CN104003991B - Balasubramide and derivative thereof and synthetic method and application - Google Patents

Abstract

The invention discloses Balasubramide and its derivatives, their synthesis method and application. The structural formula of the Balasubramide and its derivatives in the present invention is shown in formula (I), and the Balasubramide and its derivatives have excellent anti-inflammatory activity of nerve cells, and none of them has cytotoxicity. Simultaneously, the invention designs a scientific and reasonable synthetic circuit, which is simple and efficient, the total yield of (+)-balasubramide is over 45%, and the ee value is over 97%. (I).

Description

Balasubramide and its derivatives, synthesis method and application

technical field

The invention relates to the technical fields of chemical synthesis and medicine, more specifically, relates to Balasubramide and its derivatives, synthesis method and application.

Background technique

In 1996, Hofer et al. isolated an eight-membered cyclic lactam component (+)-balasubramide from the chloroform extract of the leaves of the Rutaceae genus Champagne [Clausenaindica (Datz).Oliv.] in the tropical rainforest of Sri Lanka. and (+)-prebalamide, the biological precursor of (+)-balasubramide.

Plants of the genus Rutaceae are mainly distributed in the south and southeast of Asia, and a few are distributed in southern China and Australia. There are about 30 species in the world, and nearly 10 species in my country, distributed in the middle and lower reaches of the Yangtze River and southern provinces. Most of the plants in this genus have been medicinal plants in my country since ancient times, and are used to treat diseases such as upper flu, malaria, abdominal pain and gastritis. Due to the importance of the eight-membered lactam structure and potential biological value, balasubramide and its derivatives have important research value, but there are no more technical reports on chiral (+)-balasubramide and its analogs.

However, (+)-balasubramide can be obtained by the existing method of plant separation and extraction, which is far from enough for the research on its biological activity due to the low separation efficiency and yield. Therefore, exploring a total synthesis method with higher separation efficiency and yield to obtain chiral (+)-balasubramide and its analogues is the key to research and develop its application value.

Due to the complex structure of the eight-membered lactam ring and multiple chiral carbon atoms, so far, there are few relevant literature reports on the synthesis of balasubramide. The existing literature involves reports on the synthesis of balasubramide. The disclosed synthetic methods either have long reaction routes and low yields. Low, or the preparation process of synthetic raw materials is cumbersome and the reaction conditions are special, which limits the actual synthesis, production and application research of balasubramide. There are no technical reports on the synthesis and application of balasubramide-related derivatives.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the shortcomings of the existing Balasubramide derivatives and provide a new class of Balasubramide derivatives.

Another technical problem to be solved by the present invention is to provide the application of the Balasubramide derivatives.

Another technical problem to be solved by the present invention is to provide a preparation method with simple steps, readily available raw materials and high yield. Based on the preparation method, the Balasubramide and its derivatives of the present invention can be obtained.

Another technical problem to be solved by the present invention is to provide the application of the Balasubramide and its derivatives prepared by the preparation method.

The purpose of the present invention is achieved through the following technical solutions:

Provide the derivative of Balasubramide, its structural formula is as shown in formula (I):

Among them, R ₁ is H or -CH ₃ ; R is Ph, 3-FC ₆ H ₄ , 4-FC ₆ H ₄ , 3-Cl-C ₆ H ₄ , 4-Cl-C ₆ H ₄ , 3-Br -C ₆ H ₄ , 4-Br-C ₆ H ₄ , 4-NO ₂ -C ₆ H ₄ or 3-CF ₃ -C ₆ H ₄ .

The application of the derivatives of Balasubramide in the preparation of drugs for the treatment of neuroprotective effects related to nerve cells also provides the application of the derivatives of Balasubramide in the preparation of anti-neurinflammation drugs.

Preferably, in the structure shown in formula (I), R1 is H and R is _{4 - FC6H4} , when the compound is used in the preparation of drugs for the treatment of brain protection related to nerve cells, and in the preparation of anti-neurinflammation drugs application.

The invention provides a kind of preparation method of Balasubramide and derivative thereof, comprising the following steps:

S1. One-pot method to catalyze the epoxidation of trans-cinnamaldehyde and its derivatives to obtain α, β-epoxy carboxylate;

S2. reacting the α, β-epoxy carboxylate obtained in S1 with tryptamine and its analogs to obtain prebalamide and its derivatives;

S3. Using Yb(CF ₃ SO ₃ ) ₃ as a catalyst, the prebalamide or its derivatives obtained in S2 are respectively ring-closed to synthesize (+)-balasubramide and its derivatives.

Wherein, the one-pot method described in S1 catalyzes the epoxidation of trans-cinnamaldehyde and its derivatives comprising the following steps:

S11. Under ice-bath conditions, using 40% (V/V) H ₂ O ₂ aqueous solution as an oxidant, using S-diphenylprolinol triethylsilyl ether to catalyze a series of trans-cinnamaldehyde and its derivatives Epoxidation;

S12. At room temperature, the reaction solution obtained in S11 was diluted with methanol, and NBS (N-bromosuccinimide, N-bromosuccinimide) and sodium carbonate were added to synthesize α, β-epoxy carboxylate.

The invention provides Balasubramide and derivatives thereof synthesized based on the preparation method. The structural formula is shown in formula (I):

Among them, R ₁ is H or -CH ₃ ; R is Ph, 3-FC ₆ H ₄ , 4-FC ₆ H ₄ , 3-Cl-C ₆ H ₄ , 4-Cl-C ₆ H ₄ , 3-Br -C ₆ H ₄ , 4-Br-C ₆ H ₄ , 4-NO ₂ -C ₆ H ₄ or 3-CF ₃ -C ₆ H ₄ .

The present invention also provides the application of Balasubramide and its derivatives prepared based on the preparation method in the preparation of drugs for the treatment of brain protection related to nerve cells, and also provides the application of the Balasubramide derivatives in the preparation of anti-neuroinflammatory drugs .

Beneficial effects of the present invention:

The present invention provides a class of highly enantioselective Balasubramide derivatives, which fills the gap or deficiency of optically active octa-lactam structure compounds, and provides a powerful source for the research and application of related chiral (+)-balasubramide and its analogues. technical basis.

The invention provides a new synthetic route and synthetic method of the Balasubramide and its derivatives, designs an asymmetric synthetic route of (+)-balasubramide, and successfully synthesizes the Balasubramide and its derivatives. The present invention first designs a scientific and reasonable synthesis route, optimizes the process conditions for the synthesis of the key intermediate α, β-epoxy carboxylate, and synthesizes a series of α, β-epoxy carboxylate using an optimized one-pot method , obtained the highest yield of 80% and 97% ee value. The results show that the asymmetric epoxidation and oxidative esterification of the optimized one-pot method for preparing α, β-unsaturated esters provided by the present invention is a simple and efficient method for synthesizing α, β-epoxy carboxylates. Further, based on the optimized one-pot method of the present invention to catalyze the epoxidation of trans-cinnamaldehyde and its derivatives, the α,β-epoxy carboxylate with high ee value is reacted with tryptamine and its analogues, Prebalamide and its derivatives were obtained, and the prebalamide was ring-closed with Yb(CF ₃ SO ₃ ) ₃ as a catalyst to synthesize the natural product (+)-balasubramide and its derivatives. By optimizing the reaction conditions, the present invention obtains higher yield and enantioselectivity. Among them, the total yield of (+)-balasubramide is more than 45%, and the ee value is more than 97%.

The present invention provides a new application of the Balasubramide derivatives. All the Balasubramide derivatives can significantly inhibit the inflammatory response produced by microglial cells. At the same time, cytotoxicity experiments show that these compounds have no cytotoxicity.

Description of drawings

Fig. 1 The experimental results of the cerebral protective effect of the compound of the present invention on the nerve damage caused by the nutritional deficiency of primary cultured cerebellar granule neurons of rats.

Fig. 2 The brain protection effect of test group compounds on PC12 nerve cell injury induced by hydrogen peroxide.

Fig. 3 Protective effect of test group compounds on primary rat cerebellar granule nerve cell injury induced by L-glutamic acid.

Figure 4 Inhibitory effect of test compounds on lipopolysaccharide-induced release of inflammatory factor TNFα in BV-2 microglial cells.

Fig. 5 Cytotoxic effect of test compounds on BV-2 microglial cells.

detailed description

The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments. Unless otherwise specified, the reagents and equipment used in the present invention are those conventionally used in the art.

The synthetic method condition research experiment of embodiment 1 Balasubramide derivatives

1. Synthesis of optically active α,β-epoxy carboxylates

Referring to the method reported in the literature, we optimized the reaction conditions, using 40% H ₂ O ₂ aqueous solution as the oxidant, and using the self-made chiral imine catalyst S-diphenylprolinol triethylsilyl ether to catalyze a series of reactions Formula cinnamaldehyde and its derivatives were epoxidized, reacted at room temperature for 4 hours, diluted with methanol, then added NBS and sodium carbonate for oxidative esterification, room temperature for 3 hours, and obtained (2S,3R)-α,β-epoxy carboxylate , the latter with good yield and excellent ee value. By comparing the optical rotation data of the literature, the absolute configuration of the final product was determined to be 2S, 3R. The results are shown in Table 1.

The reaction route is:

Table 1

2. Synthesis of prebalamide and its derivatives from α, β-epoxy carboxylate

1. Effect of reaction conditions on the yield of compound 2

The present invention uses methanol as a solvent, under room temperature conditions, β-phenylglycidic acid methyl ester and tryptamine undergo esteramine condensation, react for 3 hours, and obtain product 2h. However, the yield was 55%. Further research found that under low temperature conditions, the addition of a catalytic amount of base can significantly increase the yield of the reaction. The influence of various additives on the reaction was investigated, and the results are shown in Table 2.

The reaction scheme is as follows:

Table 2

The study found that the strength of the basicity of the additive has a significant impact on the reaction result. The addition of NaHCO ₃ , K ₂ CO ₃ and Na ₂ CO ₃ had little effect on the reaction yield, but the addition of catalytic amount of strong bases such as t-BuOK and NaOCH ₃ significantly increased the reaction yield. Among them, when t-BuOK was used as an additive, a yield of 81% was obtained. Therefore, the present invention selects t-BuOK as the condensing agent for the reaction.

3. Synthesis of the target product

The invention uses acetonitrile as a solvent and ytterbium trifluoromethanesulfonate (Yb(CF ₃ SO ₃ ) ₃ ) as a catalyst to synthesize (+)-balasubramide and its derivatives from prebalamide and its derivatives. In addition, the present invention investigates the influence of different reaction conditions on the cyclization reaction.

1. The influence of Lewis acid (lewisacid) on epoxy reaction, experimental result is as shown in table 3:

Examples of reaction routes:

table 3

As can be seen from Table 3, the yield of the cyclization reaction is significantly different when different Lewis acids are selected. Addition of active Lewis acid, such as AlCl ₃ , FeCl ₃ , CuCl, did not produce the target product. When the weak Lewis acid LaCl3 was added, the formation _of the target product was detected, but the yield was only 33%. When adding Yb(CF ₃ SO ₃ ) ₃ , p-TSA and other Lewis acids, the reaction of cyclization products can obtain moderate yield and excellent enantioselectivity. The addition of Yb(CF ₃ SO ₃ ) ₃ gave the best results with a yield of 73% and an ee value of 97%.

2. Effect of reaction solvent on epoxy reaction

After determining that Yb(CF ₃ SO ₃ ) ₃ is the catalyst for the ring closure reaction, the present invention investigated the influence of the reaction solvent on the reaction, and the results are shown in Table 4.

The reaction scheme is as follows:

Table 4

It can be seen from Table 4 that the cyclization reaction can proceed smoothly in most solvents, and the solvent has no effect on the ee value of the product. The reaction gave better yields in polar solvents than non-polar solvents such as CHCl ₃ solvent. Among them, using THF as the solvent, the reaction has the highest yield, reaching 75%. The research on the synthesis conditions of other derivatives is the same as the above experimental results.

Example 2

The overall synthetic route of optically active (+)-balasubramide derivatives is as follows:

Obtain (+)-balasubramide derivatives 3a～3j, R in the structural formula is shown in table 5 respectively:

table 5

The structures of (+)-balasubramide derivatives 3a～3j are as follows:

Synthesis experiment of each step:

① Synthesis of Compound 1a-1j

Dissolve 3.9g of trans-cinnamaldehyde and its derivatives in 30ml of dichloromethane, then add 1.1g~1.3g of catalyst and 3.5~4.3ml of hydrogen peroxide solution, react at room temperature for 2h, add 30ml of methanol to dilute, and then add _Na2 3.8~4.5g of CO ₃ and 6.4~7.3g of N-bromosuccinimide were continued to react for 3h. After the reaction, filtered, the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography.

Pale yellow liquid, 65% yield, [α] _D ²⁰ =+166.2 (0.5, CHCl ₃ ); ¹ HNMR (500MHz, CDCl ₃ ) δ7.34 (td, J = 8.0, 5.7Hz, 1H), 7.10 (d, J=7.7Hz, 1H), 7.04(td, J=8.4, 2.6Hz, 1H), 7.01-6.95(m, 1H), 4.10(t, J=3.3Hz, 1H), 3.83(s, 3H), 3.48 (d, J=1.7Hz, 1H); IR (KBr) v/cm ^-1 : 1752, 1634, 1442, 1292, 1233, 1210, 777, 686.

Pale yellow liquid, 63% yield, [α] _D ²⁰ =+132.2(0.5, CHCl ₃ ); ¹ HNMR (400MHz, CDCl ₃ ) δ7.22–7.16(m,2H), 7.02–6.95(m, 2H), 4.02(t, J=3.7Hz, 1H), 3.76(d, J=5.6Hz, 3H), 3.42(dd, J=7.8, 2.2Hz, 1H); IR(KBr)v/cm ^-1 : 1749, 1637, 1442, 1290, 1243, 1214, 775, 686.

Colorless oil 75% yield, [α] _D ²⁰ =+128.3 (0.5, CHCl ₃ ); ¹ HNMR (500MHz, CDCl ₃ ) δ7.63 (t, J = 7.1Hz, 1H), 7.56 (s, 1H), 7.54–7.47(m, 2H), 4.17(d, J=1.6Hz, 1H), 3.85(s, 3H), 3.51(d, J=1.7Hz, 1H); IR(KBr)v/cm ^-1 : 1755, 1636, 1405, 1328, 1125, 700, 662.

White solid, 71% yield, mp55～57℃, [α] _D ²⁰ ＝+135.2(0.5, CHCl ₃ ); ¹ HNMR(500MHz, CDCl ₃ ) δ7.51–7.45(m,1H), 7.43(s ,1H),7.23(ddd,J=5.3,3.9,1.5Hz,2H),4.07(d,J=1.7Hz,1H),3.83(s,3H),3.48(d,J=1.6Hz,1H) .IR (KBr) v/cm ^-1 : 1758, 1450, 1341, 1208, 991, 880, 784, 746, 685.

White solid, 88% yield, mp49～52℃, [α] _D ²⁰ ＝+147.7(0.5, CHCl ₃ ), [lit ^[60] :[α] _D ²⁰ ＝+145.7(0.5, CHCl ₃ )]; ¹ HNMR (500MHz, CDCl ₃ ) δ7.31(dd, J=6.5, 4.5Hz, 2H), 7.27(t, J=3.7Hz, 1H), 7.19(dt, J=7.0, 1.6Hz, 1H), 4.08(d, J=1.6Hz, 1H), 3.83(s, 3H), 3.48(d, J=1.7Hz, 1H); IR(KBr)v/cm ^-1 :1747,1638,1436,1401,1209 ,784,686.

White solid, 63% yield, mp73～74℃, [α] _D ²⁰ ＝+129.6(0.5, CHCl ₃ ), [lit ^[60] : mp69-70℃, [α] _D ²⁰ ＝+127.6(0.5, CHCl ₃ )]; ¹ HNMR (500MHz, CDCl ₃ ) δ7.52–7.50(m,1H),7.50–7.48(m,1H),7.19–7.17(m,1H),7.17–7.15(m,1H) ,4.07(d,J=1.6Hz,1H),3.83(s,3H),3.47(d,J=1.7Hz,1H); IR(KBr)v/cm ^-1 :1751,1493,1425,1339, 1211, 1091, 835, 793.

White solid, 88% yield, mp58～59℃, [α] _D ²⁰ ＝+155.1(0.5, CHCl ₃ ), [lit ^[60] :[α] _D ²⁰ ＝+150.6(0.5, CHCl ₃ )]; ¹ HNMR (500MHz, CDCl ₃ )δ7.36–7.33(m,1H),7.33–7.31(m,1H),7.24–7.22(m,1H),7.22–7.20(m,1H),4.08(d, J＝1.6Hz, 1H), 3.82(s, 3H), 3.47(d, J＝1.7Hz, 1H); IR(KBr)v/cm ^-1 : 2955, 1752, 1496, 1445, 1290, 1211, 1091 ,835,739.

Pale yellow liquid, 78% yield, [α] _D ²⁰ ＝+156.3(0.5, CHCl ₃ ), [lit ^[60] : [α] _D ²⁰ ＝+157.1(0.5, CHCl ₃ )]; ¹ HNMR( 500MHz, CDCl ₃ )δ7.40–7.34(m,3H),7.32–7.28(m,2H),4.11(t,J＝2.7Hz,1H),3.83(s,3H),3.53(d,J＝ 1.8Hz, 1H); IR (KBr) v/cm ⁻¹ : 2955, 1750, 1634, 1440, 1413, 1201, 760, 696.

Pale yellow liquid, 88% yield, mp137～138℃, [α] _D ²⁰ ＝+150.1(0.5, CHCl ₃ ), [lit ^[60] : mp137-139, [α] _D ²⁰ ＝+151.6(0.5 ,CHCl ₃ )]; ¹ HNMR (500MHz, CDCl ₃ )δ8.25(s,1H),8.23(s,1H),7.49(s,1H),7.47(s,1H),4.22(d,J= 1.5Hz, 1H), 3.85(s, 3H), 3.50(d, J=1.6Hz, 1H); IR(KBr) v/cm ^-1 : 1750, 1606, 1518, 1349, 1216, 863, 735, 690.

② Synthesis of compounds 2a-2j

(wherein R ₁ =H tryptamine, R ₁ =Me methyl tryptamine)

Dissolve 1.0g of tryptamine or N-methyltryptamine in 30ml of methanol, cool in an ice bath to 5°C, then add 112mg of potassium tert-butoxide 10ml of methanol solution dropwise, and add 1a~1j1.6~2.3g after the dropwise addition , maintain this temperature for 3h, after the reaction, the solvent was distilled off under reduced pressure, the residue was washed with dichloromethane (50ml x 3), and the organic phase was washed with distilled water (10ml×3), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the column layer of the residue was Analysis and purification, that is.

White solid, 81% yield, mp138～140℃, [α] _D ²⁰ ＝+45.1(0.5, CHCl ₃ ); ¹ HNMR (500MHz, CDCl ₃ ) δ8.18(s,1H), 7.62(d,J =7.9Hz,1H),7.45–7.37(m,1H),7.30(td,J=8.0,5.7Hz,1H),7.24(t,J=7.5Hz,1H),7.16(dd,J=7.8, 7.1Hz,1H),7.06(d,J＝2.0Hz,1H),7.05–6.97(m,2H),6.91–6.85(m,1H),6.29(s,1H),3.72–3.59(m,3H ), 3.43 (d, J=1.8Hz, 1H), 3.11–2.95 (m, 2H); IR (KBr) v/cm ⁻¹ : 3313, 1638, 1557, 1458, 1248, 743, 610.

White solid, 80% yield, mp119～121℃, [α] _D ²⁰ ＝+47.3(0.5, CHCl ₃ ); ¹ HNMR (400MHz, DMSO) δ10.82(s, 1H), 8.26(t, J＝ 5.6Hz, 1H), 7.55(d, J=7.8Hz, 1H), 7.44–7.29(m, 3H), 7.21(dd, J=18.5, 9.8Hz, 3H), 7.07(t, J=7.5Hz, 1H), 6.98(t, J=7.4Hz, 1H), 4.02(s, 1H), 3.58(d, J=1.5Hz, 1H), 3.47–3.35(m, 2H), 2.88(t, J=7.3 Hz, 2H); IR (KBr) v/cm ⁻¹ : 3448, 1639, 1556, 1514, 1228, 839, 743, 615.

White solid, 89% yield, mp127～130℃, [α] _D ²⁰ ＝+36.2(0.5, CHCl ₃ ); ¹ HNMR (500MHz, CDCl ₃ ) δ8.12(s,1H), 7.63(d,J =7.9Hz,1H),7.59(d,J=7.6Hz,1H),7.47(t,J=7.8Hz,1H),7.45–7.39(m,2H),7.37(d,J=7.7Hz,1H ), 7.24(d, J=7.3Hz, 1H), 7.17(t, J=7.4Hz, 1H), 7.08(d, J=2.2Hz, 1H), 6.28(s, 1H), 3.74–3.59(m , 3H), 3.45 (d, J=1.9Hz, 1H), 3.13-2.96 (m, 2H); IR (KBr) v/cm ^-1 : 3414, 1638, 1558, 1322, 1140, 746, 611.

White solid, 83% yield, mp168～172℃, [α] _D ²⁰ ＝+55.8(0.5, CHCl ₃ ); ¹ HNMR(500MHz, CDCl ₃ ) δ8.14(s,1H),7.62(d,J =7.9Hz,1H),7.46(d,J=8.0Hz,1H),7.40(d,J=8.1Hz,1H),7.32(d,J=1.6Hz,1H),7.26-7.10(m,4H ), 7.07(d, J=2.0Hz, 1H), 6.27(s, 1H), 3.65(tq, J=13.4, 6.7Hz, 2H), 3.59(t, J=3.0Hz, 1H), 3.42(d , J=1.9Hz, 1H), 3.11–2.95(m, 2H); IR(KBr)v/cm ⁻¹ : 3313, 1638, 1556, 1432, 1248, 744, 617.

White solid, 81% yield, mp 160～163°C, [α] _D ²⁰ ＝+40.1(0.5, CHCl ₃ ); ¹ HNMR (400MHz, DMSO) δ10.82(s, 1H), 8.28(t, J＝ 5.7Hz, 1H), 7.55(d, J=7.8Hz, 1H), 7.45(d, J=8.5Hz, 2H), 7.43–7.32(m, 3H), 7.17(d, J=2.1Hz, 1H) ,7.08(dd,J=11.0,4.0Hz,1H),6.99(dd,J=11.0,3.8Hz,1H),4.03(d,J=1.7Hz,1H),3.57(d,J=1.9Hz, 1H), 3.41(dd, J＝13.4, 7.2Hz, 2H), 2.88(t, J＝7.4Hz, 2H); IR(KBr)v/cm ^-1 : 3313, 1639, 1551, 1431, 1092, 1012 ,742,614.

White solid, 89% yield, mp177～179℃, [α] _D ²⁰ ＝+55.3(0.5, CHCl ₃ ); ¹ HNMR (400MHz, DMSO) δ10.82(s, 1H), 8.28(t, J＝ 5.6Hz, 1H), 7.57(dd, J=13.6, 8.1Hz, 3H), 7.32(dd, J=18.6, 8.2Hz, 3H), 7.17(d, J=1.7Hz, 1H), 7.07(t, J＝7.4Hz, 1H), 6.98(t, J＝7.4Hz, 1H), 4.02(d, J＝1.4Hz, 1H), 3.56(d, J＝1.7Hz, 1H), 3.41(dd, J＝ 13.4, 7.0 Hz, 2H), 2.87 (t, J = 7.3 Hz, 2H); IR (KBr) v/cm ^-1 : 3313, 1638, 1551, 1458, 1431, 1092, 742, 614.

White solid, 88% yield, mp159～153℃, [α] _D ²⁰ ＝+34.1(0.5, CHCl ₃ ); ¹ HNMR (500MHz, CDCl ₃ ) δ8.17(s,1H), 7.62(d,J =7.9Hz,1H),7.40(d,J=8.1Hz,1H),7.33-7.29(m,1H),7.27(d,J=7.6Hz,1H),7.24(t,J=6.6Hz,1H ),7.16(q,J=6.7Hz,2H),7.10–7.04(m,2H),6.28(s,1H),3.70–3.61(m,2H),3.60(d,J=1.9Hz,1H) , 3.43 (d, J=1.9Hz, 1H), 3.11–2.95 (m, 2H); IR (KBr) v/cm ⁻¹ : 3313, 1638, 1556, 1458, 1430, 744, 617.

White solid, 88% yield, mp131～133℃, [α] _D ²⁰ ＝+33.1(0.5, CHCl ₃ ), [lit ^[1] : mp125-127, [α] _D ＝+30(0.5, CHCl ₃ )]; ¹ HNMR (500MHz, CDCl ₃ ) δ8.11(s, 1H), 7.63(d, J=7.9Hz, 1H), 7.40(d, J=8.1Hz, 1H), 7.37–7.30(m, 3H), 7.23(dd, J=11.2, 4.0Hz, 1H), 7.20(dd, J=6.5, 3.1Hz, 2H), 7.16(t, J=7.4Hz, 1H), 7.08(d, J=2.2 Hz,1H),6.31(s,1H),3.66(dt,J=13.0,4.2Hz,3H),3.49(d,J=2.0Hz,1H),3.10–2.96(m,2H); IR(KBr )v/cm ^-1 : 3310, 1638, 1556, 1458, 1432, 743, 616.

White solid, 69% yield. mp167～169℃, [α] _D ²⁰ ＝+73.2(0.5, CHCl ₃ ); ¹ HNMR (500MHz, CDCl ₃ ) δ8.23–8.21(m,1H), 8.21–8.19(m,1H), 8.11( s,1H),7.63(d,J=7.9Hz,1H),7.41(d,J=8.1Hz,1H),7.38–7.32(m,2H),7.24(dd,J=8.1,1.1Hz,1H ),7.20–7.14(m,1H),7.09(d,J＝2.3Hz,1H),6.26(s,1H),3.76–3.59(m,3H),3.44(d,J＝1.9Hz,1H) ,3.14–2.95(m,2H). IR (KBr) v/cm ^-1 : 3310, 1639, 1522, 1348, 748, 612.

White solid, 80% yield, mp135～137℃, [α] _D ²⁰ ＝+35.1(0.5, CHCl ₃ ), ¹ HNMR (500MHz, CDCl ₃ ) δ8.11(s,1H), 7.63(d,J =7.9Hz,1H),7.40(d,J=8.1Hz,1H),7.37–7.30(m,3H),7.23(dd,J=11.2,4.0Hz,1H),7.20(dd,J=6.5, 3.1Hz, 2H), 7.16(t, J=7.4Hz, 1H), 7.08(d, J=2.2Hz, 1H), 3.66(dt, J=13.0, 4.2Hz, 3H), 3.49(d, J= 2.0Hz, 1H), 3.10–2.96(m, 2H), 2.90(s, 3H); IR(KBr)v/cm ^-1 : 3315, 1630, 1550, 1458, 1432, 743, 616.

③ Synthesis of compounds 3a-3j

Dissolve 670-744 mg of 2a-2j in 30 ml of dry THF, and then add 58-64 mg of ytterbium trifluoromethanesulfonate. React overnight at room temperature. After the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in 50ml of dichloromethane, then washed with saturated NaCl solution (10ml×3), washed once with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain Viscous, crude product purified by column chromatography, that is.

White solid, 76% yield, mp 114-116°C, [α] _D ²⁰ =+33 (c=0.5, MeOH); ¹ HNMR (500MHz, DMSO) δ10.79(s, 1H), 7.99(t, J =5.8Hz,1H),7.49(d,J=7.8Hz,1H),7.40–7.30(m,2H),7.25(dd,J=17.1,8.9Hz,2H),7.05(dd,J=14.2, 6.5Hz, 2H), 6.97(t, J＝7.4Hz, 1H), 5.40(d, J＝4.6Hz, 1H), 4.42–4.34(m, 1H), 3.36(s, 1H), 3.35–3.15( m,2H),2.68–2.52(m,2H); ¹³ CNMR(126MHz,DMSO)δ169.71,160.21,136.20,129.75,127.07,124.80,122.44,120.93,118.21,115.63,115.45,115.1016,1115. ,75.24,62.61,40.02,25.00; IR(KBr)v/cm ^-1 :3421,1637,1538,1488,1452,1275,1236,1114,789,696; HRMS(ES ⁺ )caculated for C ₁₉ H ₁₇ O ₂ N ₂ F[M+Na] ⁺ =347.1163, found=347.1167; ee value was determined by chiral HPLC through chiralcel AD-H column (4.6mm×25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml /min), t _minor =31.5min, t _major =35.1min, 97%ee.

White solid, 70% yield, mp88-91℃, [α] _D ²⁰ =+45 (c=0.5, MeOH); ¹ HNMR (500MHz, DMSO) δ10.79 (s, 1H), 7.95 (t, J =5.9Hz,1H),7.52–7.43(m,3H),7.32(d,J=8.1Hz,1H),7.14(t,J=8.9Hz,2H),7.04(dd,J=4.0,1.5Hz ,1H),6.97(t,J=7.4Hz,1H),5.39(d,J=4.7Hz,1H),4.36(dd,J=6.4,5.0Hz,1H),3.34(s,1H),3.32 –3.16(m,2H),2.70–2.53(m,2H); ¹³ CNMR(126MHz,DMSO)δ169.80,161.06,136.21,133.75,130.80,127.07,122.47,120.93,118.21,114.72,114.53,1111.3 75.33,62.79,40.02,25.00; IR(KBr)v/cm ^-1 :3492,1634,1506,1116,1088,879,745,670; HRMS(ES ⁺ )caculated for C ₁₉ H ₁₇ O ₂ N ₂ F[M+Na] ⁺ =347.1151, found=347.1154; ee value is determined by chiralcel AD-H column by chiral HPLC (4.6mm×25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t _minor = 32.0 min, t _major = 37.3 min, >99% ee.

White powder, 75% yield, mp94-96℃, [α] _D ²⁰ =+41 (c=0.5, MeOH); ¹ HNMR (500MHz, DMSO) δ10.78(s,1H), 7.99(t,J =5.9Hz, 1H), 7.72(d, J=7.8Hz, 1H), 7.68(d, J=7.8Hz, 1H), 7.56(t, J=7.8Hz, 1H), 7.47(d, J=7.8 Hz, 1H), 7.32(d, J=8.1Hz, 1H), 7.08–7.03(m, 1H), 7.01(d, J=2.2Hz, 1H), 6.98–6.94(m, 1H), 5.54(d ,J=4.5Hz,1H),4.42(dd,J=6.4,4.6Hz,1H),3.33–3.11(m,2H),2.64–2.52(m,2H); ¹³ CNMR(126MHz,DMSO)δ169. ^{62,138.71,136.20,132.89,128.99,127.05,125.17,125.00,122.39,120.93,118.21,118.18,111.47,111.41,75.17,62.62,39.94,39.85,118.21,118.18,111.47,111.41,75.17,62.62,39.94,39.85,369.973} 1647,1342,1122,802,746,705; HRMS (ES ⁺ ) caculated for C ₂₀ H ₁₇ O ₂ N ₂ F ₃ [M+Na] ⁺ = 397.1190, found = 397.1194; ee value was determined by chiral HPLC through chiralcel AD-H column (4.6 mm×25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t _minor =20.4min, t _major =21.4min, 96%ee.

White powder, 60% yield, mp120-123℃, [α] _D ²⁰ =-61 (c = 0.5, MeOH); ¹ HNMR (500MHz, DMSO) δ10.84 (s, 1H), 8.31 (s, 1H) ),7.55(d,J=8.1Hz,3H),7.35(s,3H),7.07(t,J=7.3Hz,1H),6.98(t,J=7.2Hz,1H),4.03(s,1H ),3.60(s,1H),3.41(d,J=6.1Hz,2H),2.87(t,J=6.9Hz,2H); ¹³ CNMR(126MHz,DMSO)δ166.10(s),138.78(s ),136.23(s),131.50(s),130.73(s),128.72(s),127.24(s),125.13(s),122.76(s),121.87(s),120.93(s),118.25(s ), 111.53, 111.39, 58.15(s), 55.78(s), 40.02(s), 24.94(s); IR(KBr)v/cm ^-1 :3399,1644,1537,1427,1342,1248,787,738,692; HRMS (ES ⁺ ) caculated for C ₁₉ H ₁₇ O ₂ N ₂ Br[M+Na] ⁺ = 407.0352, found = 407.0351; ee value was determined by chiral HPLC through chiralcelAD-H column (4.6mm×25cm, n-hexane/i - PrOH = 90/10, λ = 254 nm, 0.8 ml/min), t _minor = 31.6 min, t _major = 35.7 min, 97% ee.

White powder, 65% yield, mp151-161℃, [α] _D ²⁰ = +56 (c = 0.5, MeOH); ¹ HNMR (400MHz, DMSO) δ10.78 (s, 1H), 7.94 (t, J =5.8Hz,1H),7.50(d,J=7.8Hz,1H),7.40(dd,J=22.4,8.6Hz,4H),7.33(d,J=8.1Hz,1H),7.04(s,1H ),6.97(t,J=7.4Hz,1H),5.39(d,J=4.7Hz,1H),4.37(dd,J=6.5,4.8Hz,1H),3.32–3.19(m,2H),2.72 –2.52(m,2H); ¹³ CNMR(101MHz,DMSO)δ169.68(s),136.39(s),136.18(s),132.80(s),130.49(s),127.77(s),127.05(s ), 122.42(s), 120.89(s), 118.17(s), 111.39(d, J=19.2Hz), 75.22(s), 62.67(s), 40.13(s), 24.95(s); IR(KBr )v/cm ^-1 :3366,2956,1638,1538,1491,1458,1413,1091,1036,922,814,744; ee value was determined by chiral HPLC through chiralcelAD-H column (4.6mm×25cm, n-hexane/i -PrOH=90/10, λ=254nm, 0.8ml/min), t _minor =31.9min, t _major =36.9min, >99%ee.

White powder, 66% yield, mp147-150℃, [α] _D ²⁰ =+58 (c=0.5, MeOH); ¹ HNMR (500MHz, DMSO) δ10.85(s,1H), 8.00(s,1H ), 7.50(t, J=9.2Hz, 3H), 7.34(dd, J=14.9, 8.3Hz, 3H), 7.05(d, J=2.7Hz, 1H), 6.97(t, J=7.4Hz, 1H ), 5.37(d, J＝4.7Hz, 1H), 4.36(t, J＝5.6Hz, 1H), 3.33–3.17(m, 2H), 2.69–2.54(m, 2H); ¹³ CNMR (126MHz, DMSO )δ172.45, 136.88, ^136.20 , 130.85, 130.75, 127.06, 122.47, 121.45, 120.90, 118.20, 111.48, 111.35, 75.17, 62.73, 39.51, 24.99; , 1122,804,744,667; HRMS(ES ⁺ )caculated for C ₁₉ H ₁₇ O ₂ N ₂ Br[M+Na] ⁺ = 407.3332, found = 407.3338; ee value was determined by chiral HPLC through chiralcel AD-H column (4.6mm×25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t _minor =34.9min, t _major =39.6min, >99%ee.

White solid, 62% yield, mp 178-181°C, [α] _D ²⁰ =+120 (c = 0.5, MeOH); ¹ HNMR (500MHz, DMSO) δ10.79(s, 1H), 7.99(t, J =5.8Hz,1H),7.55–7.46(m,2H),7.35(m,4H),7.06(d,J=7.8Hz,1H),6.97(t,J=7.4Hz,1H),5.40(d ,J=4.6Hz,1H),4.37(dd,J=6.3,4.8Hz,1H),3.33–3.13(m,2H),2.69–2.52(m,2H); ¹³ CNMR(126MHz,DMSO)δ169. ^{66,139.74,136.20,132.42,129.70,128.52,128.17,127.42,127.06,122.43,120.92,118.21,111.50,111.33,75.19,62.60,39.51,25.03} 1430,1114,747,706; HRMS (ES ⁺ ) caculated for C ₁₉ H ₁₇ O ₂ N ₂ Cl[M+Na] ⁺ = 363.0862, found = 363.0865; ee value was determined by chiral HPLC through chiralcel AD-H column (4.6mm×25cm , n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t _minor ＝29.7min, t _major ＝34.0min, 97%ee.

White solid, 78% yield, mp127～130℃, [α] _D ²⁰ ＝+30(c＝0.5, MeOH); ¹ HNMR (400MHz, DMSO) δ10.85(s,1H), 7.51(d,J =7.7Hz,1H),7.36(d,J=7.5Hz,2H),7.29(t,J=7.5Hz,3H),7.20(t,J=7.2Hz,2H),7.07–6.93(m,2H ), 4.88(d, J=9.9Hz, 1H), 4.21(d, J=9.9Hz, 1H), 3.68(s, 1H), 3.32–3.17(m, 3H), 1.25(s, 1H); ¹³ CNMR (101MHz, DMSO) δ175.94, 141.65, 135.77, 135.27, 128.55, 128.49, 128.03, 126.40, 120.66, 118.21, 117.42, 110.53, 105.65, 70.43, ^51.460 , 39.51, 23.13; MS: 4; The ee value was determined by chiral HPLC through a chiralcelAD-H column (4.6mm×25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t _minor ＝33.0min, t _major ＝40.1 min,97%ee.

White powder, 72% yield, mp 162-164°C, [α] _D ²⁰ =+73 (c=0.5, MeOH); HNMR (500MHz, DMSO) δ10.78(s, 1H), 8.17(d, J= 8.8Hz, 2H), 7.99(t, J=5.8Hz, 1H), 7.67(d, J=8.7Hz, 2H), 7.46(d, J=7.9Hz, 1H), 7.10–7.03(m, 2H) ,6.96(t,J=7.3Hz,1H),5.54(d,J=4.5Hz,1H),4.47–4.39(m,1H),3.33–3.17(m,2H),2.68–2.54(m,2H ); ¹³ CNMR (126MHz, DMSO) δ169.48, 147.20, 144.70, 136.18, 130.08, 127.06, 122.94, 122.45, 120.94, 118.20, 111.47, 111.33, 75.14, 62.16, 39.51/cm -IR ( ^11K.95 ); : 3309,1642,1522,1352,1113,702; HRMS (ES ⁺ ) caculated for C ₁₉ H ₁₇ N ₃ O ₄ [M+Na] ⁺ = 374.1162, found = 374.1161; ee value by chiralcelAD-H column by chiral HPLC Determined (4.6mm×25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t _minor =40.1min, t _major =26.8min, >99%ee.

White powder, 75% yield, mp190–193°C, [α] _D ²⁰ =+7.3 (c=0.5, CHCl ₃ ), [lit ^[16] : mp185-191, [α] _D ²⁰ =+6.9 (0.5 , CHCl ₃ )]; ¹ HNMR (500MHz, CDCl3) δ7.92 (brs, 1H), 7.53 (dd, J = 6.8, 1.6Hz, 1H), 7.33–7.24 (m, 5H), 7.20 (dd, J =6.8Hz,2Hz,1H),7.15(m,1H),7.12(m,1H),4.96(br,J=6.6Hz,1H),4.37(d,J=6.0Hz,1H),4.34(vbrs ),3.96(m,1H),3.49(m,1H),3.41(m,1H),3.03(m,1H),2.84(s,3H); ¹³ CNMR(100MHz,CDCl ₃ )δ173.5,141.0,135.2 ,132.2,129.3,128.7,127.5,127.2,122.1,119.4,117.5,110.7,106.6,73.8,54.3,46.4,34.2,22.8.IR(KBr)v/cm ^-1 :3301,2926,1640,1495,1461 , 1392,1360,1340,1183,1066,909,734,700; HRMS (ES ⁺ )caculatedforC ₂₀ H ₂₀ O ₂ N ₂ [M] ⁺ = 320.1525; found: 320.1530; ee value is determined by chiralcel AD-H column by chiral HPLC ( 4.6mm×25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t _major ＝34.4min, t _minor ＝63.9min, 97%ee.

Embodiment 3 applied pharmacological test

The neuroprotective effect, antioxidant effect, anti-inflammatory effect of brain cells and cytotoxicity test of the test compound. The experimental results are shown in Table 6, Table 7, Table 8 and Table 9. It can be seen from Table 6, Table 7, Table 8 and Table 9 that the neuroprotective and antioxidant effects of the tested compounds are very low. It can be seen from Table 8 that, except for 3g, other compounds can significantly inhibit the inflammatory response produced by rat microglial cells, among which 3c has the strongest effect. Meanwhile, it can be seen from Figure 1 that the cytotoxicity test shows that the compound of the present invention has no cytotoxicity.

Table 6 The brain protection effect of the test group compounds on the nerve damage caused by the nutritional deficiency of primary cultured rat cerebellar granule neurons

Note: the cell survival rate of the blank control group (DMSO treatment group) was 100%, and the average cell survival rate of the negative control group (nutrient deficiency test group) was 38.8±1.4%. The positive control was N-acetylcysteine (NAC, which is an antioxidant as reported in the literature), and the cell survival rate of this group was 53.7±1.2% (10 mM).

Table 7 Test group compounds on the brain protection of PC12 nerve cell injury caused by hydrogen peroxide

Note: the cell survival rate of the blank control group (DMSO treatment group) was 100%, and the cell survival rate of the hydrogen peroxide treatment group was 61.9±3.8%. The positive control was N-acetylcysteine (NAC, which was reported in the literature as an antioxidant). The cell survival rate of this group was 87.8±3.8% (10 mM). Cell viability was determined by MTT assay.

Table 8 Protective effect of test group compounds on primary rat cerebellar granule neuron injury induced by L-glutamic acid

Note: The cell survival rate of the blank control group (DMSO treatment group) was 100%, and the average cell survival rate of the negative control group (glutamic acid treatment group) was 48.1%.

Table 9 Inhibitory effect of test compounds on lipopolysaccharide-induced release of inflammatory factor TNFα in BV-2 microglial cells

Note: BV-2 microglial cells were cultured alone by adding 100ng/ml lipopolysaccharide, or adding lipopolysaccharide to incubate cells after pretreatment with different doses of test compounds for 2 hours. After the cells were cultured for 6 hours, the release of cytokine TNFα was measured by ELISA method. Results are expressed as lipopolysaccharide induction rate.

Claims (7)

1. A class of Balasubramide derivatives, characterized in that its structural formula is as shown in formula (I): Among them, R ₁ is H or -CH ₃ ; R is 3-FC ₆ H ₄ , 4-FC ₆ H ₄ , 3-Cl-C ₆ H ₄ , 4-Cl-C ₆ H ₄ , 3-Br- C ₆ H ₄ , 4-Br-C ₆ H ₄ , 4-NO ₂ -C ₆ H ₄ or 3-CF ₃ -C ₆ H ₄ . 2. The application of the Balasubramide derivatives as claimed in claim 1, characterized in that it is applied to the preparation of the brain protection drug for the treatment of nerve cells. 3. the application of the described Balasubramide derivative of claim 1, is characterized in that, is applied to the aspect of preparing antineuroinflammatory drug. 4. application according to claim 2, is characterized in that, is that structural formula R shown in claim 1 formula (I) R ₁ is H and R is 4-FC ₆ H The compound characterized by 4-FC 6 H ₄ is applied to preparation treatment and nerve cell Related drug aspects of brain protection. 5. application according to claim 3, is characterized in that, is that structural formula R shown in claim 1 formula (I) R ₁ is H and R is 4-FC ₆ H ₄ The compound of characterization is applied to the preparation of anti-neuroinflammatory drugs aspect. 6. the preparation method of Balasubramide and derivative thereof described in claim 1, is characterized in that, comprises the following steps: S1. One-pot method to catalyze the epoxidation of trans-cinnamaldehyde and its derivatives to obtain α, β-epoxy carboxylate; S2. reacting the α, β-epoxy carboxylate obtained in S1 with tryptamine and its analogs to obtain prebalamide and its derivatives; S3. Using Yb(CF ₃ SO ₃ ) ₃ as a catalyst to ring-close the prebalamide or its derivatives obtained in S2 to synthesize balasubramide and its derivatives; Wherein, the trans-cinnamaldehyde and its derivatives described in step S1 are The α, β-epoxy carboxylate is Tryptamine and its analogs described in step S2 are The prebalamide and its derivatives described in step S2 are 7. preparation method according to claim 6 is characterized in that, the one-pot method catalysis trans-cinnamaldehyde and derivative epoxidation thereof of S1 comprises the following steps: S11. Using S-diphenylprolinol triethylsilyl ether to catalyze a series of epoxidation of trans-cinnamaldehyde and its derivatives with 40% H ₂ O ₂ aqueous solution as an oxidant under ice-bath conditions; S12. At room temperature, the reaction solution obtained in S11 was diluted with methanol, and NBS and sodium carbonate were added to synthesize α,β-epoxy carboxylate.