CN105343061B - The application of Balasubramide derivatives and preparation method - Google Patents

The application of Balasubramide derivatives and preparation method Download PDF

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CN105343061B
CN105343061B CN201510756523.3A CN201510756523A CN105343061B CN 105343061 B CN105343061 B CN 105343061B CN 201510756523 A CN201510756523 A CN 201510756523A CN 105343061 B CN105343061 B CN 105343061B
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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 the application of Balasubramide derivatives and preparation method.The structural formula such as formula of Balasubramide derivatives of the present invention（Ⅰ）Shown, the Balasubramide derivatives have excellent anti-nerve cell inflammation activity, and do not have cytotoxicity.The present invention while the rational synthetic line of design science, simple efficiently to obtain the yield of highest 80%, ee values are more than 97%.（Ⅰ）.

Description

The application of Balasubramide derivatives and preparation method
The present invention is denomination of invention《Balasubramide and its derivative and synthetic method and application》, the applying date be On 06 12nd, 2014, the divisional application of the patent application of Application No. 201410260588.4.
Technical field
The present invention relates to chemical synthesis and pharmaceutical technology field, more particularly, to answering for Balasubramide derivatives With and preparation method.
Background technology
1996, Hofer etc. was from the Rutaceae clausena plant Randia cochinchinensis [Clausena in Sri Lanka tropical rain forest Indica (Datz) .Oliv.] leaf chloroform extract isolated a kind of octatomic ring lactams composition (+)- Balasubramide and (+)-balasubramide bio-precursors (+)-prebalamide.
Rutaceae clausena plant is distributed mainly on the south in Asia, the southeast, and minority is distributed in SOUTHERN CHINA and Australia Big Leah.About 30 kinds in world wide, there are nearly 10 kinds within the border in China, be distributed in the middle and lower reach of Yangtze River and southern each province.Should The most plants of category are from ancient times medicinal plant in China, for treating the diseases such as upper sense, malaria, stomachache and gastritis.Due to eight The importance of membered lactams structure and potential biological value, balasubramide and its derivative have important grind Study carefully value, but have no more relevant chiral (+)-balasubramide and the like technology report at present.
However, the existing method using plant separation and Extraction can obtain (+)-balasubramide, due to low separation Efficiency and yield, it is far from enough for the research in terms of its biological activity.Therefore, one kind is explored compared with high separating efficiency Chiral (+)-balasubramide and the like is obtained with the fully synthetic method of yield, is its application of research and development The key of value.
Labyrinth and multiple asymmetric carbon atoms due to eight membered lactams rings, so far, rare pertinent literature report Road balasubramide synthesis, existing document are related to the report of balasubramide synthesis, and disclosed synthetic method will Reaction scheme is grown, and yield is very low, or the stock preparation process of synthesis is cumbersome, reaction condition is special, limits Balasubramide reality is synthetically produced and promotion applied research.Have no balasubramide related derivatives synthesis and Application technology is reported.
The content of the invention
The technical problem to be solved in the present invention is to overcome the shortcomings of existing Balasubramide derivatives, there is provided Yi Leixin Balasubramide derivatives application.
Another technical problem to be solved by the present invention is that providing, a kind of step is simple, the preparation that raw material is easy to get, yield is higher Method, Balasubramide derivatives of the present invention can be obtained based on the preparation method.
The purpose of the present invention is achieved by the following technical programs：
Balasubramide derivative is provided, shown in its structural formula such as formula (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 derivative of the Balasubramide is in terms of the treatment cerebral protection medicine related to nerve cell is prepared Application, while provide application of the Balasubramide derivatives in terms of anti-neuroinflamation medicine is prepared.
R in structure shown in preferred formula (I)1It is 4-F-C for H and R6H4When compound prepare treatment and nerve cell phase Application in terms of the cerebral protection medicine of pass, and the application in terms of anti-neuroinflamation medicine is prepared.
The invention provides a kind of Balasubramide and its derivative preparation method, comprise the following steps：
S1. one kettle way catalysis trans-cinnamic aldehyde and its derivative epoxidation, obtain α, beta epoxide carboxylate；
S2. by α obtained by S1, beta epoxide carboxylate and tryptamines and the like effect, prebalamide and its derivative are obtained Thing；
S3. with Yb (CF3SO3)3For catalyst, prebalamide obtained by S2 or derivatives thereof is set to distinguish cyclization, synthesis (+)-balasubramide and its derivative.
Wherein, one kettle way catalysis trans-cinnamic aldehyde and its derivative epoxidation comprise the following steps described in S1：
S11. under condition of ice bath, with 40% (V/V) H2O2The aqueous solution is oxidant, uses the second of S- diphenylprolinols three Base silicon ether is catalyzed a series of trans-cinnamic aldehyde and its derivative epoxidation；
S12. at ambient temperature, reaction solution methanol dilution obtained by S11, addition NBS (N-bromosuccinimide, N-bromosuccinimide) and sodium carbonate, synthesize α, beta epoxide carboxylate.
The present invention provides Balasubramide and its derivative based on preparation method synthesis.Structural formula such as formula (I) It is shown：
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。
Present invention simultaneously provides the Balasubramide being prepared based on the preparation method and its derivative to prepare Application in terms of the treatment cerebral protection medicine related to nerve cell, while provide the Balasubramide and derive Application of the thing in terms of anti-neuroinflamation medicine is prepared.
Beneficial effects of the present invention：
The invention provides a kind of high antimer selectivity Balasubramide derivatives, optical activity eight has been filled up The blank or deficiency of membered lactams structural compounds, the research for being relevant chiral (+)-balasubramide and the like should With the technical foundation that offer is strong.
The invention provides the Balasubramide and its derivative new synthetic line and synthetic method, devise One (+)-balasubramide asymmetric syntheses route, successfully synthesizes Balasubramide and its derivative.This hair It is bright to devise scientific and reasonable synthetic line first, optimize key intermediate α, the technique bar of the synthesis of beta epoxide carboxylate Part, using a series of α of one pot process of optimization, beta epoxide carboxylate, obtain the yield and 97%ee values of highest 80%. As a result show, the one kettle way of optimization provided by the present invention prepares the asymmetric Epoxidation and oxide ester of alpha, beta-unsaturated esters Change, be to synthesize α, the simple efficient method of beta epoxide carboxylate.Further, it is trans based on present invention optimization one kettle way catalysis The α for the high ee values that cinnamic acid and its derivative epoxidation obtain, beta epoxide carboxylate, by it with tryptamines and the like work With, prebalamide and its derivative have been obtained, then with Yb (CF3SO3)3For catalyst, make prebalamide cyclizations, synthesize Natural products (+)-balasubramide and its derivative.By optimizing reaction condition, present invention obtains higher yield And enantioselectivity.Wherein, (+)-balasubramide total recovery is that more than 45%, ee values are more than 97%.
The invention provides the new application of the Balasubramide derivatives, Balasubramide derivatives have aobvious Write ground and suppress inflammatory reaction effect caused by microglia, meanwhile, cytotoxicity experiment shows that these compounds do not have cell Toxicity.
Brief description of the drawings
Fig. 1 the compounds of this invention is to neurotrosis caused by the cultured rat cerebellar granule neurotrophic shortage of original cuiture Cerebral protection experimental result.
Cerebral protection of the tested group of compound of Fig. 2 to the PC12 neural cell injuries of hydrogen peroxide-induced.
Protection of the tested group of compound of Fig. 3 in the Primary rat cerebellar granule nerve cell damage that Pidolidone induces is made With.
Fig. 4 test-compounds are made to the suppression that inflammatory factor TNFalpha in lipopolysaccharide-induced BV-2 microglias discharges With.
Cytotoxic effect of Fig. 5 test-compounds to BV-2 microglias.
Embodiment
Below in conjunction with the accompanying drawings the present invention is further illustrated with specific embodiment.Unless stated otherwise, the examination that the present invention uses Agent and be reagent and equipment commonly used in the art with equipment.
The synthetic method condition research experiment of the Balasubramide derivatives of embodiment 1
First, optical activity alpha, the synthesis of beta epoxide carboxylate
The method of reference literature report, we are by optimizing reaction condition, with 40%H2O2The aqueous solution is oxidant, is used Homemade chiral imines class catalyst S- diphenylprolinol triethyl group silicon ether is catalyzed a series of trans-cinnamic aldehyde and its derivative Thing epoxidation, after reacting at room temperature 4h, with methanol dilution, add NBS and sodium carbonate oxidative esterification, room temperature 3h, obtained (2S, 3R)-α, beta epoxide carboxylate, the latter have good yield and outstanding ee values.By compareing the optically-active degrees of data of document, most The absolute configuration of end-product is defined as 2S, 3R.It the results are shown in Table shown in 1.
Reaction scheme is：
Table 1
2nd, by α, beta epoxide carboxylic acid Lipase absobed prebalamide and its derivative
1. influence of the reaction condition to the yield of compound 2
The present invention is using methanol as solvent, and at ambient temperature, beta-phenyl glycidic acid methyl esters occurs ester amine with tryptamines and contracted Close, react 3h, obtained product 2h.But yield 55%.Further study show that under cryogenic, add catalytic amount Alkali can significantly improve the yield of reaction.Influence of the reaction various additives to reaction is investigated, as a result as shown in table 3.
Reaction scheme is as follows：
Table 2
Research finds that the power of additive alkalescence has significant impact to reaction result.Add NaHCO3、K2CO3And Na2CO3 Influence to reaction yield is little, and adds catalytic amount t-BuOK and NaOCH3During Deng highly basic, the yield of reaction significantly improves. Wherein, when using t-BuOK as additive, 81% yield is obtained.Therefore, the present invention selects condensations of the t-BuOK for reaction Agent.
3rd, the synthesis of target product
The present invention is using acetonitrile as solvent, trifluoromethanesulfonic acid ytterbium (Yb (CF3SO3)3) be catalyst, by prebalamide and Its derivative has synthesized (+)-balasubramide and its derivative.In addition, the present invention has investigated differential responses condition to cyclization The influence of reaction.
1. lewis acid (lewis acid) is as shown in table 3 on epoxy reactive influence, experimental result：
Reaction scheme is illustrated：
Table 3
From table 3 it can be seen that from different lewis acids, the yield of ring-closure reaction produces obvious difference.Add and live The strong lewis acid of property, such as AlCl3、FeCl3, CuCl, without the generation of target product.Add the weak lewis acid LaCl of activity3 When, the generation of target product is detected, but yield is only 33%.As addition Yb (CF3SO3)3, during the lewis acid such as p-TSA, ring That changes product reaction obtains medium yield and outstanding corresponding selection.Wherein add Yb (CF3SO3)3Obtain optimal As a result, yield is that the ee values of 73% sum are 97%.
2. reaction dissolvent is on epoxy reactive influence
It is determined that Yb (CF3SO3)3After cyclization catalyst, the present invention has investigated shadow of the reaction dissolvent to reaction Ring, as a result as shown in table 5.
Reaction scheme is as follows：
Table 4
As can be seen from Table 4, ring-closure reaction can be smoothed out in most of solvent, and solvent is to the ee values of product Do not influence.Compared to non-polar solven such as CHCl3Solvent, react and more preferable yield is obtained in polar solvent.Wherein, with THF For solvent, reaction has highest yield, has reached 75%.Studied for the synthesis condition of other derivatives with above-mentioned experiment knot Fruit.
Embodiment 2
The overall synthetic route of optical activity (+)-balasubramide derivatives is as follows：
Obtain (+)-balasubramide derivative 3a~3j, the R in structural formula is respectively shown in table 5：
Table 5
(+)-balasubramide derivatives 3a~3j structure is as follows：
Each step compound experiment：
1. compound 1a-1j synthesis
Trans-cinnamic aldehyde and its derivative 3.9g are dissolved in 30ml dichloromethane, then add catalyst 1.1g~1.3g and 3.5~4.3ml of aqueous hydrogen peroxide solution, 2h is reacted at room temperature, add 30ml methanol dilutions, then sequentially add Na2CO33.8~ 4.5g and N- 6.4~7.3g of bromo-succinimide, continuing to react 3h, after reaction terminates, solvent is evaporated off in filtering, filtrate decompression, Residue is purified with silica gel column chromatography.
1a, weak yellow liquid shape, 65% yield, [α]D 20=+166.2 (0.5, CHCl3)；1H NMR (500MHz,CDCl3) δ 7.34 (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。
1b, weak yellow liquid shape, 63% yield, [α]D 20=+132.2 (0.5, CHCl3)；1H NMR (400MHz,CDCl3) δ 7.22-7.16 (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。
1c, the yield of colorless oil 75%, [α]D 20=+128.3 (0.5, CHCl3)；1H NMR (500MHz,CDCl3) δ 7.63 (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。
1d, white solid, 71% yield, m.p.55~57 DEG C, [α]D 20=+135.2 (0.5, CHCl3) ；1H NMR(500MHz,CDCl3) δ 7.51-7.45 (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。
1e, 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)]；1H NMR(500MHz,CDCl3) δ 7.31 (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。
1f, 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)]；1H NMR(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。
1g, 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)]；1H NMR(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。
1h, weak yellow liquid shape, 78% yield, [α]D 20=+156.3 (0.5, CHCl3),[lit[60]: [α]D 20=+157.1 (0.5, CHCl3)]；1H NMR(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。
1i, 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)]；1H NMR(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 synthesis
(wherein R1=H tryptamines, R1=Me methyltryptamines)
Tryptamines or N-mehtyltryptamine 1.0g are dissolved in 30ml methanol, ice bath is cooled to 5 DEG C, and potassium tert-butoxide is then added dropwise 112mg methanol solution 10ml, 1a~1j1.6~2.3g is added after being added dropwise, maintain this thermotonus 3h, reaction to subtract after terminating Solvent, residue 50ml dichloromethane solvents is evaporated off in pressure, and organic phase, which is used, distills water washing (10ml × 3), anhydrous sodium sulfate drying, Remove solvent under reduced pressure, the purifying of residue column chromatography, produce.
2a, white solid, 81% yield, m.p.138~140 DEG C, [α]D 20=+45.1 (0.5, CHCl3)；1H NMR(500MHz,CDCl3) δ 8.18 (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。
2b, white solid, 80% yield, m.p.119~121 DEG C, [α]D 20=+47.3 (0.5, CHCl3)；1H NMR (400MHz, DMSO) δ 10.82 (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。
2c, white solid, 89% yield, m.p.127~130 DEG C, [α]D 20=+36.2 (0.5, CHCl3)；1H NMR(500MHz,CDCl3) δ 8.12 (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。
2d, white solid, 83% yield, m.p.168~172 DEG C, [α]D 20=+55.8 (0.5, CHCl3)；1H NMR(500MHz,CDCl3) δ 8.14 (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。
2e, white solid, 81% yield, m.p.160~163 DEG C, [α]D 20=+40.1 (0.5, CHCl3)；1H NMR (400MHz, DMSO) δ 10.82 (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。
2f, white solid, 89% yield, m.p.177~179 DEG C, [α]D 20=+55.3 (0.5, CHCl3)；1H NMR (400MHz, DMSO) δ 10.82 (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。
2g, white solid, 88% yield, m.p.159~153 DEG C, [α]D 20=+34.1 (0.5, CHCl3)；1H NMR(500MHz,CDCl3) δ 8.17 (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。
2h, 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)]；1H NMR(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。
2i, white solid, 69% yield.M.p.167~169 DEG C, [α]D 20=+73.2 (0.5,CHCl3)；1H NMR(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。
2j, white solid, 80% yield, m.p.135~137 DEG C, [α]D 20=+35.1 (0.5,CHCl3),1H NMR(500MHz,CDCl3) δ 8.11 (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 synthesis
R=Ph, R1=Me, (+)-Balasubramide
R=Ph, R1=H, (+)-Norbalasubramide
2a~2j670~744mg is dissolved in the THF of 30ml dryings, then adds 58~64mg of trifluoromethanesulfonic acid ytterbium. Overnight, reaction removes solvent under reduced pressure after terminating, residue adds the dissolving of 50ml dichloromethane, then molten with saturation NaCl for room temperature reaction Liquid (10ml × 3) washs, and washes 1 time, anhydrous sodium sulfate drying, removes solvent under reduced pressure, obtain dope, crude product is pure through column chromatography Change, produce.
3a, white solid, 76% yield, m.p.114-116 DEG C, [α]D 20=+33 (c=0.5, MeOH)；1H NMR (500MHz, DMSO) δ 10.79 (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)；13C NMR(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+)caculated for C19H17O2N2F[M+Na]+=347.1163, found=347.1167；Ee values pass through Chiralcel AD-H posts determined by chiral HPLC (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), tminor=31.5min, tmajor=35.1min, 97%ee.
3b, white solid, 70% yield, m.p.88-91 DEG C, [α]D 20=+45 (c=0.5, MeOH)；1H NMR (500MHz, DMSO) δ 10.79 (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)；13C NMR(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+)caculated for C19H17O2N2F[M+Na]+=347.1151, found=347.1154；Ee values are by chiralcel AD-H posts by chiral HPLC It is determined that (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), tminor=32.0min, tmajor=37.3min,>99%ee.
3c, white powder, 75% yield, m.p.94-96 DEG C, [α]D 20=+41 (c=0.5, MeOH)；1H NMR (500MHz, DMSO) δ 10.78 (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)；13C NMR(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+)caculated for C20H17O2N2F3[M+Na]+=397.1190, found =397.1194；Ee values determine (4.6mm × 25cm, n-hexane/i-PrOH by chiralcel AD-H posts by chiral HPLC =90/10, λ=254nm, 0.8ml/min), tminor=20.4min, tmajor=21.4min, 96%ee.
3d, white powder, 60% yield, m.p.120-123 DEG C, [α]D 20=-61 (c=0.5, MeOH)；1H NMR (500MHz, DMSO) δ 10.84 (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)；13C NMR(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 C19H17O2N2Br[M+Na]+=407.0352, found=407.0351；Ee values are by chiralcel AD-H posts by chirality HPLC determines (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), tminor= 31.6min,tmajor=35.7min, 97%ee.
3e, white powder, 65% yield, m.p.151-161 DEG C, [α]D 20=+56 (c=0.5, MeOH)；1H NMR (400MHz, DMSO) δ 10.78 (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)；13C NMR (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 values determine (4.6mm × 25cm, n-hexane/ by chiralcel AD-H posts by chiral HPLC I-PrOH=90/10, λ=254nm, 0.8ml/min), tminor=31.9min, tmajor=36.9min,>99%ee.
3f, white powder, 66% yield, m.p.147-150 DEG C, [α]D 20=+58 (c=0.5, MeOH)；1H NMR (500MHz, DMSO) δ 10.85 (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)；13C NMR(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+)caculated for C19H17O2N2Br[M+Na]+=407.3332, found=407.3338；Ee values pass through Chiralcel AD-H posts determined by chiral HPLC (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), tminor=34.9min, tmajor=39.6min,>99%ee.
3g, white solid, 62% yield, m.p.178-181 DEG C, [α]D 20=+120 (c=0.5, MeOH)；1H NMR (500MHz, DMSO) δ 10.79 (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)；13C NMR(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+)caculated for C19H17O2N2Cl[M+Na]+=363.0862, found=363.0865；Ee values pass through Chiralcel AD-H posts determined by chiral HPLC (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), tminor=29.7min, tmajor=34.0min, 97%ee.
3h, white solid, 78% yield, m.p.127~130 DEG C, [α]D 20=+30 (c=0.5, MeOH)；1H NMR (400MHz, DMSO) δ 10.85 (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)；13C NMR(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 values pass through Chiralcel AD-H posts determined by chiral HPLC (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), tminor=33.0min, tmajor=40.1min, 97%ee.
3i, white powder, 72% yield, m.p.162-164 DEG C, [α]D 20=+73 (c=0.5, MeOH)；H NMR (500MHz, DMSO) δ 10.78 (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)；13C NMR(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+)caculated for C19H17N3O4[M+Na]+=374.1162, found=374.1161；Ee values pass through Chiralcel AD-H posts determined by chiral HPLC (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min), tminor=40.1min, tmajor=26.8min,>99%ee.
3j, white powder, 75% yield, m.p.190-193 DEG C, [α]D 20=+7.3 (c=0.5, CHCl3),[lit[16]:m.p.185-191,[α]D 20=+6.9 (0.5, CHCl3)]；1H NMR(500MHz,CDCl3)δ7.92 (br s, 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 (v br s), 3.96(m,1H),3.49(m,1H),3.41(m,1H),3.03(m,1H),2.84(s,3H)；13C NMR(100MHz,CDCl3)δ 173.5,141.0,135.2,132.2,129.3,128.7,127.5,127.2,122.1,119.4,117.5,110.7, 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+)caculated for C20H20O2N2[M]+=320.1525； found:320.1530；Ee values determine (4.6mm × 25cm, n-hexane/i- by chiralcel AD-H posts by chiral HPLC PrOH=90/10, λ=254nm, 0.8ml/min), tmajor=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.It is real Test and the results are shown in Table shown in 6, table 7, table 8 and table 9.From table 6, table 7, table 8 and table 9, test-compound neuroprotection and Antioxidation is very low.As can be seen from Table 8, in addition to 3g, other compounds have significantly suppress rat microglia it is thin The effect of inflammatory reaction caused by born of the same parents, wherein 3c effect are most strong.Meanwhile it will be seen from figure 1 that cytotoxicity experiment shows this hair The bright compound does not have cytotoxicity.
6 tested groups of compounds of table are to neurotrosis caused by the cultured rat cerebellar granule neurotrophic shortage of original cuiture Cerebral protection
Note：The cell survival rate of blank control group (DMSO treatment groups) is 100%, and negative control group (test by nutritional deficiency Group) cell average viability be 38.8 ± 1.4%.Positive control is N-acetylcystein (NAC, the document report chemical combination Thing is a kind of antioxidant), the cell survival rate of the group is 53.7 ± 1.2% (10mM).
Cerebral protection of the 7 tested groups of compounds of table to PC12 neural cell injuries caused by hydrogen peroxide
Note：The cell survival rate of blank control group (DMSO treatment groups) is 100%, the cell survival of hydrogen peroxide treatment group Rate is 61.9 ± 3.8%.Positive control is N-acetylcystein (NAC, the document report compound are a kind of antioxidants) The cell survival rate of the group is 87.8 ± 3.8% (10mM).Cells viability is analyzed through MTT and determined.
The protective effect in the Primary rat cerebellar granule neuron damage that Pidolidone induces of 8 tested groups of compounds of table
Note：The cell survival rate of blank control group (DMSO treatment groups) is 100%, negative control group (glutamic acid treatment group) Cell average viability be 48.1%.
The inhibitory action that the test-compound of table 9 discharges to inflammatory factor TNFalpha in lipopolysaccharide-induced BV-2 microglias
Note：BV-2 microglias add 100ng/ml lipopolysaccharides and individually cultivated, or the test-compound of various dose Lipopolysaccharides incubated cell is added after pre-processing 2h.After cell culture 6h, the burst size of cytokine TNF alpha is surveyed with ELISA method It is fixed.As a result expressed in the form of lipopolysaccharide-induced rate.

Claims (1)

1. the application of a kind of Balasubramide derivatives, it is characterised in that treatment is related to nerve cell applied to preparing In terms of the medicine of cerebral protection or anti-neuroinflamation；Shown in the structural formula such as formula (I) of the Balasubramide derivatives：
Wherein, R1For H or-CH3。
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