阅读说明：本技术 噻唑酰胺基异木兰花碱类衍生物及其制备方法和应用 (Thiazole amide isomagnoline derivative and preparation method and application thereof ) 是由 王磊 郭勇 柳继锋 于 2020-12-22 设计创作，主要内容包括：本发明公开了一种噻唑酰胺基异木兰花碱类衍生物及其制备方法和作为抑菌剂的应用,其化学结构如通式(I)所示。相较于现有的技术,本发明提供了一种新的噻唑酰胺基异木兰花碱类衍生物,其具有良好的抑菌活性,且化合物廉价易得。部分目标异木兰花碱类衍生物尤其是对小麦赤霉病菌、烟草赤星病菌、马铃薯干腐病菌、马铃薯枯萎病菌有较强的抑制活性,有望用于制备新型的天然产物抑菌剂。R选自C1-C4烷基、C1-C4卤代烷基、取代或非取代的苯基、或其中n＝0-2,R-1选自氢、C1-C4烷基、C1-C4烷氧基、卤素、硝基、醛基或氰基中的一种或几种；所述取代的苯基是被C1-C4烷基、C1-C4烷氧基、卤素、硝基、醛基或氰基取代的苯基。(The invention discloses a thiazole amide isomagnolia base derivative, a preparation method thereof and application of the derivative as a bacteriostatic agent, wherein the chemical structure of the derivative is shown as a general formula (I). Compared with the prior art, the invention provides a novel thiazole amide isomagnoline base derivative which has good antibacterial activity and is cheap and easy to obtain. Part of the target isomagnoflorine derivatives particularly have strong inhibitory activity on wheat scab, tobacco brown spot, potato dry rot and potato blight, and are expected to be used for preparing novel natural product bacteriostats. R is selected from C1-C4 alkyl, C1-C4 haloalkyl, substituted or unsubstituted phenyl, or Wherein n is 0-2, R 1 One or more selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, aldehyde group or cyano; the substituted phenyl is phenyl substituted by C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, aldehyde or cyano.)

1. A thiazole amide isomagnoline derivative has a chemical structure shown as a general formula (I):

r is selected from C1-C4 alkyl, C1-C4 haloalkyl, substituted or unsubstituted phenyl, orWherein n is 0-2, R₁One or more selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, aldehyde group or cyano;

the substituted phenyl is phenyl substituted by C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, aldehyde or cyano.

2. The thiazolylamidoisomagnoline derivative of claim 1, wherein the substituted phenyl group is a phenyl group mono-or di-substituted with a substituent selected from one or two of a C1-C4 alkyl group, a C1-C4 alkoxy group, a halogen, a nitro group, an aldehyde group, or a cyano group.

3. The thiazolylamidoisomagnanide derivative of claim 1, wherein R is₁Is mono-or di-substituted, n is 0-1.

4. The thiazolylamidoisomagnanide derivative of claim 1, wherein R is selected from the following:

5. the process for the preparation of thiazolylamidoisomagnoline derivatives according to any one of claims 1 to 4, comprising the steps of:

(1) taking isomagnoflorine (a) as a raw material, and carrying out bromination reaction on the isomagnoflorine (a) and copper bromide to obtain bromo-isomagnoflorine (b);

(2) reacting the bromo-isomagnoflorine (b) with thiourea to obtain amino thiazole substituted isomagnoflorine (c);

(3) finally, the amido thiazole substituted isomagnoflorine (c) reacts with RCOOH to obtain the compound with the general formula (I);

wherein R is as defined in any one of claims 1 to 4.

6. The method for preparing thiazolylamidoisomagnoline derivatives according to claim 5, wherein the reaction of step (1) is performed in ethyl acetate and chloroform at a temperature of 60-70 ℃.

7. The method for preparing thiazolylamidoisomagnoline derivatives according to claim 5, wherein the reaction of the step (2) is performed in absolute ethanol at a temperature of 45 to 55 ℃.

8. The method for preparing thiazolylamidoisomagnoline derivatives according to claim 5, wherein the reaction of step (3) is performed in anhydrous dichloromethane while HATU and triethylamine are added, and the reaction is performed at room temperature.

9. Use of thiazolylamidoisomagnoline derivatives according to any one of claims 1 to 4 as bacteriostatic agents.

Technical Field

The invention belongs to the technical field of organic chemistry, and particularly relates to a thiazole amide isomagnoline derivative, and a preparation method and application thereof.

Background

Isomagnoflorine (isomagnolone) with molecular formula of C₁₈H₁₈O₃Molecular weight 282.13, a colorless oil. The plant is a biphenyl neolignan compound separated from the bark of the star anise, is positioned in the west part of Sichuan, the north part and the east part of the Atamipont, and has the altitude of 1800-3000 m. Kouno I et al (Kouno I, Iwamoto C, KAMEDA Y, et al. A. New triphenyl-type neolignan and a biphenylneolignan from the bar of Illicium Simonisi [ J]Chemical and pharmaceutical bulletin,1994,42(1): 112-. Isomagnoflorine is reported to have good anticancer properties (Itogawa M, Ito C, Tokuda H, et al., cancer chemopreventive activity of photopropanoids and phytoquinones from Illicium plants [ J]Cancer Letters,2004,214(2):165-169.), anti-inflammatory (Huang D, Deng H, Chen W, et al. four new Sesquiterpene antigens from the stem bar of Illicium burmanium [ J]Fitotterapia, 2014,92:194-199.), insecticidal, anti-neurotoxicity and cytotoxicity (Kudo Y, Oka J I, Yamada K. Animatin, a potential GABAantasonist, isolated from Illicium anisum [ J ] Y]Neurosciences letters,1981,25(1):83-88.), antidepressant (Li J, Geng D, Xu J, et al]European journal of pharmacology 2013,707(1-3):112-]Chemical and pharmaceutical bulletin,1996,44(10): 1908-.

The parent isomagnoflorine has various biological activities, but the synthesis and antibacterial activity research of the derivative is not reported, and therefore, the isomagnoflorine derivative with higher antibacterial activity is obtained by structurally modifying the isomagnoflorine.

Disclosure of Invention

The purpose of the invention is as follows: aiming at the technical problems, the invention provides a thiazole amide isomagnolia base derivative with high-efficiency antibacterial activity, and a preparation method and application thereof.

The technical scheme is as follows: in order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:

a thiazole amido isomagnoline derivative has a chemical structure shown as a general formula (I):

r is selected from C1-C4 alkyl, C1-C4 haloalkyl, substituted or unsubstituted phenyl, orWherein n is 0-2, R₁One or more selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, aldehyde group or cyano;

the substituted phenyl is phenyl substituted by C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, aldehyde or cyano.

Preferably, the substituted phenyl is phenyl mono-or di-substituted with a substituent selected from one or two of C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro, aldehyde or cyano.

Preferably, said R₁Is mono-or di-substituted, n is 0-1.

Further preferably, said R is selected from the following:

the preparation method of the thiazole amide isomagnolia base derivative comprises the following steps:

(1) taking isomagnoflorine (a) as a raw material, and carrying out bromination reaction on the isomagnoflorine (a) and copper bromide to obtain bromo-isomagnoflorine (b);

(2) reacting the bromo-isomagnoflorine (b) with thiourea to obtain amino thiazole substituted isomagnoflorine (c);

(3) finally, the amido thiazole substituted isomagnoflorine (c) reacts with RCOOH to obtain the compound with the general formula (I);

wherein R is as described above.

Preferably, the reaction of step (1) is carried out in ethyl acetate and chloroform at a reaction temperature of 60-70 ℃.

Preferably, the reaction in the step (2) is carried out in absolute ethyl alcohol at the reaction temperature of 45-55 DEG C

Preferably, the reaction of step (3) is carried out in anhydrous dichloromethane, with the addition of HATU and triethylamine, and the reaction is carried out at room temperature.

Further preferred reaction procedures are as follows:

RCOOH is further preferably selected from acetic acid, chloroacetic acid, benzoic acid, (o, m, p) chlorobenzoic acid, (o, m, p) fluorobenzoic acid, (o, m, p) bromobenzoic acid, (o, m, p) methylbenzoic acid, (o, m, p) methoxybenzoic acid, 2, 4-dichlorobenzoic acid, 2-chloro-4-fluorobenzoic acid, p-cyanobenzoic acid, p-nitrobenzoic acid, p-aldehyde benzoic acid, phenylacetic acid, p-fluorophenylacetic acid, phenylpropionic acid.

The invention finally provides the application of the thiazole amide isomagnoline derivative as a bacteriostatic agent. Experiments prove that the thiazole amide isomagnoflorine derivative has good inhibitory activity on four plant pathogenic fungi, namely wheat scab, tobacco brown spot, potato blight and potato dry rot, and part of compounds are obviously higher than that of the parent isomagnoflorine.

The technical effects are as follows: compared with the prior art, the invention provides a novel thiazole amide isomagnalium base derivative which has good bacteriostatic activity, particularly has good inhibitory activity on four plant pathogenic fungi, namely wheat scab, tobacco brown spot, potato blight and potato dry rot, and is expected to be used for preparing novel natural product bacteriostatic agents. In addition, the preparation method is simple, low in cost and high in yield.

Drawings

FIG. 1 is an infrared spectrum of Compound 1 of the present invention;

FIG. 2 shows Compound 1 NMR of the present invention¹H, spectrogram;

Detailed Description

The present invention is further illustrated by the following examples.

Example 1 Synthesis of Thiazolylamidoisomagna base derivatives

(1) Synthesis of Thioisaglucone (b)

Accurately weighing copper bromide (9.5mmol,2126mg) and isomagnoflorine (4.8mmol,1343mg), adding the copper bromide and the isomagnoflorine into a 100mL round-bottom flask, adding 5mL ethyl acetate and 5mL chloroform solution into the flask, stirring and dissolving the mixture, stirring the mixture at 66 ℃ under reflux, detecting by TLC (thin layer chromatography) until the reaction is finished, filtering the copper bromide while the reaction is hot after the reaction is finished, washing and recovering the copper bromide by ethyl acetate, combining washing liquid and filtrate, recovering a solvent, and separating the obtained mixture by column chromatography (petroleum ether: ethyl acetate ═ 10:1) to obtain the thioisomagnoflorine (b), wherein the yield is 90%.

(2) Synthesis of aminothiazole substituted isomagnoflorine (c)

Weighing thiourea (5.1mmol,391mg) and adding the thiourea into the compound (b), dissolving the compound with 5mL of absolute ethanol, refluxing and stirring at 50 ℃, detecting by TLC, after the reaction is finished, drying the solvent and separating by column chromatography (petroleum ether: ethyl acetate ═ 2:1) to obtain the aminothiazole substituted isomagnoflorine (c), wherein the yield is 94%.

(3) Synthesis of Thiazolylamidoisomagna base derivatives (Compound 1)

Weighing the compound (c) (0.15mmol,50mg), benzoic acid (0.22mmol), HATU (0.22mmol,83.6mg) in a 25mL round-bottom flask, adding 2mL of anhydrous dichloromethane solution for dissolving, adding 0.06mL of triethylamine solution (0.45mmol) into the reaction solution, stirring overnight at room temperature under nitrogen protection, detecting by TLC until the reaction is finished, washing with saturated saline after the reaction is finished, extracting with dichloromethane (3X 20mL), combining organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by thin layer chromatography (PTLC) to obtain a pure product of the target compound 1, wherein the structure is as follows:

physicochemical constants and spectral data for compound 1: white solid, yield: 42%; melting point: 146-148 ℃; IR cm^-1(KBr):3060,2918,1675,1543,1468,1301,1265,1210,700；¹H NMR(400MHz CDCl₃)δ:7.90(d,J＝8Hz,2H,-Ph),7.55–7.59(m,1H,-Ph),7.45-7.52(m,4H,-Ph),6.99(d,J＝8.4Hz,2H,-Ph),6.93(d,J＝7.2Hz,1H,-Ph),6.75-6.82(m,2H,-Ph),6.01-6.08(m,1H,-CH＝CH₂),5.08-5.14(m,2H,-C ₂H＝CH),3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.52(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:164.45,156.39,155.15,145.43,143.65,143.14,136.37,132.91,131.75,129.77,129.62,128.95,127.79,127.50,125.46,121.88,119.95,117.91,116.89,115.82,34.03,12.17；MS(ESI)m/z calcd for C₂₆H₂₂N₂O₃S([M+H]+)443.14,found 443.35.

Example 2 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 2)

Compound 2 was synthesized by reacting compound (c) with 2-chlorobenzoic acid using the procedure described in example 1, compound 2 having the following structure:

physicochemical constants and spectral data for compound 2: yellow solid, yield: 56.8 percent; melting point: 158-160℃；IR cm^-1(KBr):3068,2918,2850,1654,1551,1469,1306,1264,1209,743；¹H NMR(400MHz CDCl₃)δ:7.74(d,J＝8Hz,1H,-Ph),7.48(d,J＝8.4Hz,2H,-Ph),7.42(d,J＝2.4Hz,2H,-Ph),7.33-7.35(m,1H,-Ph),7.00(d,J＝8.4Hz,2H,-Ph),6.92(t,J＝4.4Hz,1H,-Ph),6.79(d,J＝4.4Hz,2H,-Ph),5.99-6.09(m,1H,-CH＝CH₂),5.08-5.13(m,2H,-C ₂H＝CH),3.46(d,J＝6Hz,2H,-C ₂H-CH＝CH₂),2.51(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:163.48,156.25,154.10,145.44,144.49,143.20,136.38,132.57,132.28,131.31,130.82,130.70,130.06,129.77,127.74,127.27,125.42,122.19,119.93,117.83,116.88,115.78,34.02,12.20；MS(ESI)m/z calcd for C₂₆H₂₁ ³⁵ClN₂O₃S([M+H]+)477.10,found 477.35；calcd for C₂₆H₂₁ ³⁷ClN₂O₃S([M+H]+)479.10,found 479.34.

Example 3 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 3)

Compound 3 was synthesized by reacting compound (c) with 3-chlorobenzoic acid using the procedure described in example 1, compound 3 having the following structure:

physicochemical constants and spectral data for compound 3: brown solid, yield: 71.1 percent; melting point: 133 ℃ and 135 ℃; IR cm^-1(KBr):3072,2918,2850,1667,1553,1469,1311,1262,1206,739；¹H NMR(400MHz CDCl₃)δ:7.91(s,1H,-Ph),7.79(d,J＝7.2Hz,1H,-Ph),7.49(d,J＝8Hz,1H,-Ph),7.44(d,J＝7.6Hz,2H,-Ph),7.35(t,J＝8Hz,1H,-Ph),6.98(d,J＝8Hz,2H,-Ph),6.93(d,J＝7.2Hz,1H,-Ph),6.76-6.83(m,2H,-Ph),6.00-6.10(m,1H,-CH＝CH₂),5.09-5.14(m,2H,-C ₂H＝CH),3.47(d,J＝6Hz,2H,-C ₂H-CH＝CH₂),2.50(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:176.77,163.61,156.74,156.20,145.49,142.85,136.34,135.12,133.36,132.93,130.15,129.81,128.52,128.22,127.84,125.72,125.65,121.95,120.00,117.77,117.11,115.85,34.03,12.12；MS(ESI)m/z calcd for C₂₆H₂₁ ³⁵ClN₂O₃S([M+H]+)477.10,found 477.38；calcd for C₂₆H₂₁ ³⁷ClN₂O₃S([M+H]+)479.10,found 479.40.

Example 4 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 4)

Compound 4 was synthesized by reacting compound (c) with 4-chlorobenzoic acid using the procedure described in example 1, compound 4 having the following structure:

physicochemical constants and spectral data of compound 4: yellow solid, yield: 75.3 percent; melting point: 166-168 ℃; IR cm^-1(KBr):2918,1669,1538,1467,1288,1262,1203,856；¹H NMR(400MHz CDCl₃)δ:7.74(d,J＝8Hz,2H,-Ph),7.41(d,J＝8Hz,2H,-Ph),7.34(d,J＝7.6Hz,2H,-Ph),6.93(d,J＝8.4Hz,3H,-Ph),6.78(t,J＝8Hz,1H,-Ph),6.73(d,J＝8Hz,1H,-Ph),6.00-6.10(m,1H,-CH＝CH₂),5.09-5.14(m,2H,-C ₂H＝CH),3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.51(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:163.92,156.50,155.86,145.46,143.41,142.85,139.20,136.33,130.12,129.74,129.08,129.04,127.83,125.62,121.95,119.98,117.64,117.05,115.85,34.04,12.13；MS(ESI)m/z calcd for C₂₆H₂₁ ³⁵ClN₂O₃S([M+H]+)477.10,found 477.36；calcd for C₂₆H₂₁ ³⁷ClN₂O₃S([M+H]+)479.10,found 479.31.

Example 5 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 5)

Compound 5 was synthesized by reacting compound (c) with 2-bromobenzoic acid using the procedure described in example 1, compound 5 having the following structure:

physicochemical constants and spectral data of compound 5: yellow solid, yield: 72.2 percent; melting point: 68-70 ℃; IR cm^-1(KBr):3056,2918,2849,1675,1544,1468,1300,1262,1209,740；¹H NMR(400MHz CDCl₃)δ:7.55(t,J＝7.6Hz,2H,-Ph),7.43(d,J＝8.4Hz,2H,-Ph),7.31-7.33(m,2H,-Ph),6.98(d,J＝8.4Hz,2H,-Ph),6.92(d,J＝4Hz,1H,-Ph),6.81(s,2H,-Ph),5.99-6.09(m,1H,-CH＝CH₂),5.08-5.13(m,2H,-C ₂H＝CH),3.45(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.50(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:164.61,156.25,154.38,145.45,144.32,143.08,136.36,134.89,133.87,132.39,130.11,129.84,129.71,127.73,127.62,125.47,122.12,119.94,119.81,117.74,116.96,115.79,34.02,12.21；MS(ESI)m/z calcd for C₂₆H₂₁ ⁷⁹BrN₂O₃S([M+H]+)521.05,found 521.36；calcd for C₂₆H₂₁ ⁸¹BrN₂O₃S([M+H]+)523.05,found 523.33.

Example 6 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 6)

Compound 6 was synthesized by reacting compound (c) with 3-bromobenzoic acid using the procedure described in example 1, compound 6 having the following structure:

physicochemical constants and spectral data of compound 6: yellow solid, yield: 69%; melting point: 72-75 ℃; IR cm^-1(KBr):3072,2918,2849,1664,1545,1469,1303,1264,1208,732；¹H NMR(400MHz CDCl₃)δ:7.97(s,1H,-Ph),7.76(d,J＝8Hz,1H,-Ph),7.62(d,J＝8Hz,,1H,-Ph),7.43(d,J＝8.4Hz,2H,-Ph),7.28(s,1H,-Ph),6.94(d,J＝8Hz,3H,-Ph),6.78(t,J＝8Hz,1H,-Ph),6.73(d,J＝8Hz,1H,-Ph),6.00-6.10(m,1H,-CH＝CH₂),5.09-5.14(m,2H,-CH ₂ ＝CH),3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.51(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:163.54,156.38,155.66,145.45,144.07,143.00,136.36,135.56,133.95,130.94,130.26,129.80,129.52,127.76,126.07,125.51,122.97,122.18,119.95,117.70,116.95,115.82,34.02,12.13；MS(ESI)m/z calcd for C₂₆H₂₁ ⁷⁹BrN₂O₃S([M+H]+)521.05,found 521.36；calcd for C₂₆H₂₁ ⁸¹BrN₂O₃S([M+H]+)523.05,found 523.34.

Example 7 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 7)

Compound 7 was synthesized by reacting compound (c) with 4-bromobenzoic acid using the procedure described in example 1, compound 7 having the following structure:

physicochemical constants and spectral data for compound 7: white solid, yield: 52.7 percent; melting point: 165-168 ℃; IR cm^-1(KBr):2919,2850,1663,1534,1469,1307,1266,1204,746；¹H NMR(400MHz CDCl₃)δ:7.66(d,J＝8.4Hz,2H,-Ph),7.49(d,J＝8.4Hz,2H,-Ph),7.39(d,J＝8.8Hz,2H,-Ph),6.92(d,J＝8.4Hz,3H,-Ph),6.79(t,J＝8Hz,1H,-Ph),6.73(d,J＝8Hz,1H,-Ph),6.00-6.10(m,1H,-CH＝CH₂),5.09-5.14(m,2H,-C ₂H＝CH),3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.50(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:164.05,156.31,155.55,145.44,144.22,142.95,136.35,132.02,130.82,129.81,129.63,129.08,127.78,127.64,125.54,122.10,119.96,117.63,116.97,115.84,34.03,12.13；MS(ESI)m/z calcd for C₂₆H₂₁ ⁷⁹BrN₂O₃S([M+H]+)521.05,found 521.44；calcd for C₂₆H₂₁ ⁸¹BrN₂O₃S([M+H]+)523.05,found 523.37.

Example 8 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 8)

Compound 8 was synthesized by reacting compound (c) with 2-fluorobenzoic acid using the procedure described in example 1, compound 8 having the following structure:

physicochemical constants and spectral data for compound 8: white solid, yield: 63.8 percent; melting point: 170 ℃ and 172 ℃; IR cm^-1(KBr):2917,2849,1670,1549,1469,1307,1266,1211,753；¹H NMR(400MHz CDCl₃)δ:8.18(t,J＝7.6Hz,1H,-Ph),7.58(d,J＝7.6Hz,3H,-Ph),7.33(t,J＝8Hz,1H,-Ph),7.20(d,J＝8.8Hz,1H,-Ph),7.07(d,J＝8.4Hz,2H,-Ph),6.93(d,J＝3.6Hz,1H,-Ph),6.80(d,J＝4Hz,2H,-Ph),6.00-6.10(m,1H,-CH＝CH₂),5.08-5.14(m,2H,-C ₂H＝CH),3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.52(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:160.42,159.51,156.22,153.55,145.34,144.67,143.33,136.40,134.96,134.87,132.32,130.36,129.91,127.65,125.31,122.37,119.91,119.01,118.91,118.09,116.66,116.57,116.32,115.79,34.02,12.20；MS(ESI)m/z calcd for C₂₆H₂₁FN₂O₃S([M+H]+)461.13,found 461.38.

Example 9 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 9)

Compound 9 was synthesized by reacting compound (c) with 3-fluorobenzoic acid using the procedure described in example 1, compound 9 having the following structure:

physicochemical constants and spectra of Compound 9Graph data: white solid, yield: 63.8 percent; melting point: 158 ℃ and 160 ℃; IR cm^-1(KBr):2918,2849,1669,1545,1469,1303,1267,1208,746；¹H NMR(400MHz CDCl₃)δ:7.53-7.60(m,2H,-Ph),7.33-7.43(m,3H,-Ph),7.18(t,J＝8Hz,1H,-Ph),6.92-6.94(m,3H,-Ph),6.78(t,J＝7.6Hz,1H,-Ph),6.71(d,J＝8Hz,1H,-Ph),5.99-6.09(m,1H,-CH＝CH₂),5.08-5.14(m,2H,-C ₂H＝CH),3.46(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.50(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:163.96,163.51,161.49,156.28,155.07,145.40,144.36,143.07,136.35,134.28,134.21,130.52,130.44,129.84,129.74,127.75,125.47,122.89,122.22,119.94,119.85,119.64,117.77,116.86,115.83,115.04,114.81,34.02,12.16；MS(ESI)m/z calcd for C₂₆H₂₁FN₂O₃S([M+H]+)461.13,found 461.39.

Example 10 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 10)

Compound 10 was synthesized by reacting compound (c) with 4-fluorobenzoic acid using the procedure described in example 1, compound 10 having the following structure:

physicochemical constants and spectral data for compound 10: yellow solid, yield: 44.2 percent; melting point: 168-170 ℃; IR cm^-1(KBr):2919,2850,1667,1537,1508,1468,1259,1200,1157,850；¹H NMR(400MHz CDCl₃)δ:7.87-7.90(m,2H,-Ph),7.45(d,J＝8.4Hz,2H,-Ph),7.07(t,J＝8.4Hz,2H,-Ph),6.94-6.98(m,3H,-Ph),6.74-6.82(m,2H,-Ph),6.00-6.10(m,1H,-CH＝CH₂),5.09-5.15(m,2H,-C ₂H＝CH),3.47(d,J＝6Hz,2H,-C ₂H-CH＝CH₂),2.51(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:163.64,156.41,155.46,145.43,143.70,142.99,136.34,130.12,130.03,129.74,129.43,128.05,127.80,125.54,121.96,119.97,117.77,116.94,116.14,115.92,115.86,34.04,12.16；MS(ESI)m/z calcd for C₂₆H₂₁FN₂O₃S([M+H]+)461.13,found 461.30.

EXAMPLE 11 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 11)

Compound 11 was synthesized by reacting compound (c) with 2-methylbenzoic acid using the procedure described in example 1, compound 11 having the following structure:

physicochemical constants and spectral data of compound 11: white solid, yield: 52.7 percent; melting point: 140 ℃ and 143 ℃; IR cm^-1(KBr):2919,1666,1541,1469,1302,1263,1208,668；¹H NMR(400MHz CDCl₃)δ:7.44-7.48(m,3H,-Ph),7.35(t,J＝7.2Hz,1H,-Ph),7.20-7.24(m,2H,-Ph),6.91-6.99(m,3H,-Ph),6.78-6.79(m,2H,-Ph),5.97-6.07(m,1H,-CH＝CH₂),5.07-5.12(m,2H,-C ₂H＝CH),3.44(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.52(s,3H,-C ₃H-C₃H₃NS),2.49(s,3H,-C ₃H-Ph)；¹³C NMR(100MHz CDCl₃)δ:166.66,156.18,154.78,145.35,143.96,143.24,137.91,136.34,132.91,131.68,131.36,129.89,129.72,127.74,127.18,126.01,125.35,121.64,119.91,117.87,116.77,115.80,34.00,20.27,12.17；MS(ESI)m/z calcd for C₂₇H₂₄N₂O₃S([M+H]+)457.15,found 457.37.

EXAMPLE 12 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 12)

Compound 12 was synthesized by reacting compound (c) with 3-methylbenzoic acid using the procedure described in example 1, compound 12 having the following structure:

physicochemical constants and spectral data for compound 12: brown colourSolid, yield: 56.8 percent; melting point: 52-55 ℃; IR cm^-1(KBr):3050,2918,2850,1670,1541,1469,1299,1263,1208,735；¹H NMR(400MHz CDCl₃)δ:7.77(s,1H,-Ph),7.73(d,J＝6Hz,1H,-Ph),7.50(d,J＝8.4Hz,2H,-Ph),7.36(d,J＝6Hz,2H,-Ph),7.02(d,J＝8.4Hz,2H,-Ph),6.93(d,J＝6Hz,1H,-Ph),6.79-6.80(m,2H,-Ph),6.00-6.10(m,1H,-CH＝CH₂),5.08-5.14(m,2H,-C ₂H＝CH),3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.51(s,3H,-C ₃H-C₃H₃NS),2.41(s,3H,-C ₃H-Ph)；¹³C NMR(100MHz CDCl₃)δ:164.75,156.26,155.28,145.41,144.18,143.20,138.80,136.37,133.56,131.90,130.00,129.87,128.78,128.21,127.73,125.40,124.58,121.86,119.93,117.85,116.82,115.81,34.03,21.36,12.15；MS(ESI)m/z calcd for C₂₇H₂₄N₂O₃S([M+H]+)457.15,found 457.41.

Example 13 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 13)

Compound 13 was synthesized by reacting compound (c) with 4-methylbenzoic acid using the procedure described in example 1, compound 13 having the following structure:

physicochemical constants and spectral data for compound 13: yellow solid, yield: 54.9 percent; melting point: 160 ℃ and 163 ℃; IR cm^-1(KBr):2917,2850,1671,1541,1468,1294,1264,1200,668；¹H NMR(400MHz CDCl₃)δ:7.80(d,J＝7.6Hz,2H,-Ph),7.49(d,J＝8.4Hz,2H,-Ph),7.28(s,2H,-Ph),7.00(d,J＝8.4Hz,2H,-Ph),6.93(d,J＝6.8Hz,1H,-Ph),6.75-6.82(m,2H,-Ph),6.00-6.10(m,1H,-CH＝CH₂),5.08-5.14(m,2H,-C ₂H＝CH),3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.50(s,3H,-C ₃H-C₃H₃NS),2.42(s,3H,-C ₃H-Ph)；¹³C NMR(100MHz CDCl₃)δ:164.43,156.19,155.01,145.39,144.23,143.58,143.23,136.38,130.12,129.82,129.60,129.11,127.72,127.46,125.36,121.86,119.91,117.88,116.78,115.80,34.02,21.60,12.17；MS(ESI)m/z calcd for C₂₇H₂₄N₂O₃S([M+H]+)457.15,found 457.34.

Example 14 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 14)

Compound 14 was synthesized by reacting compound (c) with 2-methoxybenzoic acid using the procedure described in example 1, compound 14 having the following structure:

physicochemical constants and spectral data for compound 14: white solid, yield: 71.6 percent; melting point: 170-; IR cm^-1(KBr):2917,1657,1541,1468,1305,1260,755；¹H NMR(400MHz CDCl₃)δ:8.30(d,J＝7.6Hz,1H,-Ph),7.59(d,J＝8.4Hz,2H,-Ph),7.53(t,J＝7.6Hz,1H,-Ph),7.13(t,J＝7.2Hz,1H,-Ph),7.04(t,J＝8.8Hz,3H,-Ph),6.92(d,J＝4Hz,1H,-Ph),6.78(d,J＝4.4Hz,2H,-Ph),6.02-6.09(m,1H,-CH＝CH₂),5.08-5.14(m,2H,-C ₂H＝CH),4.08(s,3H,-OC ₃H-Ph)；3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.51(s,3H,-C ₃H-C₃H₃NS),¹³C NMR(100MHz CDCl₃)δ:162.52,157.77,156.09,154.19,145.35,144.63,143.42,136.41,134.37,132.69,130.76,129.96,127.65,125.25,121.96,121.70,119.88,119.23,118.04,116.64,115.76,111.56,56.29,34.02,12.17；MS(ESI)m/z calcd for C₂₇H₂₄N₂O₄S([M+H]+)473.15,found 473.41.

Example 15 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 15)

Compound 15 was synthesized by reacting compound (c) with 3-methoxybenzoic acid using the procedure described in example 1, compound 15 having the following structure:

physicochemical Properties of Compound 15Constant and spectrum data: yellow solid, yield: 33%; melting point: 135 ℃ and 137 ℃; IR cm^-1(KBr):3073,2917,2849,1676,1551,1467,1265,1046,668；¹H NMR(400MHz CDCl₃)δ:7.42(t,J＝8.4Hz,3H,-Ph),7.36(d,J＝7.6Hz,1H,-Ph),7.28(t,J＝8Hz,1H,-Ph),7.05(d,J＝8Hz,1H,-Ph),6.93-6.96(m,3H,-Ph),6.74-6.81(m,2H,-Ph),6.02-6.08(m,1H,-CH＝CH₂),5.09-5.14(m,2H,-C ₂H＝CH),3.84(s,3H,-OC ₃H-Ph),3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.51(s,3H,-C ₃H-C₃H₃NS),¹³C NMR(100MHz CDCl₃)δ:164.55,159.90,156.23,155.02,145.45,144.42,143.15,136.39,133.41,130.04,129.84,129.75,127.76,125.40,121.94,119.90,119.26,117.78,116.86,115.80,112.46,55.46,34.02,12.16；MS(ESI)m/z calcd for C₂₇H₂₄N₂O₄S([M+H]+)473.15,found 473.37.

EXAMPLE 16 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 16)

Compound 16 was synthesized by reacting compound (c) with 4-methoxybenzoic acid using the procedure described in example 1, compound 16 having the following structure:

physicochemical constants and spectral data for compound 16: yellow solid, yield: 29 percent; melting point: 168-170 ℃; IR cm^-1(KBr):2919,2850,1663,1605,1533,1513,1470,1258,1174,668；¹H NMR(400MHz CDCl₃)δ:7.83-7.86(m,2H,-Ph),7.48-7.51(m,2H,-Ph),6.90-7.01(m,5H,-Ph),6.77-6.81(m,2H,-Ph),6.00-6.10(m,1H,-CH＝CH₂),5.08-5.14(m,2H,-C ₂H＝CH),3.86(s,3H,-OC ₃H-Ph)；3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.50(s,3H,-C ₃H-C₃H₃NS),¹³C NMR(100MHz CDCl₃)δ:163.96,163.21,156.15,145.40,144.28,143.23,136.39,130.29,129.79,129.41,127.72,125.36,124.18,121.75,119.91,117.84,116.79,115.80,114.13,55.52,34.02,12.17；MS(ESI)m/z calcd for C₂₇H₂₄N₂O₄S([M+H]+)473.15,found 473.37.

Example 17 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 17)

Compound 17 was synthesized by reacting compound (c) with 2, 4-dichlorobenzoic acid using the procedure described in example 1, compound 17 having the following structure:

physicochemical constants and spectral data for compound 17: yellow solid, yield: 35.6 percent; melting point: 70-73 ℃; IR cm^-1(KBr):2918,2849,1668,1555,1469,1304,1262,1209,668；¹H NMR(400MHz CDCl₃)δ:7.53(t,J＝6Hz,1H,-Ph),7.41(d,J＝7.2Hz,2H,-Ph),7.36(s,1H,-Ph),7.21-7.23(m,1H,-Ph),6.99(d,J＝8Hz,2H,-Ph),6.95(d,J＝4.4Hz,1H,-Ph),6.82(d,J＝3.6Hz,2H,-Ph),6.00-6.10(m,1H,-CH＝CH₂),5.09-5.14(m,2H,-C ₂H＝CH),3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.50(s,3H,-C ₃H-C₃H₃NS),¹³C NMR(100MHz CDCl₃)δ:162.92,156.62,155.11,145.53,143.26,142.81,138.23,136.32,132.44,131.42,130.53,129.59,128.82,127.86,127.56,125.74,122.07,120.03,117.56,117.25,115.86,34.05,12.22；MS(ESI)m/z calcd for C₂₆H₂₀ ³⁵Cl₂N₂O₃S([M+H]+)511.06,found 511.35；calcd for C₂₆H₂₀ ³⁷Cl₂N₂O₃S([M+H]+)513.06,found 513.34.

EXAMPLE 18 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 18)

Compound 18 was synthesized by reacting compound (c) with 2-chloro-4-fluorobenzoic acid using the procedure described in example 1, compound 18 having the following structure:

physicochemical constants and spectral data for compound 18: white solid, yield: 60 percent; melting point: 155 ℃ and 158 ℃; IR cm^-1(KBr):3073,2920,1674,1549,1470,1305,1265,1210,925；¹H NMR(400MHz CDCl₃)δ:7.59-7.67(m,1H,-Ph),7.40-7.43(m,2H,-Ph),7.09-7.11(m,1H,-Ph),6.95-6.99(m,4H,-Ph),6.81(d,J＝4Hz,2H,-Ph),5.99-6.09(m,1H,-CH＝CH₂),5.08-5.14(m,2H,-C ₂H＝CH),3.46(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.49(s,3H,-C ₃H-C₃H₃NS),¹³C NMR(100MHz CDCl₃)δ:156.34,154.50,145.51,144.29,142.98,136.33,132.87,132.79,132.47,129.73,129.63,129.59,128.73,127.83,125.63,122.19,119.99,118.19,117.94,117.61,117.55,117.15,117.08,115.83,114.70,114.58,34.04,12.21；MS(ESI)m/z calcd for C₂₆H₂₀ ³⁵ClFN₂O₃S([M+H]+)495.09,found 495.39；calcd for C₂₆H₂₀ ³⁷ClFN₂O₃S([M+H]+)497.09,found 497.36.

Example 19 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 19)

Compound 19 was synthesized by reacting compound (c) with 4-cyanobenzoic acid using the procedure described in example 1, compound 19 having the following structure:

physicochemical constants and spectral data for compound 19: yellow solid, yield: 40 percent; melting point: 191-193 ℃; IR cm^-1(KBr):2919,2850,2233,1674,1537,1467,1290,1261,1201,668；¹H NMR(400MHz CDCl₃)δ:7.86(d,J＝8Hz,2H,-Ph),7.63(d,J＝8Hz,2H,-Ph),7.36(d,J＝8.4Hz,2H,-Ph),6.95(d,J＝7.2Hz,1H,-Ph),6.90(d,J＝8.4Hz,2H,-Ph),6.80(t,J＝7.6Hz,1H,-Ph),6.72(d,J＝8Hz,1H,-Ph),6.00-6.10(m,1H,-CH＝CH₂),5.10-5.15(m,2H,-C ₂H＝CH),3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.52(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:163.37,156.54,155.52,145.48,144.05,142.75,136.29,135.80,132.43,129.68,129.22,128.16,127.95,125.79,122.53,120.06,117.72,117.54,117.14,116.01,115.92,34.05,12.17；MS(ESI)m/z calcd for C₂₇H₂₁N₃O₃S([M+H]+)468.13,found 468.29.

EXAMPLE 20 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 20)

Compound 20 was synthesized by reacting compound (c) with 4-nitrobenzoic acid using the procedure described in example 1, compound 20 having the following structure:

physicochemical constants and spectral data for compound 20: yellow solid, yield: 27.7 percent; melting point: 172-174 ℃; IR cm^-1(KBr):2920,2850,1675,1543,1467,1344,1263,851,668；¹H NMR(400MHz CDCl₃)δ:8.19(d,J＝8.4Hz,2H,-Ph),7.98(d,J＝8.8Hz,2H,-Ph),7.37(d,J＝8.4Hz,2H,-Ph),6.95(d,J＝7.2Hz,1H,-Ph),6.90(d,J＝8.4Hz,2H,-Ph),6.80(t,J＝7.6Hz,1H,-Ph),6.74(d,J＝8Hz,1H,-Ph),6.00-6.10(m,1H,-CH＝CH₂),5.10-5.15(m,2H,-C ₂H＝CH),3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.51(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:163.21,156.56,155.64,150.08,145.49,144.20,142.73,137.48,136.30,129.77,129.25,128.81,127.94,125.78,123.83,122.61,120.03,117.51,117.14,115.91,34.05,12.16；MS(ESI)m/z calcd for C₂₆H₂₁N₃O₅S([M+H]+)488.12,found 488.38.

Example 21 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 21)

Compound 21 was synthesized by reacting compound (c) with 4-aldehyde benzoic acid using the procedure described in example 1, compound 21 having the following structure:

physicochemical constants and spectral data of compound 21: yellow solid, yield: 26.7 percent; melting point: 106-110 ℃; IR cm^-1(KBr):3073,2920,1674,1549,1470,1305,1265,1210,925；¹H NMR(400MHz CDCl₃)δ:10.05(s,1H,-CHO),7.92(d,J＝8Hz,2H,-Ph),7.84(d,J＝7.6Hz,2H,-Ph),7.35(d,J＝8.4Hz,2H,-Ph),6.93(d,J＝7.2Hz,1H,-Ph),6.85(d,J＝8.4Hz,2H,-Ph),6.78(t,J＝7.6Hz,1H,-Ph),6.70(d,J＝8Hz,1H,-Ph),6.00-6.08(m,1H,-CH＝CH₂),5.09-5.14(m,2H,-C ₂H＝CH),3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.51(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:191.38,163.82,156.50,155.52,145.48,144.22,142.92,138.88,136.96,136.34,130.78,129.91,129.64,129.41,128.34,127.83,125.61,122.32,119.98,118.28,117.68,117.05,115.85,34.04,12.12；MS(ESI)m/z calcd for C₂₇H₂₂N₂O₄S([M+H]+)471.13,found 471.33.

EXAMPLE 22 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 22)

Compound 22 was synthesized by reacting compound (c) with phenylacetic acid using the procedure described in example 1, compound 22 having the following structure:

physicochemical constants and spectral data for compound 22: brown solid, yield: 21.4 percent; melting point: 155 ℃ and 158 ℃; IR cm^-1(KBr):3077,2995,2920,1655,1560,1469,1310,1264,719,668；¹H NMR(400MHz CDCl₃)δ:7.46(d,J＝8Hz,2H,-Ph),7.27-7.38(m,5H,-Ph),7.03(d,J＝8.4Hz,2H,-Ph),6.93(s,1H,-Ph),6.77(d,J＝4Hz,2H,-Ph),5.99-6.09(m,1H,-CH＝CH₂),5.08-5.14(m,2H,-C ₂H＝CH),3.72(s,2H,-C ₂H-CONH),3.46(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.45(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:168.76,156.41,154.86,145.40,143.73,143.09,136.35,133.11,129.91,129.78,129.53,129.21,127.84,127.72,125.46,121.79,119.94,117.92,116.86,115.81,43.23,34.01,12.05；MS(ESI)m/z calcd for C₂₇H₂₄N₂O₃S([M+H]+)457.15,found 457.34.

Example 23 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 23)

Compound 23 was synthesized by reacting compound (c) with 4-fluorophenylacetic acid using the procedure described in example 1, compound 23 having the following structure:

physicochemical constants and spectral data for compound 23: yellow solid, yield: 25.4 percent; melting point: 158 ℃ and 160 ℃; IR cm^-1(KBr):3049,2973,2919,2849,1686,1546,1509,1468,1265,1221,1156,835；¹H NMR(400MHz CDCl₃)δ:7.48(d,J＝8.4Hz,2H,-Ph),7.18-7.22(m,2H,-Ph),7.00(t,J＝8.4Hz,4H,-Ph),6.93(d,J＝6.8Hz,1H,-Ph),6.75-6.81(m,2H,-Ph),6.01-6.07(m,1H,-CH＝CH₂),5.09-5.14(m,2H,-C ₂H＝CH),3.59(s,2H,-C ₂H-CONH),3.46(d,J＝6Hz,2H,-C ₂H-CH＝CH₂),2.46(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:168.61,161.14,156.80,155.32,145.45,142.86,142.48,136.31,131.16,131.08,129.84,128.81,128.64,127.85,125.67,121.76,120.02,117.95,117.04,116.16,115.94,115.87,42.08,34.04,12.07；MS(ESI)m/z calcd for C₂₇H₂₃FN₂O₃S([M+H]+)475.14,found 475.42.

EXAMPLE 24 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 24)

Compound 24 was synthesized by reacting compound (c) with acetic acid using the procedure described in example 1, compound 24 having the structure:

chemical combinationPhysicochemical constants and spectrum data of substance 24: white solid, yield: 58.4 percent; melting point: 108-110 ℃; IR cm^-1(KBr):3078,3000,2921,1654,1557,1470,1296,1266,1224,1201,985,852,740；¹H NMR(400MHz CDCl₃)δ:7.53(d,J＝8Hz,2H,-Ph),7.05(d,J＝8.4Hz,2H,-Ph),6.94(d,J＝6.4Hz,1H,-Ph),6.78-6.83(m,2H,-Ph),6.00-6.10(m,1H,-CH＝CH₂),5.09-5.14(m,2H,-C ₂H＝CH),3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.48(s,3H,-C ₃H-C₃H₃NS),1.81(s,3H,-C ₃H-CONH)；¹³C NMR(100MHz CDCl₃)δ:168.08,156.61,155.90,145.45,143.01,136.33,129.95,129.66,127.83,125.61,121.47,120.03,117.98,116.93,115.86,34.04,22.52,12.03；MS(ESI)m/z calcd for C₂₁H₂₀N₂O₃S([M+H]+)381.12,found 381.22.

Example 25 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 25)

Compound 25 was synthesized by reacting compound (c) with chloroacetic acid using the procedure described in example 1, compound 25 having the following structure:

physicochemical constants and spectral data for compound 25: white solid, yield: 52.9 percent; melting point: 173-175 ℃; IR cm^-1(KBr):3179,3061,2999,2874,1654,1583,1496,1470,1267,1225,853；¹H NMR(400MHz CDCl₃)δ:7.54(d,J＝8.4Hz,2H,-Ph),7.06(d,J＝8.4Hz,2H,-Ph),6.93(d,J＝4Hz,1H,-Ph),6.80(d,J＝4.4Hz,2H,-Ph),6.00-6.10(m,1H,-CH＝CH₂),5.09-5.14(m,2H,-C ₂H＝CH),4.18(s,2H,-C ₂H-CONH),3.47(d,J＝6.4Hz,2H,-C ₂H-CH＝CH₂),2.50(s,3H,-C ₃H-C₃H₃NS)；¹³C NMR(100MHz CDCl₃)δ:164.04,156.73,153.84,145.44,143.45,143.00,136.34,129.87,129.01,127.80,125.58,122.43,120.00,118.02,116.98,115.84,41.91,34.03,12.19；MS(ESI)m/z calcd for C₂₁H₁₉ ³⁵ClN₂O₃S([M+H]+)415.08,found 415.21；calcd for C₂₁H₁₉ ³⁷ClN₂O₃S([M+H]+)417.08,found 417.21.

EXAMPLE 26 Synthesis of Thiazolylamidoisomagnoflorine derivatives (Compound 26)

Compound 26 was synthesized by reacting compound (c) with propionic acid using the procedure described in example 1, compound 26 having the structure:

physicochemical constants and spectral data for compound 26: yellow solid, yield: 40.9 percent; melting point: 70-73 ℃; IR cm^-1(KBr):3059,2920,2852,1685,1549,1497,1469,1264,1211,1167,981,837,668；¹H NMR(400MHz CDCl₃)δ:7.45(d,J＝7.6Hz,2H,-Ph),7.16-7.23(m,3H,-Ph),7.08(d,J＝6.8Hz,2H,-Ph),6.98(d,J＝8Hz,2H,-Ph),6.93(d,J＝6.8Hz,1H,-Ph),6.75-6.81(m,2H,-Ph),6.00-6.10(m,1H,-CH＝CH₂),5.09-5.14(m,2H,-C ₂H＝CH),3.46(d,J＝6Hz,2H,-C ₂H-CH＝CH₂),2.91(t,J＝7.6Hz,2H,-C ₂H-Ph),2.46(s,3H,-C ₃H-C₃H₃NS),2.39-2.43(m,2H,-C ₂H-CONH)；¹³C NMR(100MHz CDCl₃)δ:170.07,156.39,145.43,143.51,142.97,140.01,136.34,129.86,128.51,128.24,127.76,126.38,125.55,121.56,119.98,117.87,116.92,115.85,37.30,34.03,30.79,12.07；MS(ESI)m/z calcd for C₂₈H₂₆N₂O₃S([M+H]+)471.17,found 471.42.

Application example: experiment for inhibiting activity of plant pathogenic fungi:

1. experimental Material

Anhydrous glucose, agar and acetone

2. Sample to be tested

Isomagnoflorine, target compound 1-26 and hymexazol

3. Test strains

Wheat scab (Fusarium graminearum), Alternaria alternata (Alternaria alternate), potato pythium (Fusarium solani), potato Fusarium oxysporum (Fusarium oxysporum). The test strains were purchased and introduced to agricultural academy of Henan province and then subcultured in this laboratory.

4. The bioassay method comprises the following steps:

preparing a PDA culture medium: peeling fresh potatoes, weighing 200g, dicing, adding ultrapure water, boiling for about 30min, filtering potato residues with a plurality of layers of gauze, only retaining filtrate, adding ultrapure water, and fixing the volume of the filtrate to 1000 mL. And weighing 20g of glucose, adding the glucose into the filtrate, stirring and dissolving, then weighing 20g of agar, adding the agar into the filtrate, stirring uniformly, filtering to remove residues, subpackaging the culture solution in a plurality of 250mL triangular flasks, and sealing. The dishes and the culture solution were sterilized in an autoclave (121 ℃ C., 30min), and about 12.5mL of PDA culture solution was poured into each dish while it was still hot, and cooled and solidified for use.

Activating and passaging strains: taking out the strain to be tested which is frozen in the refrigerator, inoculating the strain to be tested into a solidified culture dish by a puncher and an inoculating loop under the aseptic condition, repeating each strain for three times, and putting the inoculated strain into an incubator at 28 ℃ for culture. Continuously culturing for 3 generations after the mycelium grows, observing the growth condition of the mycelium, and storing in a refrigerator at-4 deg.C if the growth condition is good. The strain was taken out 3 days before the experiment and activated once as described above, and placed in an incubator for use.

Preparation of a liquid medicine: weighing 7.5mg of the compound, dissolving in 2mL of acetone solution, and making into medicinal liquid.

Preparation of a drug-containing culture medium: transferring the sterilized culture solution to a 200mL liquid phase bottle while the culture solution is hot, fixing the volume to 150mL, adding the prepared medicine solution, fully mixing to prepare a medicine-containing culture solution with the volume of 50 mu g/mL, and cooling and solidifying the medicine-containing culture solution; 2mL of acetone solution was added to 150mL of the culture medium to prepare a drug-free medium plate as a blank control.

Inoculating and culturing the fungus cake: punching activated strains to be tested on the edges of bacterial colonies by using a puncher with the inner diameter of 6mm to prepare bacterial cakes, picking the bacterial cakes into culture dishes containing a medicine-containing culture medium by using an inoculating loop, inoculating one bacterial cake into each culture dish, enabling the side with the hyphae to face downwards, covering with a mark, repeating the steps for three times for each group, and culturing in a constant-temperature incubator at the temperature of 28 ℃.

Measurement of data: the plates in the incubator were incubated for 72 hours, and after taking out, the diameter of the colony on each plate was measured by the cross method, and the inhibition rate was calculated according to the following formula.

Hypha growth inhibition (%) - (average value of blank colony diameter-average value of compound colony diameter)/(average value of blank colony diameter-0.6 cm)

5. Activity results:

the inhibition conditions of the isomagnoflorine, the hymexazol and the target compounds 1-26 are measured under the condition that the concentration is 50 mu g/mL by a hypha growth rate method, wherein acetone is used as a blank control, and the hymexazol is used as a positive control. The growth rate of the test strain containing the drug in 72h is measured, and specific activity data are shown in the following table 1. As can be seen from the table, for alternaria alternate, the bacteriostatic activity of 15 compounds is superior to that of the parent isomagnoflorine, wherein the bacteriostatic activity of the compounds 3 and 23 is more than 60 percent and is superior to that of a positive control medicament hymexazol; for wheat scab, the activity of 12 compounds is better than that of isomagnoflorine, wherein the compounds 20-24 and 26 are more prominent, the bacteriostasis rates are respectively 61.9%, 63.5%, 64.2%, 53.6%, 58.2% and 58.5%, and the inhibition activity is better than that of hymexazol; the isomagnoflorine has a weak inhibition activity on potato dry rot, the inhibition rate of the isomagnoflorine is 29.5%, the majority of the inhibition activity of a target compound is higher than that of a parent compound, wherein the inhibition activity of the compounds 22 and 23 is superior to that of hymexazol, and the inhibition rates are 47.5% and 51.1% respectively. For potato blight bacteria, the inhibition rate of most target compounds is higher than that of a parent isomagnoflorine, wherein the inhibition rates of the compounds 1-16 and 22 exceed that of a positive drug hymexazol, the compounds 3 and 6 are best in performance, the inhibition rates are respectively 60.6% and 66.5%, and the inhibition rates are superior to that of the positive drug hymexazol.

TABLE 1 inhibitory Activity of target Compounds 1-30 against four plant pathogenic fungi

Note: hymexazol is a positive drug; the concentration of the test drug is 50 mug/mL; the activity values are the average of three sets of data.

In conclusion, the thiazole amide isomagnoline derivatives 3, 20-24 and 26 prepared by introducing thiazole amide groups through structure optimization show better antibacterial activity, and the inhibition rate of the thiazole amide isomagnoline derivatives on tobacco gibberellin, wheat gibberellin, potato dry rot or potato blight bacteria is superior to that of a market bacteriostatic agent hymexazol, so that the thiazole amide isomagnoline derivatives prepared by the invention are expected to be used as efficient natural product bacteriostatic agents.