CN105343061A - Application and preparation method of Balasubramide derivatives - Google Patents

Application and preparation method of Balasubramide derivatives Download PDF

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CN105343061A
CN105343061A CN201510756523.3A CN201510756523A CN105343061A CN 105343061 A CN105343061 A CN 105343061A CN 201510756523 A CN201510756523 A CN 201510756523A CN 105343061 A CN105343061 A CN 105343061A
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balasubramide
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synthesis
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CN105343061B (en
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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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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/407—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 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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
    • C07D487/04—Ortho-condensed systems

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Abstract

Application and preparation method the invention discloses Balasubramide derivative. Shown in the structural formula such as formula (I) of Balasubramide derivative of the present invention, the Balasubramide derivative has excellent anti-nerve cell inflammation activity, and without cytotoxicity. The present invention synthetic line that design is scientific and reasonable simultaneously, is simple and efficient, and obtains the yield of highest 80%, and ee value is 97% or more. (I).

Description

The application of Balasubramide derivant and preparation method
The divisional application that the present invention is denomination of invention " Balasubramide and derivant thereof and synthetic method and application ", the applying date is on 06 12nd, 2014, application number is 201410260588.4 patent applications.
Technical field
The present invention relates to chemosynthesis and medical art, more specifically, relate to application and the preparation method of Balasubramide derivant.
Background technology
1996, Hofer etc. isolated bio-precursors (+)-prebalamide of a kind of octatomic ring lactams composition (+)-balasubramide and (+)-balasubramide from the chloroform extract of Rutaceae clausena plant Cortex Clausenae Excavatae [Clausenaindica (Datz) .Oliv.] leaf Sri Lanka's Tropical rain forest.
Rutaceae clausena plant is mainly distributed in south, the southeast in Asia, and minority is distributed in SOUTHERN CHINA and Australia.In world wide nearly 30 kinds, there are nearly 10 kinds within the border in China, are distributed in the middle and lower reach of Yangtze River and southern each province.The most plants of this genus is medicinal plants in China from ancient times, is used for the treatment of the diseases such as sense, malaria, stomachache and gastritis.Due to importance and the potential biological value of eight membered lactams structures, balasubramide and derivant thereof have important researching value, but have no the technology report of more relevant chiral (+)-balasubramide and analog thereof at present.
But the existing method of plant separation and Extraction that utilizes can obtain (+)-balasubramide, due to low separation efficiency and productive rate, be nowhere near for the research of its biologic activity aspect.Therefore, exploring (+)-balasubramide and analog thereof that a kind of complete synthesis method compared with high separating efficiency and productive rate obtains chirality, is the key of its using value of research and development.
Due to labyrinth and multiple chiral carbon atom of eight membered lactams rings, up to now, the synthesis of rare pertinent literature report balasubramide, existing document relates to the report of balasubramide synthesis, disclosed synthetic method otherwise reaction scheme long, productive rate is very low, or the stock preparation process synthesized is loaded down with trivial details, reaction condition is special, and the actual synthesis limiting balasubramide is produced and promotion applied research.Have no synthesis and the application technology report of balasubramide related derivatives.
Summary of the invention
The technical problem to be solved in the present invention is the deficiency overcoming existing Balasubramide derivant, the application of the Balasubramide derivant providing a class new.
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 derivant of the present invention based on described preparation method.
Object of the present invention is achieved by the following technical programs:
There is provided the derivant of Balasubramide, its structural formula is as shown in formula 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 derivant in the cerebral protection medicine that preparation treatment is relevant to neurocyte of described Balasubramide, provides described Balasubramide derivant simultaneously and is preparing the application in neuritis disease drug.
R in structure shown in preferred formula I 1for H and R is 4-F-C 6h 4time compound in the application in the preparation treatment cerebral protection medicine relevant to neurocyte, and preparing the application in neuritis disease drug.
The invention provides the preparation method of a kind of Balasubramide and derivant thereof, comprise the following steps:
S1. one kettle way catalysis trans-cinnamic aldehyde and derivant epoxidation thereof, obtains α, beta epoxide carboxylate;
S2. by S1 gained α, beta epoxide carboxylate and tryptamines and analog effect thereof, obtain prebalamide and derivant thereof;
S3. with Yb (CF 3sO 3) 3for catalyst, make the prebalamide or derivatives thereof cyclization respectively of S2 gained, synthesis (+)-balasubramide and derivant thereof.
Wherein, one kettle way catalysis trans-cinnamic aldehyde described in S1 and derivant epoxidation thereof comprise the following steps:
S11. under condition of ice bath, with 40% (V/V) H 2o 2aqueous solution is oxidant, uses the S-diphenylprolinol triethyl group silicon a series of trans-cinnamic aldehyde of ether catalysis and derivant epoxidation thereof;
S12. at ambient temperature, S11 gained reactant liquor methanol dilution, adds NBS (N-bromosuccinimide, N-bromosuccinimide) and sodium carbonate, synthesis α, beta epoxide carboxylate.
The invention provides the Balasubramide and derivant thereof that synthesize based on described preparation method.Structural formula is as shown in formula 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 Balasubramide and the application of derivant in the cerebral protection medicine that preparation treatment is relevant to neurocyte thereof that prepare based on described preparation method simultaneously, provides described Balasubramide derivant simultaneously and is preparing the application in neuritis disease drug.
Beneficial effect of the present invention:
The invention provides a class high antimer selectivity Balasubramide derivant, the blank or deficiency that have optical activity eight membered lactams structural compounds are filled up, for the research application of relevant chiral (+)-balasubramide and analog thereof provides strong technical foundation.
The invention provides described Balasubramide and the new synthetic line of derivant thereof and synthetic method, devise the asymmetric synthesis route of (+)-balasubramide, successfully synthesize Balasubramide and derivant thereof.First the present invention devises scientific and reasonable synthetic line, optimize key intermediate α, the process conditions of the synthesis of beta epoxide carboxylate, adopt a series of α of the one pot process optimized, beta epoxide carboxylate, obtains productive rate and the 97%ee value of the highest 80%.Result shows, the one kettle way of optimization provided by the present invention prepares asymmetric Epoxidation and the oxidative esterification of alpha, beta-unsaturated esters, is synthesis α, the simple method efficiently of beta epoxide carboxylate.Further, based on the present invention optimize the high ee value that one kettle way catalysis trans-cinnamic aldehyde and derivant epoxidation thereof obtain α, beta epoxide carboxylate, by itself and tryptamines and analog effect thereof, obtains prebalamide and derivant thereof, then with Yb (CF 3sO 3) 3for catalyst, make prebalamide cyclization, synthesize natural product (+)-balasubramide and derivant thereof.By Optimal reaction conditions, present invention obtains higher yield and enantioselectivity.Wherein, the total recovery of (+)-balasubramide is more than 45%, ee value is more than 97%.
The invention provides the application that described Balasubramide derivant is new, Balasubramide derivant all has the inflammatory reaction effect suppressing microglia to produce significantly, and meanwhile, cytotoxicity experiment shows these compounds does not have cytotoxicity.
Accompanying drawing explanation
Fig. 1 the compounds of this invention lacks the cerebral protection experimental result of the nerve injury caused to the cultured rat cerebellar granule neurotrophic of original cuiture.
Fig. 2 tested group of compound is to the cerebral protection of the PC12 neural cell injury of hydrogen peroxide-induced.
Protective effect in the Primary rat cerebellar granule neural cell injury that Fig. 3 tested group of compound is induced at Pidolidone.
Fig. 4 test-compound is to the inhibitory action of inflammatory factor TNFalpha release in lipopolysaccharide-induced BV-2 microglia.
Fig. 5 test-compound is to the cytotoxic effect of BV-2 microglia.
Detailed description of the invention
The present invention is further illustrated below in conjunction with the drawings and specific embodiments.Unless stated otherwise, the present invention adopt reagent and and equipment be this area routine use reagent and equipment.
The synthetic method condition research experiment of embodiment 1Balasubramide derivant
One, optical activity alpha, the synthesis of beta epoxide carboxylate
The method of reference literature report, we are by Optimal reaction conditions, with 40%H 2o 2aqueous solution is oxidant, use homemade chiral imines class catalyst S-diphenylprolinol triethyl group silicon a series of trans-cinnamic aldehyde of ether catalysis and derivant epoxidation thereof, after room temperature reaction 4h, with methanol 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 contrasting the optical rotation data of 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, beta epoxide carboxylate synthesis prebalamide and derivant thereof
1. reaction condition is on the impact of compound 2 productive rate
The present invention take methanol as solvent, and at ambient temperature, beta-phenyl glycidic acid methyl ester and tryptamines generation ester-amide condensation, reaction 3h, obtains product 2h.But, productive rate 55%.Further research finds under cryogenic, and the alkali adding catalytic amount can significantly improve the yield of reaction.Investigated the impact of the various additive of reaction 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 significantly improves.Wherein, when taking t-BuOK as additive, the productive rate of 81% is obtained.Therefore, the present invention selects t-BuOK to be the condensing agent reacted.
Three, the synthesis of target product
The present invention take acetonitrile as solvent, trifluoromethanesulfonic acid ytterbium (Yb (CF 3sO 3) 3) be catalyst, synthesize (+)-balasubramide and derivant thereof by prebalamide and derivant 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 illustrated:
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, what cyclisation product was reacted obtains medium productive rate and outstanding corresponding selection.Wherein add Yb (CF 3sO 3) 3obtain best result, productive rate be 73% and ee value be 97%.
2. reaction dissolvent is on epoxy reactive impact
Determining Yb (CF 3sO 3) 3after cyclization catalyst, the present invention has investigated the impact of reaction dissolvent on reaction, and result is as shown in table 5.
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 solvent is on the not impact of the ee value of product.Compare non-polar solven as CHCl 3solvent, reacts and obtain better productive rate in polar solvent.Wherein, take THF as solvent, reaction has the highest productive rate, reaches 75%.Synthesis condition for other derivants is studied with above-mentioned experimental result.
Embodiment 2
The overall synthetic route of optical activity (+)-balasubramide derivant is as follows:
Obtain (+)-balasubramide derivant 3a ~ 3j, the R in structural formula is respectively shown in table 5:
Table 5
The structure of (+)-balasubramide derivant 3a ~ 3j is as follows:
Each step compound experiment:
1. the synthesis of compound 1a-1j
Trans-cinnamic aldehyde and derivant 3.9g thereof are dissolved in 30ml dichloromethane, then add catalyst 1.1g ~ 1.3g and aqueous hydrogen peroxide solution 3.5 ~ 4.3ml, room temperature reaction 2h, add 30ml methanol dilution, then add Na successively 2cO 33.8 ~ 4.5g and N-bromo-succinimide 6.4 ~ 7.3g, continues reaction 3h, after reaction terminates, filters, and filtrate decompression is steamed and desolventized, residue purification by silica gel column chromatography.
1a, weak yellow liquid shape, 65% yield, [α] d 20=+166.2 (0.5, CHCl 3); 1hNMR (500MHz, CDCl 3) 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, CHCl 3); 1hNMR (400MHz, CDCl 3) 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, colorless oil 75% yield, [α] d 20=+128.3 (0.5, CHCl 3); 1hNMR (500MHz, CDCl 3) 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, CHCl 3); 1hNMR (500MHz, CDCl 3) 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, CHCl 3), [lit [60]: [α] d 20=+145.7 (0.5, CHCl 3)]; 1hNMR (500MHz, CDCl 3) 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, CHCl 3), [lit [60]: m.p.69-70 DEG C, [α] d 20=+127.6 (0.5, CHCl 3)]; 1hNMR (500MHz, 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=1.6Hz, 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, CHCl 3), [lit [60]: [α] d 20=+150.6 (0.5, CHCl 3)]; 1hNMR (500MHz, 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=1.6Hz, 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, CHCl 3), [lit [60]: [α] d 20=+157.1 (0.5, CHCl 3)]; 1hNMR (500MHz, CDCl 3) δ 7.40 – 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, CHCl 3), [lit [60]: m.p.137-139, [α] d 20=+151.6 (0.5, CHCl 3)]; 1hNMR (500MHz, CDCl 3) δ 8.25 (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. the synthesis of compound 2a-2j
(wherein R 1=H tryptamines, R 1=Me methyltryptamine)
Tryptamines or N-mehtyltryptamine 1.0g are dissolved in 30ml methanol, ice bath is cooled to 5 DEG C, then drips potassium tert-butoxide 112mg methanol solution 10ml, adds 1a ~ 1j1.6 ~ 2.3g after dropwising, maintain this thermotonus 3h, remove solvent under reduced pressure, residue 50ml dichloromethane solvent after reaction terminates, organic facies is with distilled water wash (10ml × 3), anhydrous sodium sulfate drying, remove solvent under reduced pressure, residue column chromatography purification, to obtain final product.
2a, white solid, 81% yield, m.p.138 ~ 140 DEG C, [α] d 20=+45.1 (0.5, CHCl 3); 1hNMR (500MHz, CDCl 3) 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, CHCl 3); 1hNMR (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, CHCl 3); 1hNMR (500MHz, CDCl 3) 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, CHCl 3); 1hNMR (500MHz, CDCl 3) 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, CHCl 3); 1hNMR (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, CHCl 3); 1hNMR (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, CHCl 3); 1hNMR (500MHz, CDCl 3) 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, CHCl 3), [lit [1]: m.p.125-127, [α] d=+30 (0.5, CHCl 3)]; 1hNMR (500MHz, CDCl 3) 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), 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℃,[α] D 20＝+73.2(0.5,CHCl 3)； 1HNMR(500MHz,CDCl 3)δ8.23–8.21(m,1H),8.21–8.19(m,1H),8.11(s,1H),7.63(d,J＝7.9Hz,1H),7.41(d,J＝8.1Hz,1H),7.38–7.32(m,2H),7.24(dd,J＝8.1,1.1Hz,1H),7.20–7.14(m,1H),7.09(d,J＝2.3Hz,1H),6.26(s,1H),3.76–3.59(m,3H),3.44(d,J＝1.9Hz,1H),3.14–2.95(m,2H)。IR(KBr)v/cm -1:3310,1639,1522,1348,748,612。
2j, white solid, 80% yield, m.p.135 ~ 137 DEG C, [α] d 20=+35.1 (0.5, CHCl 3), 1hNMR (500MHz, CDCl 3) 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. the synthesis of compound 3a-3j
R＝Ph,R 1＝Me,(+)-Balasubramide
R＝Ph,R 1＝H,(+)-Norbalasubramide
2a ~ 2j670 ~ 744mg is dissolved in the THF of 30ml drying, then adds trifluoromethanesulfonic acid ytterbium 58 ~ 64mg.Room temperature reaction spends the night, and removes solvent under reduced pressure after reaction terminates, and residue adds 50ml dichloromethane and dissolves, and then washs by saturated NaCl solution (10ml × 3), wash 1 time, anhydrous sodium sulfate drying, removes solvent under reduced pressure, obtain dope, crude product, through column chromatography purification, to obtain final product.
3a, white solid, 76% yield, m.p.114-116 DEG C, [α] d 20=+33 (c=0.5, MeOH); 1hNMR (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); 13cNMR (126MHz, 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 +) caculatedforC 19h 17o 2n 2f [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) by chirality HPLC by chiralcelAD-H post, t minor=31.5min, t major=35.1min, 97%ee.
3b, white solid, 70% yield, m.p.88-91 DEG C, [α] d 20=+45 (c=0.5, MeOH); 1hNMR (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); 13cNMR (126MHz, 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 +) caculatedforC 19h 17o 2n 2f [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) by chirality HPLC by chiralcelAD-H post, t minor=32.0min, t major=37.3min, >99%ee.
3c, white powder, 75% yield, m.p.94-96 DEG C, [α] d 20=+41 (c=0.5, MeOH); 1hNMR (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); 13cNMR (126MHz, 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 +) caculatedforC 20h 17o 2n 2f 3[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) by chirality HPLC by chiralcelAD-H post, t minor=20.4min, t major=21.4min, 96%ee.
3d, white powder, 60% yield, m.p.120-123 DEG C, [α] d 20=-61 (c=0.5, MeOH); 1hNMR (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); 13cNMR (126MHz, 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 +) caculatedforC 19h 17o 2n 2br [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) by chirality HPLC by chiralcelAD-H post, t minor=31.6min, t major=35.7min, 97%ee.
3e, white powder, 65% yield, m.p.151-161 DEG C, [α] d 20=+56 (c=0.5, MeOH); 1hNMR (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); 13cNMR (101MHz, 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=19.2Hz), 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) by chirality HPLC by chiralcelAD-H post, t minor=31.9min, t major=36.9min, >99%ee.
3f, white powder, 66% yield, m.p.147-150 DEG C, [α] d 20=+58 (c=0.5, MeOH); 1hNMR (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); 13cNMR (126MHz, 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 +) caculatedforC 19h 17o 2n 2br [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) by chirality HPLC by chiralcelAD-H post, t minor=34.9min, t major=39.6min, >99%ee.
3g, white solid, 62% yield, m.p.178-181 DEG C, [α] d 20=+120 (c=0.5, MeOH); 1hNMR (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); 13cNMR (126MHz, 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 +) caculatedforC 19h 17o 2n 2cl [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) by chirality HPLC by chiralcelAD-H post, t minor=29.7min, t major=34.0min, 97%ee.
3h, white solid, 78% yield, m.p.127 ~ 130 DEG C, [α] d 20=+30 (c=0.5, MeOH); 1hNMR (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); 13cNMR (101MHz, 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 (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min) by chirality HPLC by chiralcelAD-H post, t minor=33.0min, t major=40.1min, 97%ee.
3i, white powder, 72% yield, m.p.162-164 DEG C, [α] d 20=+73 (c=0.5, MeOH); HNMR (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); 13cNMR (126MHz, 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 +) caculatedforC 19h 17n 3o 4[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) by chirality HPLC by chiralcelAD-H post, t minor=40.1min, t major=26.8min, >99%ee.
3j, white powder, 75% productive rate, m.p.190 – 193 DEG C, [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)]; 1hNMR (500MHz, CDCl3) δ 7.92 (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, 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 +) caculatedforC 20h 20o 2n 2[M] +=320.1525; Found:320.1530; Ee value is determined (4.6mm × 25cm, n-hexane/i-PrOH=90/10, λ=254nm, 0.8ml/min) by chirality HPLC by chiralcelAD-H post, t major=34.4min, t minor=63.9min, 97%ee.
Embodiment 3 applies pharmacological testing
Test-compound neuroprotective, 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 neuroprotective and antioxidation are very low.As can be seen from Table 8, except 3g, other compound all has the effect of the inflammatory reaction suppressing rat microglia cells to produce significantly, and wherein 3c effect is the strongest.Meanwhile, as can be seen from Figure 1, cytotoxicity experiment shows compound of the present invention does not have cytotoxicity.
Table 6 tested group of compound lacks the cerebral protection of the nerve injury caused to the cultured rat cerebellar granule neurotrophic of original cuiture
Note: the cell survival rate of blank group (DMSO processed group) is 100%, the cell average viability of negative control group (malnutrition 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).
Table 7 tested group of compound is to the cerebral protection of the PC12 neural cell injury that hydrogen peroxide causes
Note: the cell survival rate of blank group (DMSO processed group) is 100%, the cell survival rate of hydrogen peroxide treatment group is 61.9 ± 3.8%.Positive control is the cell survival rate of N-acetylcystein (NAC, this compound of bibliographical information is a kind of antioxidant) this group is 87.8 ± 3.8% (10mM).Cells viability is analyzed through MTT and is measured.
The protective effect in the Primary rat cerebellar granule neuron that Pidolidone is induced damages of table 8 tested group of compound
Note: the cell survival rate of blank group (DMSO processed group) is 100%, the cell average viability of negative control group (glutamic acid processed group) is 48.1%.
Table 9 test-compound is to the inhibitory action of inflammatory factor TNFalpha release in lipopolysaccharide-induced BV-2 microglia
Note: BV-2 microglia adds 100ng/ml lipopolysaccharide single culture, or add lipopolysaccharide incubated cell after the test-compound pretreatment 2h of various dose.After cell culture 6h, the burst size ELISA method of cytokine TNF alpha measures.Result is expressed with the form of lipopolysaccharide-induced rate.

Claims (3)

1. the application of a class Balasubramide derivant, is characterized in that, is applied to the medicine aspect of the preparation treatment cerebral protection relevant to neurocyte or neuritis disease; The structural formula of described Balasubramide derivant is as shown in formula I:
（Ⅰ），
Wherein, R 1for H or-CH 3.
2. the preparation method of Balasubramide derivant described in claim 1, is characterized in that, comprise the following steps:
S1. one kettle way catalysis trans-cinnamic aldehyde and derivant epoxidation thereof, obtains α, beta epoxide carboxylate;
S2. by S1 gained α, beta epoxide carboxylate and tryptamines and analog effect thereof, obtain prebalamide and derivant thereof;
S3. with Yb (CF 3sO 3) 3for catalyst, make the prebalamide or derivatives thereof cyclization respectively of S2 gained, synthesis balasubramide and derivant thereof.
3. preparation method according to claim 2, is characterized in that, one kettle way catalysis trans-cinnamic aldehyde described in S1 and derivant epoxidation thereof comprise the following steps:
S11. under condition of ice bath, with 40%H 2o 2aqueous solution is oxidant, uses the S-diphenylprolinol triethyl group silicon a series of trans-cinnamic aldehyde of ether catalysis and derivant epoxidation thereof;
S12. at ambient temperature, S11 gained reactant liquor methanol dilution, adds NBS and sodium carbonate, synthesis α, beta epoxide carboxylate.
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