CN104003991A - Balasubramide, derivative of balasubramide, synthesis method and application - Google Patents
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- CN104003991A CN104003991A CN201410260588.4A CN201410260588A CN104003991A CN 104003991 A CN104003991 A CN 104003991A CN 201410260588 A CN201410260588 A CN 201410260588A CN 104003991 A CN104003991 A CN 104003991A
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Abstract
The invention discloses balasubramide, a derivative of the balasubramide, a synthesis method and the application. The structural formulas of the balasubramide and the derivative of the balasubramide are shown in the formula (I), the balasubramide and the derivative of the balasubramide have the superior nerve cell inflammation resistance activity and are free of cytotoxicity. Meanwhile, a scientific and reasonable synthesis route is designed, simplicity and high efficiency are achieved, the total yield of (+)-balasubramide is more than 45%, and the ee value is more than 97%.
Description
Technical field
The present invention relates to chemosynthesis and medical technical field, more specifically, relate to Balasubramide and
Derivative and synthetic method and application.
Background technology
1996, the chloroform extract of the Rutaceae clausena plant Cortex Clausenae Excavatae in Hofer Deng Cong Sri Lanka tropical rain forest [Clausena indica (Datz) .Oliv.] leaf was isolated biology precursor (+)-prebalamide of a kind of octatomic ring lactan 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 analogue thereof.
Yet the existing method of plant separation and Extraction of utilizing can obtain (+)-balasubramide, due to low separation efficiency and productive rate, is to be nowhere near for the research of its biologic activity aspect.Therefore, exploring a kind of (+)-balasubramide and analogue thereof that obtains chirality compared with the complete synthesis method of high separating efficiency and productive rate, is the key of its using value of research and development.
Complex construction and a plurality of chiral carbon atom due to 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 conditions is special, has limited synthetic the production and promotion applied research of reality of balasubramide.Have no the synthetic of balasubramide related derivatives and utilisation 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 that a kind of step is simple, raw material is easy to get, productive rate is higher
Preparation method, based on described preparation method, can obtain Balasubramide of the present invention and derivative thereof.
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 as shown in formula I:
(Ⅰ),
Wherein, R
1for H or-CH
3; R is Ph, 3-F-C
6h
4, 4-F-C
6h
4, 3-Cl-C
6h
4, 4-Cl-C
6h
4, 3-Br-C
6h
4, 4-Br-C
6h
4, 4-NO
2-C
6h
4or 3-CF
3-C
6h
4.
The application of the derivative of described Balasubramide aspect the preparation treatment cerebral protection medicine relevant to neurocyte 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-C
6h
4time compound in the application aspect the preparation treatment cerebral protection medicine relevant to neurocyte, 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-Cinnamylaldehyde and derivative epoxidation thereof, obtain α, beta epoxide carboxylicesters;
S2. by S1 gained α, beta epoxide carboxylicesters and tryptamines and analogue effect thereof, obtain prebalamide and derivative thereof;
S3. with Yb (CF
3sO
3)
3for catalyzer, 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-Cinnamylaldehyde and derivative epoxidation thereof comprise the following steps:
S11. under condition of ice bath, with 40% (V/V) H
2o
2the aqueous solution is oxygenant, uses the S-diphenylprolinol triethyl silicon a series of trans-Cinnamylaldehyde of ether catalysis and derivative epoxidation thereof;
S12. at ambient temperature, S11 gained reaction solution dilutes with methyl alcohol, adds NBS(N-bromosuccinimide, N-bromosuccinimide) and sodium carbonate, synthetic α, beta epoxide carboxylicesters.
The invention provides based on the synthetic Balasubramide of described preparation method and derivative thereof.Structural formula is as shown in formula I:
(Ⅰ),
Wherein, R
1for H or-CH
3; R is Ph, 3-F-C
6h
4, 4-F-C
6h
4, 3-Cl-C
6h
4, 4-Cl-C
6h
4, 3-Br-C
6h
4, 4-Br-C
6h
4, 4-NO
2-C
6h
4or 3-CF
3-C
6h
4.
The present invention provides the application aspect the preparation treatment cerebral protection medicine relevant to neurocyte 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 a class high antimer selectivity Balasubramide derivative, filled up and had the blank or not enough of optical activity eight membered lactams structural compounds, for the research of relevant chirality (+)-balasubramide and analogue thereof, applied strong technical foundation is provided.
The invention provides synthetic line and synthetic method that described Balasubramide and derivative thereof are new, designed the asymmetric synthesis 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 processing condition of beta epoxide carboxylicesters, adopt the one kettle way of optimizing to synthesize a series of α, beta epoxide carboxylicesters, 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 carboxylicesters.Further, based on the present invention optimize high ee value that one kettle way catalysis trans-Cinnamylaldehyde and derivative epoxidation thereof obtain α, beta epoxide carboxylicesters, by itself and tryptamines and analogue effect thereof, has obtained prebalamide and derivative thereof, then with Yb (CF
3sO
3)
3for catalyzer, make prebalamide cyclization, synthesized natural product (+)-balasubramide and derivative thereof.By optimizing reaction conditions, 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.
Accompanying drawing explanation
The cerebral protection experimental result of the nerve injury that Fig. 1 the compounds of this invention causes the cultured rat cerebellar granule neurone nutritive deficiency of former culture.
The cerebral protection of tested group of compound of Fig. 2 to the PC12 neural cell injury of hydrogen peroxide-induced.
The provide protection of tested group of compound of Fig. 3 in the primary cultured rat cerebellar granule neural cell injury of Pidolidone induction.
The restraining effect 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.
Embodiment
Below in conjunction with the drawings and specific embodiments, further illustrate the present invention.Unless stated otherwise, the reagent that the present invention adopts and and equipment be conventional reagent and the equipment using in this area.
embodiment 1the synthetic method condition research experiment of Balasubramide derivative
One, optical activity alpha, beta epoxide carboxylicesters synthetic
The method of reference literature report, we are by optimizing reaction conditions, with 40% H
2o
2the aqueous solution is oxygenant, use homemade chiral imines class catalyst S-diphenylprolinol triethyl silicon a series of trans-Cinnamylaldehyde of ether catalysis and derivative epoxidation thereof, after room temperature reaction 4 h, with methyl alcohol dilution, then add NBS and sodium carbonate oxidative esterification, room temperature 3 h, obtained (2S, 3R)-α, beta epoxide carboxylicesters, the latter has good productive rate and outstanding ee value.By the specific rotation data of contrast document, the absolute configuration of final 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 carboxylicesters and derivative thereof
1. the impact of reaction conditions on compound 2 productive rates
The present invention be take methyl alcohol as solvent, at ambient temperature, beta-phenyl glycidic acid methyl esters and the condensation of tryptamines generation ester amine, reaction 3 h, have obtained product
2h.But, productive rate 55%.Further research is found under cold condition, adds 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 3.
Reaction scheme is as follows:
Table 2
Research finds that the power of additive alkalescence has significant impact to reaction result.Add NaHCO
3, K
2cO
3and Na
2cO
3very micro-on the impact of reaction yield, and add catalytic amount t-BuOK and NaOCH
3during in highly basic, the productive rate of reaction has significantly improved.Wherein, when take t-BuOK during 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 be take acetonitrile as solvent, trifluoromethanesulfonic acid ytterbium (Yb (CF
3sO
3)
3) be catalyzer, by prebalamide and derivative thereof, synthesized (+)-balasubramide and derivative thereof.In addition, the present invention has investigated the impact of differential responses condition on ring-closure reaction.
1., on epoxy reactive impact, experimental result is as shown in table 3 for Lewis acid (lewis acid):
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 AlCl
3, FeCl
3, CuCl, there is no the generation of target product.Add active weak Lewis acid LaCl
3time, the generation of target product detected, but productive rate is only 33%.When adding Yb (CF
3sO
3)
3, during the Lewis acids such as p-TSA, cyclisation product reaction obtain medium productive rate and outstanding corresponding selection.Wherein add Yb (CF
3sO
3)
3obtained best result, productive rate be 73% and ee value be 97%.
2. reaction solvent is on epoxy reactive impact
At definite Yb (CF
3sO
3)
3after cyclization catalyst, the present invention has investigated the impact of reaction solvent on reaction, and result is as shown in table 5.
Reaction scheme is as follows:
Table 4
Project | Solvent | Yield (%) | Ee(%) |
1 | CHCl 3 | 67 | 97 |
2 | THF | 75 | 97 |
3 | CH 3CN | 73 | 97 |
4 | DMF | 72 | 97 |
5 | DMSO | 70 | 97 |
As can be seen from Table 4, ring-closure reaction can carry out smoothly in most of solvent, and the not impact of solvent on the ee value of product.Compare non-polar solvent as CHCl
3solvent, reaction obtains better productive rate in polar solvent.Wherein, take 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 whole 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
Sequence number | Structure |
3a | R=3-F-C 6H 4 , R 1=H |
3b | R=4-F-C 6H 4 , R 1=H |
3c | R=3-CF 3-C 6H 4 , R 1=H |
3d | R=3-Br-C 6H 4 , R 1=H |
3e | R=4-Cl-C 6H 4 , R 1=H |
3f | R=4-Br-C 6H 4 , R 1=H |
3g | R=3-Cl-C 6H 4 , R 1=H |
3h | R=Ph , R 1=H |
3i | R=4-NO 2-C 6H 4 , R 1=H |
3j | R=Ph, R 1=Me |
The structure of (+)-balasubramide derivative 3a~3j is as follows:
3a 3b 3c 3d
3e 3f 3g 3h
3i 3j
Each step compound experiment:
1. compound 1a-1j's is synthetic
1
Trans-Cinnamylaldehyde and derivative 3.9 g thereof are dissolved in to 30 ml methylene dichloride, then add catalyzer 1.1g ~ 1.3 g and aqueous hydrogen peroxide solution 3.5 ~ 4.3 ml, room temperature reaction 2 h, add 30 ml methyl alcohol dilutions, then add successively Na
2cO
33.8 ~ 4.5 g and N-bromo-succinimide 6.4 ~ 7.3 g, continue reaction 3 h, 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, CHCl
3);
1h NMR (500 MHz, CDCl
3) δ 7.34 (td,
j=8.0,5.7 Hz, 1H), 7.10 (d,
j=7.7 Hz, 1H), 7.04 (td,
j=8.4,2.6 Hz, 1H), 7.01-6.95 (m, 1H), 4.10 (t,
j=3.3 Hz, 1H), 3.83 (s, 3H), 3.48 (d,
j=1.7 Hz, 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, CHCl
3);
1h NMR (400 MHz, CDCl
3) δ 7.22 – 7.16 (m, 2H), 7.02 – 6.95 (m, 2H), 4.02 (t,
j=3.7 Hz, 1H), 3.76 (d,
j=5.6 Hz, 3H), 3.42 (dd,
j=7.8,2.2 Hz, 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);
1h NMR (500 MHz, CDCl
3) δ 7.63 (t,
j=7.1 Hz, 1H), 7.56 (s, 1H), 7.54 – 7.47 (m, 2H), 4.17 (d,
j=1.6 Hz, 1H), 3.85 (s, 3H), 3.51 (d,
j=1.7 Hz, 1H); IR (KBr) v/cm
-1: 1755,1636,1405,1328,1125,700,662.
1d, white solid, 71% yield, 55~57 ° of C of m.p., [α]
d 20=+135.2 (0.5, CHCl
3);
1h NMR (500 MHz, CDCl
3) δ 7.51 – 7.45 (m, 1H), 7.43 (s, 1H), 7.23 (ddd,
j=5.3,3.9,1.5 Hz, 2H), 4.07 (d,
j=1.7 Hz, 1H), 3.83 (s, 3H), 3.48 (d,
j=1.6 Hz, 1H). IR (KBr) v/cm
-1: 1758,1450,1341,1208,991,880,784,746,685.
1e, white solid, 88% yield, 49~52 ° of C of m.p., [α]
d 20=+147.7 (0.5, CHCl
3), [lit
[60]: [α]
d 20=+145.7 (0.5, CHCl
3)];
1h NMR (500 MHz, CDCl
3) δ 7.31 (dd,
j=6.5,4.5 Hz, 2H), 7.27 (t,
j=3.7 Hz, 1H), 7.19 (dt,
j=7.0,1.6 Hz, 1H), 4.08 (d,
j=1.6 Hz, 1H), 3.83 (s, 3H), 3.48 (d,
j=1.7 Hz, 1H); IR (KBr) v/cm
-1: 1747,1638,1436,1401,1209,784,686.
1f, white solid, 63% yield, 73~74 ° of C of m.p., [α]
d 20=+129.6 (0.5, CHCl
3), [lit
[60]: m.p. 69-70 ° C, [α]
d 20=+127.6 (0.5, CHCl
3)];
1h NMR (500 MHz, CDCl
3) δ 7.52 – 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=1.6 Hz, 1H), 3.83 (s, 3H), 3.47 (d,
j=1.7 Hz, 1H); IR (KBr) v/cm
-1: 1751,1493,1425,1339,1211,1091,835,793.
1g, white solid, 88% yield, 58~59 ° of C of m.p., [α]
d 20=+155.1 (0.5, CHCl
3), [lit
[60]: [α]
d 20=+150.6 (0.5, CHCl
3)];
1h NMR (500 MHz, CDCl
3) δ 7.36 – 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=1.6 Hz, 1H), 3.82 (s, 3H), 3.47 (d,
j=1.7 Hz, 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, CHCl
3), [lit
[60]: [α]
d 20=+157.1 (0.5, CHCl
3)];
1h NMR (500 MHz, CDCl
3) δ 7.40 – 7.34 (m, 3H), 7.32 – 7.28 (m, 2H), 4.11 (t,
j=2.7 Hz, 1H), 3.83 (s, 3H), 3.53 (d,
j=1.8 Hz, 1H); IR (KBr) v/cm
-1: 2955,1750,1634,1440,1413,1201,760,696.
1i, weak yellow liquid shape, 88% yield, 137~138 ° of C of m.p., [α]
d 20=+150.1 (0.5, CHCl
3), [lit
[60]: m.p. 137-139, [α]
d 20=+151.6 (0.5, CHCl
3)];
1h NMR (500 MHz, CDCl
3) δ 8.25 (s, 1H), 8.23 (s, 1H), 7.49 (s, 1H), 7.47 (s, 1H), 4.22 (d,
j=1.5 Hz, 1H), 3.85 (s, 3H), 3.50 (d,
j=1.6 Hz, 1H); IR (KBr) v/cm
-1: 1750,1606,1518,1349,1216,863,735,690.
2. compound 2a-2j's is synthetic
1 2
(R wherein
1=H tryptamines, R
1=Me methyltryptamine)
Tryptamines or N-mehtyltryptamine 1.0g are dissolved in 30 ml methyl alcohol, ice bath is cooled to 5 ℃, then drips potassium tert.-butoxide 112 mg methanol solution 10 ml, adds 1a ~ 1j 1.6 ~ 2.3 g after dropwising, maintain this thermotonus 3 h, after finishing, reaction removes solvent under reduced pressure, 50 ml dichloromethane solvents for residue, distilled water wash for organic phase (10ml * 3), anhydrous sodium sulfate drying, remove solvent under reduced pressure, residue column chromatography purification, obtains.
, white solid, 81% yield, 138~140 ° of C of m.p., [α]
d 20=+45.1 (0.5, CHCl
3);
1h NMR (500 MHz, CDCl
3) δ 8.18 (s, 1H), 7.62 (d,
j=7.9 Hz, 1H), 7.45 – 7.37 (m, 1H), 7.30 (td,
j=8.0,5.7 Hz, 1H), 7.24 (t,
j=7.5 Hz, 1H), 7.16 (dd,
j=7.8,7.1 Hz, 1H), 7.06 (d,
j=2.0 Hz, 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=1.8 Hz, 1H), 3.11 – 2.95 (m, 2H); IR (KBr) v/cm
-1: 3313,1638,1557,1458,1248,743,610.
2b, white solid, 80% yield, 119~121 ° of C of m.p., [α]
d 20=+47.3 (0.5, CHCl
3);
1h NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.26 (t,
j=5.6 Hz, 1H), 7.55 (d,
j=7.8 Hz, 1H), 7.44 – 7.29 (m, 3H), 7.21 (dd,
j=18.5,9.8 Hz, 3H), 7.07 (t,
j=7.5 Hz, 1H), 6.98 (t,
j=7.4 Hz, 1H), 4.02 (s, 1H), 3.58 (d,
j=1.5 Hz, 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.
2c, white solid, 89% yield, 127~130 ° of C of m.p., [α]
d 20=+36.2 (0.5, CHCl
3);
1h NMR (500 MHz, CDCl
3) δ 8.12 (s, 1H), 7.63 (d,
j=7.9 Hz, 1H), 7.59 (d,
j=7.6 Hz, 1H), 7.47 (t,
j=7.8 Hz, 1H), 7.45 – 7.39 (m, 2H), 7.37 (d,
j=7.7 Hz, 1H), 7.24 (d,
j=7.3 Hz, 1H), 7.17 (t,
j=7.4 Hz, 1H), 7.08 (d,
j=2.2 Hz, 1H), 6.28 (s, 1H), 3.74 – 3.59 (m, 3H), 3.45 (d,
j=1.9 Hz, 1H), 3.13-2.96 (m, 2H); IR (KBr) v/cm
-1: 3414,1638,1558,1322,1140,746,611.
2d, white solid, 83% yield, 168~172 ° of C of m.p., [α]
d 20=+55.8 (0.5, CHCl
3);
1h NMR (500 MHz, CDCl
3) δ 8.14 (s, 1H), 7.62 (d,
j=7.9 Hz, 1H), 7.46 (d,
j=8.0 Hz, 1H), 7.40 (d,
j=8.1 Hz, 1H), 7.32 (d,
j=1.6 Hz, 1H), 7.26-7.10 (m, 4H), 7.07 (d,
j=2.0 Hz, 1H), 6.27 (s, 1H), 3.65 (tq,
j=13.4,6.7 Hz, 2H), 3.59 (t,
j=3.0 Hz, 1H), 3.42 (d,
j=1.9 Hz, 1H), 3.11 – 2.95 (m, 2H); IR (KBr) v/cm
-1: 3313,1638,1556,1432,1248,744,617.
2e, white solid, 81% yield, 160~163 ° of C of m.p., [α]
d 20=+40.1 (0.5, CHCl
3);
1h NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.28 (t,
j=5.7 Hz, 1H), 7.55 (d,
j=7.8 Hz, 1H), 7.45 (d,
j=8.5 Hz, 2H), 7.43 – 7.32 (m, 3H), 7.17 (d,
j=2.1 Hz, 1H), 7.08 (dd,
j=11.0,4.0 Hz, 1H), 6.99 (dd,
j=11.0,3.8 Hz, 1H), 4.03 (d,
j=1.7 Hz, 1H), 3.57 (d,
j=1.9 Hz, 1H), 3.41 (dd,
j=13.4,7.2 Hz, 2H), 2.88 (t,
j=7.4 Hz, 2H); IR (KBr) v/cm
-1: 3313,1639,1551,1431,1092,1012,742,614.
2f, white solid, 89% yield, 177~179 ° of C of m.p., [α]
d 20=+55.3 (0.5, CHCl
3);
1h NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.28 (t,
j=5.6 Hz, 1H), 7.57 (dd,
j=13.6,8.1 Hz, 3H), 7.32 (dd,
j=18.6,8.2 Hz, 3H), 7.17 (d,
j=1.7 Hz, 1H), 7.07 (t,
j=7.4 Hz, 1H), 6.98 (t,
j=7.4 Hz, 1H), 4.02 (d,
j=1.4 Hz, 1H), 3.56 (d,
j=1.7 Hz, 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, 159~153 ° of C of m.p., [α]
d 20=+34.1 (0.5, CHCl
3);
1h NMR (500 MHz, CDCl
3) δ 8.17 (s, 1H), 7.62 (d,
j=7.9 Hz, 1H), 7.40 (d,
j=8.1 Hz, 1H), 7.33-7.29 (m, 1H), 7.27 (d,
j=7.6 Hz, 1H), 7.24 (t,
j=6.6 Hz, 1H), 7.16 (q,
j=6.7 Hz, 2H), 7.10 – 7.04 (m, 2H), 6.28 (s, 1H), 3.70 – 3.61 (m, 2H), 3.60 (d,
j=1.9 Hz, 1H), 3.43 (d,
j=1.9 Hz, 1H), 3.11 – 2.95 (m, 2H); IR (KBr) v/cm
-1: 3313,1638,1556,1458,1430,744,617.
2h, white solid, 88% yield, 131~133 ° of C of m.p., [α]
d 20=+33.1 (0.5, CHCl
3), [lit
[1]: m.p. 125-127, [α]
d=+30 (0.5, CHCl
3)];
1h NMR (500 MHz, CDCl
3) δ 8.11 (s, 1H), 7.63 (d,
j=7.9 Hz, 1H), 7.40 (d,
j=8.1 Hz, 1H), 7.37 – 7.30 (m, 3H), 7.23 (dd,
j=11.2,4.0 Hz, 1H), 7.20 (dd,
j=6.5,3.1 Hz, 2H), 7.16 (t,
j=7.4 Hz, 1H), 7.08 (d,
j=2.2 Hz, 1H), 6.31 (s, 1H), 3.66 (dt,
j=13.0,4.2 Hz, 3H), 3.49 (d,
j=2.0 Hz, 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 °C, [α]
D 20 = +73.2 (0.5, CHCl
3);
1H NMR (500 MHz, CDCl
3) δ 8.23 – 8.21 (m, 1H), 8.21 – 8.19 (m, 1H), 8.11 (s, 1H), 7.63 (d,
J = 7.9 Hz, 1H), 7.41 (d,
J = 8.1 Hz, 1H), 7.38 – 7.32 (m, 2H), 7.24 (dd,
J = 8.1, 1.1 Hz, 1H), 7.20 – 7.14 (m, 1H), 7.09 (d,
J = 2.3 Hz, 1H), 6.26 (s, 1H), 3.76 – 3.59 (m, 3H), 3.44 (d,
J = 1.9 Hz, 1H), 3.14 – 2.95 (m, 2H)。IR (KBr) v/cm
-1: 3310, 1639, 1522, 1348, 748, 612。
, white solid, 80% yield, 135~137 ° of C of m.p., [α]
d 20=+35.1 (0.5, CHCl
3),
1h NMR (500 MHz, CDCl
3) δ 8.11 (s, 1H), 7.63 (d,
j=7.9 Hz, 1H), 7.40 (d,
j=8.1 Hz, 1H), 7.37 – 7.30 (m, 3H), 7.23 (dd,
j=11.2,4.0 Hz, 1H), 7.20 (dd,
j=6.5,3.1 Hz, 2H), 7.16 (t,
j=7.4 Hz, 1H), 7.08 (d,
j=2.2 Hz, 1H), 3.66 (dt,
j=13.0,4.2 Hz, 3H), 3.49 (d,
j=2.0 Hz, 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~2j 670 ~ 744 mg are dissolved in the THF that 30 ml are dry, then add trifluoromethanesulfonic acid ytterbium 58 ~ 64 mg.Room temperature reaction spends the night, and after reaction finishes, removes solvent under reduced pressure, and residue adds 50 ml methylene dichloride to dissolve, and then uses saturated NaCl solution (10 ml * 3) washing, wash 1 time, anhydrous sodium sulfate drying, removes solvent under reduced pressure, obtain dope, crude product, through column chromatography purification, obtains.
3a, white solid, 76% yield, m.p. 114-116 ° C, [α]
d 20=+33 (c=0.5, MeOH);
1h NMR (500 MHz, DMSO) δ 10.79 (s, 1H), 7.99 (t,
j=5.8 Hz, 1H), 7.49 (d,
j=7.8 Hz, 1H), 7.40 – 7.30 (m, 2H), 7.25 (dd,
j=17.1,8.9 Hz, 2H), 7.05 (dd,
j=14.2,6.5 Hz, 2H), 6.97 (t,
j=7.4 Hz, 1H), 5.40 (d,
j=4.6 Hz, 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 (126 MHz, DMSO) δ 169.71,160.21,136.20,129.75,127.07,124.80; 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 C
19h
17o
2n
2f [M+Na]
+=347.1163, found=347.1167; Ee value is determined (4.6 mm * 25 cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8 ml/min), t by chiralcel AD-H post by chirality HPLC
minor=31.5 min, t
major=35.1 min, 97% ee.
3b,white solid, 70% yield, m.p. 88-91 ° C, [α]
d 20=+45 (c=0.5, MeOH);
1h NMR (500 MHz, DMSO) δ 10.79 (s, 1H), 7.95 (t,
j=5.9 Hz, 1H), 7.52 – 7.43 (m, 3H), 7.32 (d,
j=8.1 Hz, 1H), 7.14 (t,
j=8.9 Hz, 2H), 7.04 (dd,
j=4.0,1.5 Hz, 1H), 6.97 (t,
j=7.4 Hz, 1H), 5.39 (d,
j=4.7 Hz, 1H), 4.36 (dd,
j=6.4,5.0 Hz, 1H), 3.34 (s, 1H), 3.32 – 3.16 (m, 2H), 2.70 – 2.53 (m, 2H);
13c NMR (126 MHz, DMSO) δ 169.80,161.06,136.21,133.75,130.80; 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 C
19h
17o
2n
2f [M+Na]
+=347.1151, found=347.1154; Ee value is determined (4.6 mm * 25 cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8 ml/min), t by chiralcel AD-H post by chirality HPLC
minor=32.0 min, t
major=37.3 min, >99% ee.
3c, white powder, 75% yield, m.p. 94-96 ° C, [α]
d 20=+41 (c=0.5, MeOH);
1h NMR (500 MHz, DMSO) δ 10.78 (s, 1H), 7.99 (t,
j=5.9 Hz, 1H), 7.72 (d,
j=7.8 Hz, 1H), 7.68 (d,
j=7.8 Hz, 1H), 7.56 (t,
j=7.8 Hz, 1H), 7.47 (d,
j=7.8 Hz, 1H), 7.32 (d,
j=8.1 Hz, 1H), 7.08 – 7.03 (m, 1H), 7.01 (d,
j=2.2 Hz, 1H), 6.98 – 6.94 (m, 1H), 5.54 (d,
j=4.5 Hz, 1H), 4.42 (dd,
j=6.4,4.6 Hz, 1H), 3.33 – 3.11 (m, 2H), 2.64 – 2.52 (m, 2H);
13c NMR (126 MHz, DMSO) δ 169.62,138.71,136.20; 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 C
20h
17o
2n
2f
3[M+Na]
+=397.1190, found=397.1194; Ee value is determined (4.6 mm * 25 cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8 ml/min), t by chiralcel AD-H post by chirality HPLC
minor=20.4 min, t
major=21.4 min, 96% ee.
3d, white powder, 60% yield, m.p. 120-123 ° C, [α]
d 20=-61 (c=0.5, MeOH);
1h NMR (500 MHz, DMSO) δ 10.84 (s, 1H), 8.31 (s, 1H), 7.55 (d,
j=8.1 Hz, 3H), 7.35 (s, 3H), 7.07 (t,
j=7.3 Hz, 1H), 6.98 (t,
j=7.2 Hz, 1H), 4.03 (s, 1H), 3.60 (s, 1H), 3.41 (d,
j=6.1 Hz, 2H), 2.87 (t,
j=6.9 Hz, 2H);
13c NMR (126 MHz; DMSO) δ 166.10 (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
19h
17o
2n
2br [M+Na]
+=407.0352, found=407.0351; Ee value is determined (4.6 mm * 25 cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8 ml/min), t by chiralcel AD-H post by chirality HPLC
minor=31.6 min, t
major=35.7 min, 97% ee.
3e, white powder, 65% yield, m.p. 151-161 ° C, [α]
d 20=+56 (c=0.5, MeOH);
1h NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 7.94 (t,
j=5.8 Hz, 1H), 7.50 (d,
j=7.8 Hz, 1H), 7.40 (dd,
j=22.4,8.6 Hz, 4H), 7.33 (d,
j=8.1 Hz, 1H), 7.04 (s, 1H), 6.97 (t,
j=7.4 Hz, 1H), 5.39 (d,
j=4.7 Hz, 1H), 4.37 (dd,
j=6.5,4.8 Hz, 1H), 3.32 – 3.19 (m, 2H), 2.72 – 2.52 (m, 2H);
13c NMR (101 MHz, DMSO) δ 169.68 (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=19.2 Hz), 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 (4.6 mm * 25 cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8 ml/min), t by chiralcel AD-H post by chirality HPLC
minor=31.9 min, t
major=36.9 min, >99% ee.
3f, white powder, 66% yield, m.p. 147-150 ° C, [α]
d 20=+58 (c=0.5, MeOH);
1h NMR (500 MHz, DMSO) δ 10.85 (s, 1H), 8.00 (s, 1H), 7.50 (t,
j=9.2 Hz, 3H), 7.34 (dd,
j=14.9,8.3 Hz, 3H), 7.05 (d,
j=2.7 Hz, 1H), 6.97 (t,
j=7.4 Hz, 1H), 5.37 (d,
j=4.7 Hz, 1H), 4.36 (t,
j=5.6 Hz, 1H), 3.33 – 3.17 (m, 2H), 2.69 – 2.54 (m, 2H);
13c NMR (126 MHz, DMSO) δ 172.45,136.88,136.20,130.85,130.75,127.06,122.47,121.45,120.90,118.20,111.48,111.35,75.17,62.73,39.51,24.99; IR (KBr) v/cm
-1: 3408,1656,1640,1196,1122,804,744,667; HRMS (ES
+) caculated for C
19h
17o
2n
2br [M+Na]
+=407.3332, found=407.3338; Ee value is determined (4.6 mm * 25 cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8 ml/min), t by chiralcel AD-H post by chirality HPLC
minor=34.9 min, t
major=39.6 min, >99% ee.
3g, white solid, 62% yield, m.p. 178-181 ° C, [α]
d 20=+120 (c=0.5, MeOH);
1h NMR (500 MHz, DMSO) δ 10.79 (s, 1H), 7.99 (t,
j=5.8 Hz, 1H), 7.55 – 7.46 (m, 2H), 7.35 (m, 4H), 7.06 (d,
j=7.8 Hz, 1H), 6.97 (t,
j=7.4 Hz, 1H), 5.40 (d,
j=4.6 Hz, 1H), 4.37 (dd,
j=6.3,4.8 Hz, 1H), 3.33 – 3.13 (m, 2H), 2.69 – 2.52 (m, 2H);
13c NMR (126 MHz, DMSO) δ 169.66,139.74,136.20,132.42,129.70,128.52; 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 C
19h
17o
2n
2cl [M+Na]
+=363.0862, found=363.0865; Ee value is determined (4.6 mm * 25 cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8 ml/min), t by chiralcel AD-H post by chirality HPLC
minor=29.7 min, t
major=34.0 min, 97% ee.
3h, white solid, 78% yield, 127~130 ° of C of m.p., [α]
d 20=+30 (c=0.5, MeOH);
1h NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 7.51 (d,
j=7.7 Hz, 1H), 7.36 (d,
j=7.5 Hz, 2H), 7.29 (t,
j=7.5 Hz, 3H), 7.20 (t,
j=7.2 Hz, 2H), 7.07 – 6.93 (m, 2H), 4.88 (d,
j=9.9 Hz, 1H), 4.21 (d,
j=9.9 Hz, 1H), 3.68 (s, 1H), 3.32 – 3.17 (m, 3H), 1.25 (s, 1H);
13c NMR (101 MHz, DMSO) δ 175.94,141.65,135.77,135.27,128.55; 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 (4.6 mm * 25 cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8 ml/min), t by chiralcel AD-H post by chirality HPLC
minor=33.0 min, t
major=40.1 min, 97% ee.
3i, white powder, 72% yield, m.p.162-164 ° of C, [α]
d 20=+73 (c=0.5, MeOH); H NMR (500 MHz, DMSO) δ 10.78 (s, 1H), 8.17 (d,
j=8.8 Hz, 2H), 7.99 (t,
j=5.8 Hz, 1H), 7.67 (d,
j=8.7 Hz, 2H), 7.46 (d,
j=7.9 Hz, 1H), 7.10 – 7.03 (m, 2H), 6.96 (t,
j=7.3 Hz, 1H), 5.54 (d,
j=4.5 Hz, 1H), 4.47 – 4.39 (m, 1H), 3.33 – 3.17 (m, 2H), 2.68 – 2.54 (m, 2H);
13c NMR (126 MHz, DMSO) δ 169.48,147.20,144.70,136.18,130.08,127.06,122.94,122.45,120.94,118.20,111.47,111.33,75.14,62.16,39.51,24.95; IR (KBr) v/cm
-1: 3309,1642,1522,1352,1113,702; HRMS (ES
+) caculated for C
19h
17n
3o
4[M+Na]
+=374.1162, found=374.1161; Ee value is determined (4.6 mm * 25 cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8 ml/min), t by chiralcel AD-H post by chirality HPLC
minor=40.1 min, t
major=26.8 min, >99% ee.
3j, white powder, 75% productive rate, 193 ° of C of m.p. 190 –, [α]
d 20=+7.3 (c=0.5, CHCl
3), [lit
[16]: m.p. 185-191, [α]
d 20=+6.9 (0.5, CHCl
3)];
1h NMR (500 MHz, CDCl3) δ 7.92 (br s, 1 H), 7.53 (dd; J=6.8,1.6 Hz, 1 H), 7.33 – 7.24 (m; 5 H), 7.20 (dd, J=6.8 Hz, 2 Hz; 1 H), 7.15 (m, 1 H), 7.12 (m; 1 H), 4.96 (br, J=6.6 Hz; 1 H), 4.37 (d, J=6.0 Hz; 1 H), 4.34 (v br s), 3.96 (m; 1 H), 3.49 (m, 1 H); (3.41 m, 1 H), 3.03 (m; 1 H), 2.84 (s, 3 H);
13c NMR (100 MHz, CDCl
3) 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 C
20h
20o
2n
2[M]
+=320.1525; Found:320.1530; Ee value is determined (4.6 mm * 25 cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8 ml/min), t by chiralcel AD-H post by chirality HPLC
major=34.4 min, t
minor=63.9 min, 97% ee.
embodiment 3application pharmacological testing
Test-compound neuroprotective, antioxygenation, anti-brain cell inflammatory effect and cell toxicity test.Experimental result is in Table 6, shown in table 7, table 8 and table 9.From table 6, table 7, table 8 and table 9, test-compound neuroprotective and antioxygenation 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 nerve injury that tested group of compound of table 6 causes the cultured rat cerebellar granule neurone nutritive deficiency of former culture
Note: the cell survival rate of blank group (DMSO treatment group) is 100%, the average survival rate of cell of negative control group (nutritive 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% (10 mM).
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 treatment 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% (10 mM).Cell survival is analyzed and is measured through MTT.
The provide protection in the primary cultured rat cerebellar granule neuronal damage of Pidolidone induction of tested group of compound of table 8
Note: the cell survival rate of blank group (DMSO treatment group) is 100%, the average survival rate of cell of negative control group (L-glutamic acid treatment group) is 48.1%.
The restraining effect that table 9 test-compound discharges inflammatory factor TNFalpha in lipopolysaccharide-induced BV-2 microglia
Compound number | Test event | Lipopolysaccharide-induced rate (1 μ M) | Lipopolysaccharide-induced rate (10 μ M) |
3a | The effect of anti-neuritis disease | 102.0 ± 7.7 | 51.4 ± 5.3 |
3b | The effect of anti-neuritis disease | 96.3 ± 7.5 | 45.9 ± 3.4 |
3c | The effect of anti-neuritis disease | 72.8 ± 5.4 | 26.9 ± 3.6 |
3d | The effect of anti-neuritis disease | 108.0 ± 6.9 | 36.5 ± 3.7 |
3e | The effect of anti-neuritis disease | 105.9 ± 7.6 | 58.0 ± 5.1 |
3f | The effect of anti-neuritis disease | 94.5 ± 7.7 | 65.0 ± 6.3 |
3g | The effect of anti-neuritis disease | 112.4 ± 11.8 | 97.1 ± 8.6 |
3h | The effect of anti-neuritis disease | 104.5 ± 6.1 | 55.5 ± 5.6 |
3i | The effect of anti-neuritis disease | 90.9 ± 5.3 | 63.6 ± 6.5 |
3j | The effect of anti-neuritis disease | 105.9 ± 6.3 | 52.3 ± 5.2 |
Note: BV-2 microglia adds 100 ng/ml lipopolysaccharides single culture, or add lipopolysaccharides incubated cell after test-compound pre-treatment 2 h of various dose.After cell cultures 6 h, the burst size of cytokine TNF alpha is measured by ELISA method.Result is expressed with the form of lipopolysaccharide-induced rate.
Claims (10)
1. a class Balasubramide derivative, is characterized in that, its structural formula is as shown in formula I:
(Ⅰ),
Wherein, R
1for H or-CH
3; R is respectively Ph, 3-F-C
6h
4, 4-F-C
6h
4, 3-Cl-C
6h
4, 4-Cl-C
6h
4, 3-Br-C
6h
4, 4-Br-C
6h
4, 4-NO
2-C
6h
4or 3-CF
3-C
6h
4.
2. the application of Balasubramide derivative described in claim 1, is characterized in that, is applied to the preparation treatment cerebral protection medicine aspect relevant to neurocyte.
3. the application of Balasubramide derivative described in claim 1, is characterized in that, is applied to prepare anti-neuritis disease drug aspect.
4. application according to claim 2, is characterized in that, is by formula R shown in formula I in claim 1
1for H and R are 4-F-C
6h
4the compound characterizing is applied to the preparation treatment cerebral protection medicine aspect relevant to neurocyte.
5. application according to claim 3, is characterized in that, is by formula R shown in formula I in claim 1
1for H and R are 4-F-C
6h
4the compound characterizing is applied to prepare anti-neuritis disease drug aspect.
The preparation method of 6.Balasubramide and derivative thereof, is characterized in that, comprises the following steps:
S1. one kettle way catalysis trans-Cinnamylaldehyde and derivative epoxidation thereof, obtain α, beta epoxide carboxylicesters;
S2. by S1 gained α, beta epoxide carboxylicesters and tryptamines and analogue effect thereof, obtain prebalamide and derivative thereof;
S3. with Yb (CF
3sO
3)
3for catalyzer, make the prebalamide or derivatives thereof cyclization respectively of S2 gained, synthetic balasubramide and derivative thereof.
7. preparation method according to claim 5, is characterized in that, one kettle way catalysis trans-Cinnamylaldehyde and derivative epoxidation thereof comprise the following steps described in S1:
S11. under condition of ice bath, with 40% H
2o
2the aqueous solution is oxygenant, uses the S-diphenylprolinol triethyl silicon a series of trans-Cinnamylaldehyde of ether catalysis and derivative epoxidation thereof;
S12. at ambient temperature, S11 gained reaction solution dilutes with methyl alcohol, adds NBS and sodium carbonate, synthetic α, beta epoxide carboxylicesters.
8. described in claim 6 or 7, preparation method prepares Balasubramide and derivative thereof, is characterized in that, its structural formula is as shown in formula I:
(Ⅰ),
Wherein, R
1for H or-CH
3; R is Ph, 3-F-C
6h
4, 4-F-C
6h
4, 3-Cl-C
6h
4, 4-Cl-C
6h
4, 3-Br-C
6h
4, 4-Br-C
6h
4, 4-NO
2-C
6h
4or 3-CF
3-C
6h
4.
9. the application of Balasubramide and derivative thereof described in claim 8, is characterized in that, is applied to the preparation treatment cerebral protection medicine aspect relevant to neurocyte.
10. the application of Balasubramide and derivative thereof described in claim 8, is characterized in that, is applied to prepare anti-neuritis disease drug aspect.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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CN201510756523.3A CN105343061B (en) | 2014-06-12 | 2014-06-12 | The application of Balasubramide derivatives and preparation method |
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CN110684027A (en) * | 2019-09-12 | 2020-01-14 | 广东药科大学 | Application of dextro-fluoro-barnacamide and derivative thereof and preparation method of derivative |
CN110684027B (en) * | 2019-09-12 | 2020-08-25 | 广东药科大学 | Application of dextro-fluoro-barnacamide and derivative thereof and preparation method of derivative |
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