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

Balasubramide and derivative thereof and synthetic method and application Download PDF

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CN104003991B
CN104003991B CN201410260588.4A CN201410260588A CN104003991B CN 104003991 B CN104003991 B CN 104003991B CN 201410260588 A CN201410260588 A CN 201410260588A CN 104003991 B CN104003991 B CN 104003991B
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balasubramide
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林汉森
庞涛
李建组
张陆勇
徐渊
宣宜宁
定力
李骏
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Guangdong Pharmaceutical University
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses Balasubramide and derivative thereof and synthetic method and application. The structural formula of Balasubramide of the present invention and derivative thereof is suc as formula shown in (I), and described Balasubramide and derivative thereof have excellent anti-nerve cell inflammation activity, and all there is no cytotoxicity. The present invention is the rational synthetic line of design science simultaneously, and simply efficient, the total recovery of (+)-balasubramide is more than 45%, and ee value is more than 97%.（Ⅰ）。

Description

Balasubramide and derivative thereof and synthetic method and application
Technical field
The present invention relates to chemical synthesis and medical technical field, more specifically, relate to Balasubramide and derivative thereof and synthetic method and application.
Background technology
1996, the chloroform extract of Rutaceae clausena plant Randia cochinchinensis [Clausenaindica (Datz) .Oliv.] leaf from Sri Lanka tropical rain forest such as Hofer was isolated biology precursor (+)-prebalamide of a kind of octatomic ring lactams composition (+)-balasubramide and (+)-balasubramide.
Rutaceae clausena plant is mainly distributed in south, the southeast in Asia, and minority is distributed in SOUTHERN CHINA and Australia. Interior nearly 30 kinds of world wide, has nearly 10 kinds within the border in China, is distributed in the middle and lower reach of Yangtze River and southern each province. The most plants of this genus is medicinal plant in China from ancient times, is used for the treatment of the diseases such as sense, malaria, stomachache and gastritis. Due to the importance of eight membered lactams structures and potential biological value, balasubramide and derivative thereof have important researching value, but have no at present the technology report of more heterogeneous pass chirality (+)-balasubramide and analog thereof.
But the existing method of utilizing plant separation and Extraction can obtain (+)-balasubramide, due to low separative efficiency and productive rate, for the research of its BA aspect, be to be nowhere near. Therefore, exploring a kind of (+)-balasubramide and analog thereof that obtains chirality compared with the complete synthetic method of high separating efficiency and productive rate, is the key of its using value of research and development.
Due to labyrinth and multiple asymmetric carbon atom of eight membered lactams rings, up to now, rare pertinent literature report balasubramide's is synthetic, existing document relates to the synthetic report of balasubramide, disclosed synthetic method or reaction scheme are long, and productive rate is very low, or synthetic raw material preparation process is loaded down with trivial details, reaction condition is special, has limited synthetic the production and promotion applied research of reality of balasubramide. Have no the synthetic of balasubramide related derivatives and application technology report.
Summary of the invention
The technical problem to be solved in the present invention is the deficiency that overcomes existing Balasubramide derivative, and the Balasubramide derivative that a class is new is provided.
Another technical problem that the present invention will solve is to provide the application of described Balasubramide derivative.
Another technical problem that the present invention will solve is to provide the preparation method that a kind of step is simple, raw material is easy to get, productive rate is higher, can obtain Balasubramide of the present invention and derivative thereof based on described preparation method.
The also technical problem that the present invention will solve is to provide and adopts Balasubramide that described preparation method prepares and the application of derivative thereof.
Object of the present invention is achieved by the following technical programs:
The derivative of Balasubramide is provided, and its structural formula is suc as formula shown in (I):
Wherein, R1For H or-CH3; R is Ph, 3-F-C6H4、4-F-C6H4、3-Cl-C6H4、4-Cl-C6H4、3-Br-C6H4、4-Br-C6H4、4-NO2-C6H4Or 3-CF3-C6H4。
The application of the derivative of described Balasubramide aspect the preparation treatment cerebral protection medicine relevant to nerve cell provides described Balasubramide derivative in the application of preparing aspect anti-neuritis disease drug simultaneously.
R in structure shown in preferred formula (I)1For H and R are 4-F-C6H4Time compound in the application aspect the preparation treatment cerebral protection medicine relevant to nerve cell, and in the application of preparing aspect anti-neuritis disease drug.
The preparation method who the invention provides a kind of Balasubramide and derivative thereof, comprises the following steps:
S1. one kettle way catalysis trans-cinnamic aldehyde and derivative epoxidation thereof, obtains α, beta epoxide carboxylate;
S2. by S1 gained α, beta epoxide carboxylate and tryptamines and analog effect thereof, obtain prebalamide and derivative thereof;
S3. with Yb (CF3SO3)3For catalyst, make the prebalamide or derivatives thereof cyclization respectively of S2 gained, synthetic (+)-balasubramide and derivative thereof.
Wherein, described in S1, one kettle way catalysis trans-cinnamic aldehyde and derivative epoxidation thereof comprise the following steps:
S11. under condition of ice bath, with 40% (V/V) H2O2The aqueous solution is oxidant, uses the S-diphenylprolinol triethyl group silicon a series of trans-cinnamic aldehyde of ether catalysis and derivative epoxidation thereof;
S12. at ambient temperature, S11 gained reactant liquor dilutes with methyl alcohol, adds NBS (N-bromosuccinimide, N-bromosuccinimide) and sodium carbonate, synthetic α, beta epoxide carboxylate.
The invention provides the Balasubramide synthetic based on described preparation method and derivative thereof. Structural formula is suc as formula shown in (I):
Wherein, R1For H or-CH3; R is Ph, 3-F-C6H4、4-F-C6H4、3-Cl-C6H4、4-Cl-C6H4、3-Br-C6H4、4-Br-C6H4、4-NO2-C6H4Or 3-CF3-C6H4。
The present invention provides the application aspect the preparation treatment cerebral protection medicine relevant to nerve cell of the Balasubramide for preparing based on described preparation method and derivative thereof simultaneously, provides described Balasubramide derivative in the application of preparing aspect anti-neuritis disease drug simultaneously.
Beneficial effect of the present invention:
The invention provides the selective Balasubramide derivative of a class high antimer, fill up and had the blank or not enough of optical activity eight membered lactams structural compounds, for the research application of relevant chirality (+)-balasubramide and analog thereof provides strong technical foundation.
The invention provides synthetic line and synthetic method that described Balasubramide and derivative thereof are new, designed the asymmetric syntheses route of one (+)-balasubramide, successfully synthesize Balasubramide and derivative thereof. First the present invention has designed scientific and reasonable synthetic line, optimized key intermediate α, the synthetic process conditions of beta epoxide carboxylate, adopt the one kettle way of optimizing to synthesize a series of α, beta epoxide carboxylate, has obtained the highest 80% productive rate and 97%ee value. Result shows, the one kettle way of optimization provided by the present invention is prepared asymmetric Epoxidation and the oxidative esterification of alpha, beta-unsaturated esters, is synthetic α, the simple method efficiently of beta epoxide carboxylate. Further, based on the present invention optimize high ee value that one kettle way catalysis trans-cinnamic aldehyde and derivative epoxidation thereof obtain α, beta epoxide carboxylate, by itself and tryptamines and analog effect thereof, has obtained prebalamide and derivative thereof, then with Yb (CF3SO3)3For catalyst, make prebalamide cyclization, synthesize natural products (+)-balasubramide and derivative thereof. By optimizing reaction condition, the present invention has obtained higher yield and enantioselectivity. Wherein, the total recovery of (+)-balasubramide is more than 45%, and ee value is more than 97%.
The invention provides the new application of described Balasubramide derivative, Balasubramide derivative all has the inflammatory reaction effect that suppresses significantly microglia generation, and meanwhile, cytotoxicity experiment shows that these compounds do not have cytotoxicity.
Brief description of the drawings
The cerebral protection experimental result of the neurotrosis that Fig. 1 the compounds of this invention causes the cultured rat cerebellar granule neuron nutritional deficiency of former culture.
The cerebral protection of the PC12 neural cell injury of tested group of compound of Fig. 2 to hydrogen peroxide-induced.
The protective effect of tested group of compound of Fig. 3 in the primary cultured rat cerebellar granule neural cell injury of Pidolidone induction.
The inhibitory action that Fig. 4 test-compound discharges inflammatory factor TNFalpha in lipopolysaccharide-induced BV-2 microglia.
The cytotoxic effect of Fig. 5 test-compound to BV-2 microglia.
Detailed description of the invention
Further illustrate the present invention below in conjunction with the drawings and specific embodiments. Unless stated otherwise, the reagent that the present invention adopts and and equipment be conventional reagent and the equipment using in this area.
The synthetic method condition research experiment of embodiment 1Balasubramide derivative
One, optical activity alpha, beta epoxide carboxylate synthetic
The method of reference literature report, we are by optimizing reaction condition, with 40%H2O2The aqueous solution is oxidant, use homemade chiral imines class catalyst S-diphenylprolinol triethyl group silicon a series of trans-cinnamic aldehyde of ether catalysis and derivative epoxidation thereof, after room temperature reaction 4h, with methyl alcohol dilution, then add NBS and sodium carbonate oxidative esterification, room temperature 3h, obtain (2S, 3R)-α, beta epoxide carboxylate, the latter has good productive rate and outstanding ee value. By the optical activity data of contrast document, the absolute configuration of end product is defined as 2S, 3R. The results are shown in Table shown in 1.
Reaction scheme is:
Table 1
Two, by α, the synthetic prebalamide of beta epoxide carboxylate and derivative thereof
1. the impact of reaction condition on compound 2 productive rates
The present invention is taking methyl alcohol as solvent, and at ambient temperature, beta-phenyl glycidic acid methyl esters and the condensation of tryptamines generation ester amine, react 3h, obtained product 2h. But, productive rate 55%. Further research is found, under cryogenic conditions, to add the alkali of catalytic amount can significantly improve the yield of reaction. Investigated and reacted the impact of various additives on reaction, result is as shown in table 2.
Reaction scheme is as follows:
Table 2
Research finds that the power of additive alkalescence has significant impact to reaction result. Add NaHCO3、K2CO3And Na2CO3Very micro-on the impact of reaction yield, and add catalytic amount t-BuOK and NaOCH3During in highly basic, the productive rate of reaction has significantly improved. Wherein, when taking t-BuOK as additive, obtained 81% productive rate. Therefore, the present invention select t-BuOK be reaction condensing agent.
Three, target product is synthetic
The present invention is taking acetonitrile as solvent, TFMS ytterbium (Yb (CF3SO3)3) be catalyst, synthesize (+)-balasubramide and derivative thereof by prebalamide and derivative thereof. In addition, the present invention has investigated the impact of differential responses condition on ring-closure reaction.
1. lewis acid (lewisacid) is on epoxy reactive impact, and experimental result is as shown in table 3:
Reaction scheme is given an example:
Table 3
As can be seen from Table 3, select different lewis acids, the productive rate of ring-closure reaction produces significantly difference. Add active strong lewis acid, as AlCl3、FeCl3, CuCl, there is no the generation of target product. Add active weak lewis acid LaCl3Time, the generation of target product detected, but productive rate is only 33%. When adding Yb (CF3SO3)3, when the lewis acids such as p-TSA, what cyclisation product was reacted obtains medium productive rate and outstanding corresponding selection. Wherein add Yb (CF3SO3)3Obtained best result, productive rate be 73% and ee value be 97%.
2. reaction dissolvent is on epoxy reactive impact
At definite Yb (CF3SO3)3After cyclization catalyst, the present invention has investigated the impact of reaction dissolvent on reaction, and result is as shown in table 4.
Reaction scheme is as follows:
Table 4
As can be seen from Table 4, ring-closure reaction can carry out smoothly in most of solvent, and the not impact of the ee value of solvent on product. Compare non-polar solven as CHCl3Solvent, reaction obtains better productive rate in polar solvent. Wherein, taking THF as solvent, reaction has the highest productive rate, has reached 75%. Synthesis condition for other derivatives is studied with above-mentioned experimental result.
Embodiment 2
The overall synthetic route of optical activity (+)-balasubramide derivative is as follows:
Obtain (+)-balasubramide derivative 3a～3j, the R in structural formula is respectively shown in table 5:
Table 5
The structure of (+)-balasubramide derivative 3a～3j is as follows:
Each step compound experiment:
1. compound 1a-1j's is synthetic
Trans-cinnamic aldehyde and derivative 3.9g thereof are dissolved in to 30ml carrene, then add catalyst 1.1g～1.3g and aqueous hydrogen peroxide solution 3.5～4.3ml, room temperature reaction 2h, adds the dilution of 30ml methyl alcohol, then adds successively Na2CO33.8～4.5g and N-bromo-succinimide 6.4～7.3g, continue reaction 3h, after reaction finishes, filters, and filtrate decompression is steamed and desolventized, residue purification by silica gel column chromatography.
Weak yellow liquid shape, 65% yield, [α]D 20＝+166.2(0.5,CHCl3)；1HNMR(500MHz,CDCl3)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。
Weak yellow liquid shape, 63% yield, [α]D 20＝+132.2(0.5,CHCl3)；1HNMR(400MHz,CDCl3)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,CHCl3)；1HNMR(500MHz,CDCl3)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, m.p.55～57 DEG C, [α]D 20＝+135.2(0.5,CHCl3)；1HNMR(500MHz,CDCl3)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, m.p.49～52 DEG C, [α]D 20＝+147.7(0.5,CHCl3),[lit[60]:[α]D 20＝+145.7(0.5,CHCl3)]；1HNMR(500MHz,CDCl3)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, m.p.73～74 DEG C, [α]D 20＝+129.6(0.5,CHCl3),[lit[60]:m.p.69-70℃,[α]D 20＝+127.6(0.5,CHCl3)]；1HNMR(500MHz,CDCl3)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, m.p.58～59 DEG C, [α]D 20＝+155.1(0.5,CHCl3),[lit[60]:[α]D 20＝+150.6(0.5,CHCl3)]；1HNMR(500MHz,CDCl3)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。
Weak yellow liquid shape, 78% yield, [α]D 20＝+156.3(0.5,CHCl3),[lit[60]:[α]D 20＝+157.1(0.5,CHCl3)]；1HNMR(500MHz,CDCl3)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。
Weak yellow liquid shape, 88% yield, m.p.137～138 DEG C, [α]D 20＝+150.1(0.5,CHCl3),[lit[60]:m.p.137-139,[α]D 20＝+151.6(0.5,CHCl3)]；1HNMR(500MHz,CDCl3)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. compound 2a-2j's is synthetic
(wherein R1=H tryptamines, R1=Me methyltryptamine)
Tryptamines or N-mehtyltryptamine 1.0g are dissolved in 30ml methyl alcohol, ice bath is cooled to 5 DEG C, then drips potassium tert-butoxide 112mg methanol solution 10ml, after dropwising, adds 1a～1j1.6～2.3g, maintain this thermotonus 3h, after finishing, reaction removes solvent under reduced pressure, residue 50ml dichloromethane solvent, distilled water washing (10ml × 3) for organic phase, anhydrous sodium sulfate drying, remove solvent under reduced pressure, residue column chromatography purification, to obtain final product.
White solid, 81% yield, m.p.138～140 DEG C, [α]D 20＝+45.1(0.5,CHCl3)；1HNMR(500MHz,CDCl3)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, m.p.119～121 DEG C, [α]D 20＝+47.3(0.5,CHCl3)；1HNMR(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＝7.3Hz,2H)；IR(KBr)v/cm-1:3448,1639,1556,1514,1228,839,743,615。
White solid, 89% yield, m.p.127～130 DEG C, [α]D 20＝+36.2(0.5,CHCl3)；1HNMR(500MHz,CDCl3)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, m.p.168～172 DEG C, [α]D 20＝+55.8(0.5,CHCl3)；1HNMR(500MHz,CDCl3)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, m.p.160～163 DEG C, [α]D 20＝+40.1(0.5,CHCl3)；1HNMR(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, m.p.177～179 DEG C, [α]D 20＝+55.3(0.5,CHCl3)；1HNMR(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＝13.4,7.0Hz,2H),2.87(t,J＝7.3Hz,2H)；IR(KBr)v/cm-1:3313,1638,1551,1458,1431,1092,742,614。
White solid, 88% yield, m.p.159～153 DEG C, [α]D 20＝+34.1(0.5,CHCl3)；1HNMR(500MHz,CDCl3)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, m.p.131～133 DEG C, [α]D 20＝+33.1(0.5,CHCl3),[lit[1]:m.p.125-127,[α]D＝+30(0.5,CHCl3)]；1HNMR(500MHz,CDCl3)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),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. M.p.167～169 DEG C, [α]D 20＝+73.2(0.5,CHCl3)；1HNMR(500MHz,CDCl3)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, m.p.135～137 DEG C, [α]D 20＝+35.1(0.5,CHCl3),1HNMR(500MHz,CDCl3)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. compound 3a-3j's is synthetic
2a～2j670～744mg is dissolved in the THF that 30ml is dry, then adds TFMS ytterbium 58～64mg. Room temperature reaction spends the night, and after reaction finishes, removes solvent under reduced pressure, and residue adds 50ml carrene to dissolve, and then uses saturated NaCl solution (10ml × 3) washing, wash 1 time, anhydrous sodium sulfate drying, removes solvent under reduced pressure, obtain dope, crude product, through column chromatography purification, to obtain final product.
White solid, 76% yield, m.p.114-116 DEG C, [α]D 20＝+33(c＝0.5,MeOH)；1HNMR(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)；13CNMR(126MHz,DMSO)δ169.71,160.21,136.20,129.75,127.07,124.80,122.44,120.93,118.21,115.63,115.45,115.16,115.00,111.51,111.33,75.24,62.61,40.02,25.00；IR(KBr)v/cm-1:3421,1637,1538,1488,1452,1275,1236,1114,789,696；HRMS(ES+)caculatedforC19H17O2N2F[M+Na]+=347.1163, found=347.1167; Ee value is determined (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t by chiralcelAD-H post by chirality HPLCminor＝31.5min,tmajor＝35.1min,97％ee。
White solid, 70% yield, m.p.88-91 DEG C, [α]D 20＝+45(c＝0.5,MeOH)；1HNMR(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)；13CNMR(126MHz,DMSO)δ169.80,161.06,136.21,133.75,130.80,127.07,122.47,120.93,118.21,114.72,114.54,111.51,111.33,75.33,62.79,40.02,25.00；IR(KBr)v/cm-1:3492,1634,1506,1116,1088,879,745,670；HRMS(ES+)caculatedforC19H17O2N2F[M+Na]+=347.1151, found=347.1154; Ee value is determined (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t by chiralcelAD-H post by chirality HPLCminor＝32.0min,tmajor＝37.3min,>99％ee。
White powder, 75% yield, m.p.94-96 DEG C, [α]D 20＝+41(c＝0.5,MeOH)；1HNMR(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＝7.8Hz,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)；13CNMR(126MHz,DMSO)δ169.62,138.71,136.20,132.89,128.99,127.05,125.17,125.00,122.39,120.93,118.21,118.18,111.47,111.41,75.17,62.62,39.94,39.85,39.01,24.97；IR(KBr)v/cm-1:3436,1647,1342,1122,802,746,705；HRMS(ES+)caculatedforC20H17O2N2F3[M+Na]+=397.1190, found=397.1194; Ee value is determined (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t by chiralcelAD-H post by chirality HPLCminor＝20.4min,tmajor＝21.4min,96％ee。
White powder, 60% yield, m.p.120-123 DEG C, [α]D 20＝-61(c＝0.5,MeOH)；1HNMR(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)；13CNMR(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+)caculatedforC19H17O2N2Br[M+Na]+=407.0352, found=407.0351; Ee value is determined (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t by chiralcelAD-H post by chirality HPLCminor＝31.6min,tmajor＝35.7min,97％ee。
White powder, 65% yield, m.p.151-161 DEG C, [α]D 20＝+56(c＝0.5,MeOH)；1HNMR(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)；13CNMR(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 is determined (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t by chiralcelAD-H post by chirality HPLCminor＝31.9min,tmajor＝36.9min,>99％ee。
White powder, 66% yield, m.p.147-150 DEG C, [α]D 20＝+58(c＝0.5,MeOH)；1HNMR(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)；13CNMR(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；IR(KBr)v/cm-1:3408,1656,1640,1196,1122,804,744,667；HRMS(ES+)caculatedforC19H17O2N2Br[M+Na]+=407.3332, found=407.3338; Ee value is determined (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t by chiralcelAD-H post by chirality HPLCminor＝34.9min,tmajor＝39.6min,>99％ee。
White solid, 62% yield, m.p.178-181 DEG C, [α]D 20＝+120(c＝0.5,MeOH)；1HNMR(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)；13CNMR(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；IR(KBr)v/cm-1:3425,1634,1536,1430,1114,747,706；HRMS(ES+)caculatedforC19H17O2N2Cl[M+Na]+=363.0862, found=363.0865; Ee value is determined (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t by chiralcelAD-H post by chirality HPLCminor＝29.7min,tmajor＝34.0min,97％ee.
White solid, 78% yield, m.p.127～130 DEG C, [α]D 20＝+30(c＝0.5,MeOH)；1HNMR(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)；13CNMR(101MHz,DMSO)δ175.94,141.65,135.77,135.27,128.55,128.49,128.03,126.40,120.66,118.21,117.42,110.53,105.65,70.43,51.40,39.51,23.13；ES-MS:306.14[M+]; Ee value is determined (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t by chiralcelAD-H post by chirality HPLCminor＝33.0min,tmajor＝40.1min,97％ee。
White powder, 72% yield, m.p.162-164 DEG 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)；13CNMR(126MHz,DMSO)δ169.48,147.20,144.70,136.18,130.08,127.06,122.94,122.45,120.94,118.20,111.47,111.33,75.14,62.16,39.51,24.95；IR(KBr)v/cm-1:3309,1642,1522,1352,1113,702；HRMS(ES+)caculatedforC19H17N3O4[M+Na]+=374.1162, found=374.1161; Ee value is determined (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t by chiralcelAD-H post by chirality HPLCminor＝40.1min，tmajor＝26.8min,>99％ee。
White powder, 75% productive rate, 193 DEG C of m.p.190 –, [α]D 20＝+7.3(c＝0.5,CHCl3),[lit[16]:m.p.185-191,[α]D 20＝+6.9(0.5,CHCl3)]；1HNMR(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)；13CNMR(100MHz,CDCl3)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+)caculatedforC20H20O2N2[M]+=320.1525; Found:320.1530; Ee value is determined (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), t by chiralcelAD-H post by chirality HPLCmajor＝34.4min,tminor＝63.9min,97％ee.
Embodiment 3 applies pharmacological testing
Test-compound neuroprotection, antioxidation, anti-brain cell inflammatory effect and cell toxicity test. Experimental result is in shown in table 6, table 7, table 8 and table 9. From table 6, table 7, table 8 and table 9, test-compound neuroprotection and antioxidation are very low. As can be seen from Table 8, except 3g, other compound all has the effect of the inflammatory reaction that suppresses significantly the generation of rat microglia, and wherein 3c effect is the strongest. Meanwhile, as can be seen from Figure 1, cytotoxicity experiment shows that compound of the present invention does not have cytotoxicity.
The cerebral protection of the neurotrosis that tested group of compound of table 6 causes the cultured rat cerebellar granule neuron nutritional deficiency of former culture
Note: the cell survival rate of blank group (DMSO processed group) is 100%, the average survival rate of cell of negative control group (nutritional deficiency test group) is 38.8 ± 1.4%. Positive control is N-acetylcystein (NAC, this compound of bibliographical information is a kind of antioxidant), and the cell survival rate of this group is 53.7 ± 1.2% (10mM).
The cerebral protection of the PC12 neural cell injury that tested group of compound of table 7 causes hydrogen peroxide
Note: the cell survival rate of blank group (DMSO processed group) is 100%, and the cell survival rate of hydrogen peroxide treatment group is 61.9 ± 3.8%. Positive control is that the cell survival rate of this group of N-acetylcystein (NAC, this compound of bibliographical information is a kind of antioxidant) is 87.8 ± 3.8% (10mM). Cell survival is analyzed and is measured through MTT.
The protective effect in the primary cultured rat cerebellar granule neure damage of Pidolidone induction of tested group of compound of table 8
Note: the cell survival rate of blank group (DMSO processed group) is 100%, the average survival rate of cell of negative control group (glutamic acid processed group) is 48.1%.
The inhibitory action that table 9 test-compound discharges inflammatory factor TNFalpha in lipopolysaccharide-induced BV-2 microglia
Note: BV-2 microglia adds 100ng/ml lipopolysaccharides to cultivate separately, or add lipopolysaccharides incubated cell after the test-compound pretreatment 2h of various dose. Cell is cultivated after 6h, and the burst size of cytokine TNF alpha is measured by ELISA method. Result is expressed with the form of lipopolysaccharide-induced rate.

Claims (7)

1. a class Balasubramide derivative, is characterized in that, its structural formula is suc as formula shown in (I):
Wherein, R1For H or-CH3; R is respectively 3-F-C6H4、4-F-C6H4、3-Cl-C6H4、4-Cl-C6H4、3-Br-C6H4、4-Br-C6H4、4-NO2-C6H4Or 3-CF3-C6H4。
2. the application of Balasubramide derivative described in claim 1, is characterized in that, is applied to preparationTreat the cerebral protection medicine aspect relevant to nerve cell.
3. the application of Balasubramide derivative described in claim 1, is characterized in that, is applied to preparationAnti-neuritis disease drug aspect.
4. application according to claim 2, is characterized in that, is by claim 1 Chinese style (I) instituteShow formula R1For H and R are 4-F-C6H4It is relevant to nerve cell that the compound characterizing is applied to preparation treatmentCerebral protection medicine aspect.
5. application according to claim 3, is characterized in that, is by claim 1 Chinese style (I) instituteShow formula R1For H and R are 4-F-C6H4The compound characterizing is applied to preparation anti-neuritis disease drug aspect.
6. the preparation method of Balasubramide and derivative thereof described in claim 1, is characterized in that, bagDraw together following steps:
S1. one kettle way catalysis trans-cinnamic aldehyde and derivative epoxidation thereof, obtains α, beta epoxide carboxylate;
S2. by S1 gained α, beta epoxide carboxylate and tryptamines and analog effect thereof, obtain prebalamide andIts derivative;
S3. with Yb (CF3SO3)3For catalyst, the prebalamide or derivatives thereof of S2 gained is encircled respectivelyClose synthetic balasubramide and derivative thereof;
Wherein, described in step S1, trans-cinnamic aldehyde and derivative thereof areDescribed α, beta epoxide carboxylic acidEster is
Described in step S2, tryptamines and analog thereof are
Described in step S2, prebalamide and derivative thereof are
7. preparation method according to claim 6, is characterized in that, the trans meat of one kettle way catalysis described in S1Cinnamic aldehyde and derivative epoxidation thereof comprise the following steps:
S11. under condition of ice bath, with 40%H2O2The aqueous solution is oxidant, uses S-diphenylprolinol threeThe a series of trans-cinnamic aldehyde of ethyl silicon ether catalysis and derivative epoxidation thereof;
S12. at ambient temperature, S11 gained reactant liquor dilutes with methyl alcohol, adds NBS and sodium carbonate, syntheticα, beta epoxide carboxylate.
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