. The corresponding synthetic route and specific operation are described in Example 1.

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

[0098] The relevant spectral 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] As can be seen from the spectral data, this embodiment obtained pure product 3h.

[0104] Example 9

[0105] In this embodiment, compound 3i was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

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

[0107] The relevant spectral 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] As can be seen from the spectral data, this embodiment obtained the pure product 3i.

[0113] Example 10

[0114] In this embodiment, compound 3j was synthesized. The corresponding synthetic route and specific operations are described 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. [α] D 25 = +16.8 (c = 0.20 in CHCl3).

[0116] The relevant spectral 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] As can be seen from the spectral data, pure product 3j was obtained in this embodiment.

[0122] Example 11

[0123] In this embodiment, compound 3k was synthesized. The corresponding synthetic route and specific operations are described 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. [α] D 25 = +10.0 (c = 0.25 in CHCl3).

[0125] The relevant spectral 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] As can be seen from the spectral data, this embodiment obtained the pure product 3k.

[0131] Example 12

[0132] In this embodiment, compound 3l was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

[0133] The obtained pure product 3l was a pale yellow solid with a yield of 77% and a melting point of 176–177 °C. [α] D 25 = -31.7 (c = 0.33 in CHCl3).

[0134] The relevant spectral 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] As can be seen from the spectral data, pure product 3l was obtained in this embodiment.

[0140] Example 13

[0141] In this embodiment, compound 3m was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

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

[0143] The relevant spectral 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] As can be seen from the spectral data, this embodiment obtained the pure product 3m.

[0149] Example 14

[0150] In this embodiment, compound 3n was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

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

[0152] The relevant spectral 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] As can be seen from the spectral data, this embodiment obtained the pure product 3n.

[0158] Example 15

[0159] In this embodiment, compound 3o was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

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

[0161] The relevant spectral 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)calcd.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] As can be seen from the spectral data, pure product 3o was obtained in this embodiment.

[0167] Example 16

[0168] In this embodiment, compound 3p was synthesized. The corresponding synthetic route and specific operations are described 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. [α] D 25 = +18.2 (c = 0.25 in CHCl3).

[0170] The relevant spectral 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)calcd.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] As can be seen from the spectral data, this embodiment obtained the pure product 3p.

[0176] Example 17

[0177] In this embodiment, compound 3q was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

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

[0179] The relevant spectral data are as follows:

[0180] 1H NMR (400MHz, CDCl3) δ: 7.93 (dt, J=7.5, 1.1Hz, 1H), 7.75 (td, J=7.5, 1.1Hz, 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)calcd.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] As can be seen from the spectral data, this embodiment obtained the pure product 3q.

[0185] Example 18

[0186] In this embodiment, compound 3r was synthesized. The corresponding synthetic route and specific operations are described 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. [α] D 25 = +14.0 (c = 0.40 in CHCl3).

[0188] The relevant spectral 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)calcd.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] As can be seen from the spectral data, this embodiment obtained the pure product 3r.

[0194] Example 19

[0195] In this embodiment, compound 3s was synthesized. The corresponding synthetic route and specific operations are described 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. [α] D 25 = +59.6 (c = 0.33 in CHCl3).

[0197] The relevant spectral 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)calcd.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] As can be seen from the spectral data, this embodiment obtained the pure product 3s.

[0203] Example 20

[0204] In this embodiment, compound 3t was synthesized. The corresponding synthetic route and specific operation are described in Example 1.

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

[0206] The relevant spectral 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)calcd.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] As can be seen from the spectral data, 3t of pure product was obtained in this embodiment.

[0212] Example 21

[0213] In this embodiment, compound 3u was synthesized. The corresponding synthetic route and specific operations are described 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. [α] D 25 = +24.9 (c = 0.33 in CHCl3).

[0215] The relevant spectral 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)calcd.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] As can be seen from the spectral data, this embodiment obtained the pure product 3u.

[0221] Example 22

[0222] In this embodiment, compound 3v was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

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

[0224] The relevant spectral 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)calcd.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] As can be seen from the spectral data, this embodiment obtained the pure product 3v.

[0230] Example 23

[0231] In this embodiment, compound 3w was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

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

[0233] The relevant spectral 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)calcd.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] As can be seen from the spectral data, this embodiment obtained 3w of pure product.

[0239] Example 24

[0240] In this embodiment, compound 3x was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

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

[0242] The relevant spectral 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)calcd.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] As can be seen from the spectral data, this embodiment obtained the pure product 3x.

[0248] Example 25

[0249] In this embodiment, compound 4a was synthesized. The corresponding synthetic route and specific operations are described 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. [α] D 25 = +26.2 (c = 0.20 in CHCl3).

[0251] The relevant spectral 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)calcd.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] As can be seen from the spectral data, pure product 4a was obtained in this embodiment.

[0257] Example 26

[0258] In this embodiment, compound 4b was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

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

[0260] The relevant spectral 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)calcd.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] As can be seen from the spectral data, pure product 4b was obtained in this embodiment.

[0266] Example 27

[0267] In this embodiment, compound 4c was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

[0268] The obtained pure product 4c was a pale yellow oily substance with a yield of 87%, [α]. D 25 = +31.3 (c = 0.40 in CHCl3).

[0269] The relevant spectral 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)calcd.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] As can be seen from the spectral data, this embodiment obtained the pure product 4c.

[0275] Example 28

[0276] In this embodiment, compound 4d was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

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

[0278] The relevant spectral 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)calcd.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] As can be seen from the spectral data, this embodiment obtained the pure product 4d.

[0284] Example 29

[0285] In this embodiment, compound 4e was synthesized. The corresponding synthetic route and specific operations are described 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. [α] D 25 = +13.8 (c = 0.33 in CHCl3).

[0287] The relevant spectral 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)calcd.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] As can be seen from the spectral data, this embodiment obtained the pure product 4e.

[0293] Example 30

[0294] In this embodiment, compound 4f was synthesized. The corresponding synthetic route and specific operations are described in Example 1.

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

[0296] The relevant spectral 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)calcd.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] As can be seen from the spectral data, this embodiment obtained the pure product 4f.

[0302] Example 31

[0303] In this embodiment, 4g of compound was synthesized. The corresponding synthetic route and specific operation are described in Example 1.

[0304] The obtained pure product, 4g, was a pale yellow oily substance, with a yield of 97%. [α] D 25= +135.4 (c = 0.50 in CHCl3).

[0305] The relevant spectral 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)calcd.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] As can be seen from the spectral data, 4g of pure product was obtained in this embodiment.

[0311] Example 32

[0312] In this embodiment, the compound was synthesized over 4 hours. The corresponding synthetic route and specific operations are described in Example 1.

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

[0314] The relevant spectral 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] As can be seen from the spectral data, this embodiment obtained pure product 4h.

[0320] The embodiments described above merely illustrate specific implementation methods of this application, and while the descriptions are detailed and specific, they should not be construed as limiting the scope of protection of this application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the technical solution of this application, and these modifications and improvements all fall within the scope of protection of this application.

Claims

1. A method for preparing a chiral phthaloyl ester 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: 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 compound 1; the solvent used is mesitylene; compound 3 / 4 is one of the following compounds: The general structural formula of the isothiourea is shown in Formula 2: In Equation 2, R 1 It is 8-chloro, R 2 It is a phenyl group, R 3 The amount of hydrogen is used, and the amount of isothiourea added is 5%-20% of 1 mole of the compound in Formula 1.

2. The method for preparing a chiral phthaloyl ester prodrug as described in claim 1, characterized in that, The reaction time in Formula 1 is 12 hours.

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