CN103570665A - Enantiomers of 3-methyl-7, 8-dihydroxy-isochroman-4-one, and applications thereof in controlling cardiovascular diseases - Google Patents
Enantiomers of 3-methyl-7, 8-dihydroxy-isochroman-4-one, and applications thereof in controlling cardiovascular diseases Download PDFInfo
- Publication number
- CN103570665A CN103570665A CN201210253664.XA CN201210253664A CN103570665A CN 103570665 A CN103570665 A CN 103570665A CN 201210253664 A CN201210253664 A CN 201210253664A CN 103570665 A CN103570665 A CN 103570665A
- Authority
- CN
- China
- Prior art keywords
- methyl
- xjp
- dihydroxyl
- isochroman
- dihydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 CC1OCc(c(*)c(cc2)OC)c2C1=O Chemical compound CC1OCc(c(*)c(cc2)OC)c2C1=O 0.000 description 1
- GYQLQRKNCRZYMN-QMMMGPOBSA-N C[C@@H]1OCc(c(OC)c(cc2)[O](C)=C)c2C1=O Chemical compound C[C@@H]1OCc(c(OC)c(cc2)[O](C)=C)c2C1=O GYQLQRKNCRZYMN-QMMMGPOBSA-N 0.000 description 1
- VNUOYAPMHILZDH-MRVPVSSYSA-N C[C@H]1OCc(c([O](C)=C)c(cc2)OC)c2C1=O Chemical compound C[C@H]1OCc(c([O](C)=C)c(cc2)OC)c2C1=O VNUOYAPMHILZDH-MRVPVSSYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of organic chemistry and pharmaceutical chemistry, and specifically relates to a levorotatory enantiomer and a dextrorotatory enantiomer of a natural product 3-methyl-7, 8-dihydroxy-isochroman-4-one (XJP), a preparation method thereof, and applications of the levorotatory enantiomer and the dextrorotatory enantiomer in controlling cardiovascular diseases.
Description
Technical field
The present invention relates to organic chemistry and pharmaceutical chemistry field, be specifically related to a kind of natural product 3-methyl-7, the levo-enantiomer of the different chroman-4-on-of 8-dihydroxyl (XJP) and dextrorotation enantiomorph, and the purposes aspect anti-cardiovascular disease.
Background technology
In Pericarpium Musae, extract separated isochromanome compounds 3-methyl-7 that obtain, it is active that the different chroman-4-on-of 8-dihydroxyl (XJP) has multiple anti-cardiovascular disease, as hypertension, anti-oxidant, atherosclerosis, the extensive biological activity such as cardiovascular protection and anti-angiogenic inflammation is (referring to Liu J, Xu J Y, Bai R R, et al.Total synthesis and antihypertensive activity of 7, 8-dihydroxy-3-methyl-isochromanone-4[J] .Bioorganic & Medicinal Chemistry Letters, 2009, 19:1822-1824, Fu R, Xu J Y, Wu X M.et al.XJP-1, a novel ACEI, with anti-inflammatory properties in HUVECs.Atherosclerosis, 2011,219:40-48).But at 3 of XJP, have a chiral carbon, pharmacodynamic study is in the past all that to take its raceme (±)-XJP be experimental subjects.In order to illustrate the activity difference of two enantiomorph in pharmacodynamics, need to synthesize or the method such as chiral separation by chirality, obtain respectively two mapping monomers.
Summary of the invention
The object of patent of the present invention is synthesized or to XJP enantiomorph chiral separation method, obtained respectively two mapping monomers of XJP, and the cardiac vascular activity of its levo form and dextrorotatory form is compared by chirality.The invention discloses Chiral Synthesis and method for splitting, configuration structure and the purposes aspect anti-cardiovascular disease thereof of two mapping monomer R-of XJP (-)-XJP and S-(+)-XJP.
Formula I of the present invention and formula II can prepare by following method:
Reaction 1
With reference to reaction 1, bromo-2 with 6-, 3-dimethoxybenzyl bromide (1) is raw material, reacts and makes compound 2 with S-methyl lactate under alkaline condition.Compound 2 ester hydrolysis, acidifying under alkaline condition make intermediate 3, by the nucleophilic substitution reaction cyclization generation compound 4 of organolithium catalysis.Compound 4 is protected and is obtained S-(+)-XJP by Using Aluminium Trichloride as Catalyst demethylation.Bromo-2 with 6-equally, 3-dimethoxybenzyl bromide (1) is raw material, can make R-(+)-XJP with R-methyl lactate according to above method.
Reaction 2
With reference to reaction 2, the chiral separation of XJP enantiomorph, according to the method in patent CN 200710020463.4, by chemosynthesis, prepare XJP raceme, adopt again chromatogram Split Method to carry out chiral separation to raceme, using starch-polysaccharides derivative as chiral stationary phase, prepared higher two the mapping monomers of XJP of purity.
In order to confirm the RS configuration of levo form and dextrorotation, we adopt Gaussian to calculate two enantiomorphs.(referring to Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., Petersson, G.A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H.P., Izmaylov, A.F., Bloino, J., Zheng, G., Sonnenberg, J.L., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Montgomery, J.A.Jr., Peralta, J.E., Ogliaro, F., Bearpark, M., Heyd, J.J., Brothers, E., Kudin, K.N., Staroverov, V.N., Keith, T., Kobayashi, R., Normand, J., Raghavachari, K., Rendell, A., Burant, J.C., Iyengar, S.S., Tomasi, J., Cossi, M., Rega, N., Millam, J.M., Klene, M., Knox, J.E., Cross, J.B., Bakken, V., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R.E., Yazyev, O., Austin, A.J., Cammi, R., Pomelli, C., Ochterski, J.W., Martin, R.L., Morokuma, K., Zakrzewski, V.G., Voth, G.A., Salvador, P., Dannenberg, J.J., Dapprich, S., Daniels, A.D., Farkas, O., Foresman, J.B., Ortiz, J.V., Cioslowski, J., and Fox, D.J., 2010.Gaussian 09, Revision B.01, Gaussian, Inc., WallingfordCT.)
Calculation result: calculate gained S configuration CD spectral data close with dextrorotatory form; CD spectrogram data calculated and the levo form of R configuration are close, confirm that dextrorotatory form is S configuration, and levo form is R configuration.
Therefore, by configuration, determine and confirm that the structure of two enantiomorphs is as follows:
Be pharmacology test and the data of the compounds of this invention below, the structure that in pharmacological testing, compound code name is corresponding is shown in embodiment.Instrument material:
BP-2000 measures system (production of U.S. Visitech company) without wound animal blood pressure
Standard mercury sphygmomanometer (Yuyue Medical Apparatus Co., Ltd., Jiangsu)
Spontaneous hypertensive rat (SHR), male, SPF level, purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., credit number SCXK (capital) 2012-0001, experimentation on animals environment occupancy permit number: SYXK (Soviet Union) 2011-0017.
Experimental technique:
Animal grouping and administration: choose 8 of the male SHR rats of body weight 200~250g, gavage gives XJP80mg/kg respectively.
Instrument arranges: open without wound animal blood pressure and measure system, with standard mercury sphygmomanometer, instrument is calibrated, each parameter arranges as follows: top pressure 250mmHg, 37 ℃ of mensuration temperature, predict 3 times, survey 20 times, at every turn interval time 3s.Pressure when setting signal strength retrogression arrives average pulse intensity 90% is as diastolic pressure (DAP), and the pressure while decaying to 20% is as systolic pressure (SAP).
Mouse tail tag note: according to tail cover method operability, mouse tail is divided into 4 sections, and is labeled as successively 1,2,3 and 4 positions from root of the tail to tail point, the rest with 3,4 stage casings, position as infrared inductor, and with blue marking pen marker determination position.
Blood pressure determination: animal, before experiment is formally carried out, has acclimatization training respectively twice, each 2h, and uninterruptedly monitor its blood pressure, blood pressure is on the low side, and person (SAP < 150mmHg, DAP < 110mmHg) discards.Choose compliance good, the rat that blood pressure is qualified carries out random packet and test.Before pressure measurement, instrument is preheated to 37 ℃, animal is put into fixer by number, mouse tail is through pressing cercoids, be nested with infrared rays determinator, pre-adaptation 10min, after there is rat normal pulse oscillogram on computer monitor, start to measure (during mensuration, animal may shake off, and retightens rear continuation).After having surveyed, choose the normal person's of waveform data as valid data, the valid data of each time point are no less than 3, and ineligible person redeterminates, and gets the mean value of each mensuration as a result of.Each mouse is first measured the blood pressure before administration, thereafter by respectively administration of group, before recording administration and after administration 1,2,4,6,8,10,12 and blood pressure (systolic pressure, diastolic pressure, mean arterial pressure) and the heart rate of 24h rat.
Statistical procedures method: the blood pressure (SAP, DAP, MAP) that each treated animal is measured and heart rate (HR) result with
represent, carry out self administration front and back (pairing) t-test statistics and process.
Experimental result:
During in SHR body, step-down is tested, R-(-)-XJP, S-(+)-XJP all have good hypotensive effect, and Amplitude of Hypotensive comparative result is as follows: R-(-)-XJP > (±)-XJP > S-(+)-XJP.
Note: with comparison before administration, *: P < 0.05; *: P < 0.01.
Embodiment
Below in conjunction with specific examples, the present invention is further elaborated, but the present invention is not limited to these embodiment.
Embodiment 1
S-2-(2,3-dimethoxy 6-bromo-benzyloxy-) methyl propionate (2)
Raw material 1 (3.1g, 0.01mol) is dissolved in to 20mL DMF, and gradation adds NaH (content 60%, 7.5g, 0.02mol), under condition of ice bath, stir, after reaction 0.5h, drip the S-methyl lactate (2.1mL, 0.02mol) that is dissolved in 20mL DMF, after ice bath reaction 6h, finish, filter, filtrate is immersed in 100ml ice saturated aqueous common salt, separate organic layer, water layer extracted with diethyl ether 3 times, each 100mL, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Organic layer is concentrated, silica gel column chromatography [sherwood oil (60 ℃~90 ℃): ethyl acetate=8: 1 (v: v)] wash-out, obtain colorless oil 2.82g, yield 85.0%.
IR(KBr),cm
-1:2980,2938,1746,1692,1587,1483,1266,1082
1H-NMR(CDCl
3,300MHz)δ:1.31(d,3H,J=6.8Hz,-CH
3),4.23(q,3H,J=7.1Hz,-CH
3),3.84(s,3H,-OCH
3),3.89(S,3H,-OCH
3),4.15(q,1H,J=6.8Hz,-CH-),4.57(q,1H,J=9.9Hz,-CH
2-),4.92(d,1H,J=9.9Hz,-CH
2-),6.78(d,1H,J=8.8Hz,Ar-H),7.27(d,1H,J=8.8Hz,Ar-H)
MS(EI?m/z):[M+H]
+?333.3
Embodiment 2
S-2-(2,3-dimethoxy-6-bromo-benzyloxy-) propionic acid (3)
By S-2-(2,3-dimethoxy 6-bromo-benzyloxy-) methyl propionate (2) (3.33g, 0.1mol), add in the 50% ethanol 20ml solution that 20mL contains 2gNaOH, stirring at room 3h, then concentrating under reduced pressure eliminates ethanol, hydrochloric acid adjust pH to 2~3 with 10%, extracted with diethyl ether 3 times, each 20mL, merges ether solution, anhydrous sodium sulfate drying, concentrate to obtain white solid 2.92g, yield 92.0%, mp56-58 ℃.
IR(KBr),cm
-1:3488,3415,2938,1727,1638,1620,1476,1274,1232,1089,1016
1H-NMR(CDCl
3,300MHz)δ:1.37(d,3H,J=6.7Hz,-CH
3),3.85(s,6H,-OCH
3),4.09(q,1H,J=6.7Hz,-CH-),6.96(d,1H,J=8.5Hz,Ar-H),7.30(d,1H,J=8.5Hz,Ar-H)
MS(ESI?m/z):[M-H]
-318
Embodiment 3
S-3-methyl-7,8-dimethoxy isochromanome-4 (4)
By S-2-(2; 3-dimethoxy-6-bromo-benzyloxy-) propionic acid (3) (6.36g; 0.02mol) add in the anhydrous THF of 50mL; nitrogen protection; be cooled to-78 ℃, add n-BuLi hexane solution (24mL, 2.5mol/L; 0.06mol); after 2h, be gradually warming up to room temperature, then finish reaction after reacting 30min, by reaction solution impouring 50ml saturated aqueous ammonium chloride; by extracted with diethyl ether; each 100mL, extracts 2 times, merges ether solution; by saturated sodium bicarbonate solution, saturated aqueous common salt extraction, wash successively anhydrous sodium sulfate drying.Extraction liquid is concentrated, silica gel column chromatography, [sherwood oil (60 ℃~90 ℃): ethyl acetate=4: 1 (v: v)], obtain white solid 2.67g, mp121~122 ℃, yield 65.0%.
IR(KBr),cm
-1:2991,2979,2963,2937,2844,2826,1693,1597,1580,1494,1454,1358,1288,1272,1126,1079
1H-NMR(CDCl
3,300MHz)δ:1.50(d,3H,J=6.6Hz,-CH
3),3.85(s,3H,-OCH
3),3.95(S,3H,-OCH
3),4.19(q,1H,J=6.6Hz,-CH-),4.79(d,1H,J=15.9Hz,-CH
2-),5.13(d,1H,J=15.9Hz,-CH
2-),6.95(d,1H,J=8.7Hz,Ar-H),7.83(d,1H,J=8.7Hz,Ar-H)
MS(ESI,m/z):[M+H]
+223,[M+Na]
+245
Embodiment 4
S-3-methyl-7,8-dihydroxyl isochromanome-4 (S-XJP)
By S-3-methyl-7,8-dimethoxy isochromanome-4 (4) (2.22g, 0.01mol) are dissolved in 25mL chloroform, and gradation adds AlCl
3after (5.34g, 0.04mol) reflux 3h, by ice-cold 10% dilute hydrochloric acid of reaction solution impouring, separate organic layer, water layer extracted with diethyl ether, each 10mL, extract 2 times, merge organic layer, anhydrous sodium sulfate drying, after organic layer is concentrated, silica gel column chromatography, [sherwood oil (60 ℃~90 ℃): ethyl acetate=4: 1 (v: v)] wash-out, obtain white solid 1.07g, mp174~176 ℃ (decomposition), yield 55.1%.
m.p.163-164℃(dec.)。
1H?NMR(DMSO-D
6,300MHz):δ(ppm)1.29(d,J=6.7Hz,3H,-CH
3),4.19(q,J=6.7Hz,1H,-CH-),4.68(d,J=15.5Hz,1H,-CH
2-),4.97(d,J=15.9Hz,1H,-CH
2-),6.82(d,J=8.7Hz,1H,Ar-H),7.31(d,J=8.7Hz,1H,Ar-H),8.90(1H,-OH),10.40(1H,-OH).
13C?NMR(DMSO-D
6,75MHz):δ(ppm)194.8,150.8,139.8,130.3,121.7,119.0,114.6,76.8,62.6,15.9。HR-MS(ESI)calcd?for?C
10H
11O
4[M+H]
+:195.0652,found?195.0653
Embodiment 5
R-2-(2,3-dimethoxy 6-bromo-benzyloxy-) methyl propionate (5)
Raw material 1 (3.1g, 0.01mol) is dissolved in to 20mL DMF, and gradation adds NaH (content 60%, 7.5g, 0.02mol), under condition of ice bath, stir, after reaction 0.5h, drip the S-methyl lactate (2.1mL, 0.02mol) that is dissolved in 20mL DMF, after ice bath reaction 6h, finish, filter, filtrate is immersed in 100ml ice saturated aqueous common salt, separate organic layer, water layer extracted with diethyl ether 3 times, each 100mL, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Organic layer is concentrated, silica gel column chromatography [sherwood oil (60 ℃~90 ℃): ethyl acetate=8: 1 (v: v)] wash-out, obtain colorless oil 2.73g, yield 83.0%.
IR(KBr),cm
-1:2980,2938,1746,1692,1587,1483,1266,1082
1H-NMR(CDCl
3,300MHz)δ:1.31(d,3H,J=6.8Hz,-CH
3),4.23(q,3H,J=7.1Hz,-CH
3),3.84(s,3H,-OCH
3),3.89(S,3H,-OCH
3),4.15(q,1H,J=6.8Hz,-CH-),4.57(q,1H,J=9.9Hz,-CH
2-),4.92(d,1H,J=9.9Hz,-CH
2-),6.78(d,1H,J=8.8Hz,Ar-H),7.27(d,1H,J=8.8Hz,Ar-H)
MS(EI?m/z):[M+H]
+?333.3
Embodiment 6
R-2-(2,3-dimethoxy-6-bromo-benzyloxy-) propionic acid (6)
By R-2-(2,3-dimethoxy 6-bromo-benzyloxy-) methyl propionate (2) (3.33g, 0.1mol), add in the 50% ethanol 20ml solution that 20mL contains 2gNaOH, stirring at room 3h, then concentrating under reduced pressure eliminates ethanol, hydrochloric acid adjust pH to 2~3 with 10%, extracted with diethyl ether 3 times, each 20mL, merges ether solution, anhydrous sodium sulfate drying, concentrate to obtain white solid 2.85g, yield 89.0%, mp56-58 ℃.
IR(KBr),cm
-1:3488,3415,2938,1727,1638,1620,1476,1274,1232,1089,1016
1H-NMR(CDCl
3,300MHz)δ:1.37(d,3H,J=6.7Hz,-CH
3),3.85(s,6H,-OCH
3),4.09(q,1H,J=6.7Hz,-CH-),6.96(d,1H,J=8.5Hz,Ar-H),7.30(d,1H,J=8.5Hz,Ar-H)
MS(ESI?m/z):[M-H]
-318
Embodiment 7
R-3-methyl-7,8--dimethoxy isochromanome-4 (7)
By R-2-(2; 3-dimethoxy-6-bromo-benzyloxy-) propionic acid (6) (6.36g; 0.02mol) add in the anhydrous THF of 50mL; nitrogen protection; be cooled to-78 ℃, add n-BuLi hexane solution (24mL, 2.5mol/L; 0.06mol); after 2h, be gradually warming up to room temperature, then finish reaction after reacting 30min, by reaction solution impouring 50ml saturated aqueous ammonium chloride; by extracted with diethyl ether; each 100mL, extracts 2 times, merges ether solution; by saturated sodium bicarbonate solution, saturated aqueous common salt extraction, wash successively anhydrous sodium sulfate drying.Extraction liquid is concentrated, silica gel column chromatography, [sherwood oil (60 ℃~90 ℃): ethyl acetate=4: 1 (v: v)], obtain white solid 2.87g, mp121~122 ℃, yield 67.0%.
IR(KBr),cm
-1:2991,2979,2963,2937,2844,2826,1693,1597,1580,1494,1454,1358,1288,1272,1126,1079
1H-NMR(CDCl
3,300MHz)δ:1.50(d,3H,J=6.6Hz,-CH
3),3.85(s,3H,-OCH
3),3.95(S,3H,-OCH
3),4.19(q,1H,J=6.6?Hz,-CH-),4.79(d,1H,J=15.9Hz,-CH
2-),5.13(d,1H,J=15.9Hz,-CH
2-),6.95(d,1H,J=8.7Hz,Ar-H),7.83(d,1H,J=8.7Hz,Ar-H)
MS(ESI,m/z):[M+H]
+?223,[M+Na]
+245
Embodiment 8
R-3-methyl-7,8-dihydroxyl isochromanome-4(R-XJP)
By S-3-methyl-7,8-dimethoxy isochromanome-4 (7) (2.22g, 0.01mol) are dissolved in 25mL chloroform, and gradation adds AlCl
3after (5.34g, 0.04mol) reflux 3h, by ice-cold 10% dilute hydrochloric acid of reaction solution impouring, separate organic layer, water layer extracted with diethyl ether, each 10mL, extract 2 times, merge organic layer, anhydrous sodium sulfate drying, after organic layer is concentrated, silica gel column chromatography, [sherwood oil (60 ℃~90 ℃): ethyl acetate=4: 1 (v: v)] wash-out, obtain white solid 1.17g, mp174~176 ℃ (decomposition), yield 59.1%.
m.p.163-164℃(dec.)。
1H?NMR(DMSO-D
6,300MHz):δ(ppm)1.29(d,J=6.7Hz,3H,-CH
3),4.19(q,J=6.7Hz,1H,-CH-),4.68(d,J=15.5Hz,1H,-CH
2-),4.97(d,J=15.9Hz,1H,-CH
2-),6.82(d,J=8.7Hz,1H,Ar-H),7.31(d,J=8.7Hz,1H,Ar-H),8.90(1H,-OH),10.40(1H,-OH).
13C?NMR(DMSO-D
6,75MHz):δ(ppn)194.8,150.8,139.8,130.3,121.7,119.0,114.6,76.8,62.6,15.9。HR-MS(ESI)calcd?for?C
10H
11O
4[M+H]
+:195.0652,found?195.0653
Embodiment 9
The chiral separation preparation of S-(+)-XJP
Chiral column: CHIRALPAKAD-H, 5cm I.D. * 25cm L
Moving phase: CO2/MeOH=85/15
Flow velocity: 130g/min
Detect: UV 208nm
Temperature: 35 ℃
Sample solution: be configured to 20mg/mL with moving phase
According to above preparation condition, can prepare more than 98 S-(+)-XJP enantiomorph (white solid) of e.e. (%).
m.p.163-164℃(dec.)。
1H?NMR(DMSO-D
6,300MHz):δ(ppm)1.29(d,J=6.7Hz,3H,-CH
3),4.19(q,J=6.7Hz,1H,-CH-),4.68(d,J=15.5Hz,1H,-CH
2-),4.97(d,J=15.9Hz,1H,-CH
2-),6.82(d,J=8.7Hz,1H,Ar-H),7.31(d,J=8.7Hz,1H,Ar-H),8.90(1H,-OH),10.40(1H,-OH).
13C?NMR(DMSO-D
6,75MHz):δ(ppm)194.8,150.8,139.8,130.3,121.7,119.0,114.6,76.8,62.6,15.9。HR-MS(ESI)calcd?for?C
10H
11O
4[M+H]
+:195.0652,found?195.0653。
Embodiment 10
The chiral separation preparation of R-(-)-XJP
Chiral column: CHIRALPAK AD-H, 5cm I.D. * 25cm L
Moving phase: CO2/MeOH=85/15
Flow velocity: 130g/min
Detect: UV 208nm
Temperature: 35 ℃
Sample solution: be configured to 20mg/mL with moving phase
According to above preparation condition, can prepare more than 98 R-(-)-XJP enantiomorph (white solid) of e.e. (%).
m.p.163-164℃(dec.)。
1H?NMR(DMSO-D
6,300MHz):δ(ppm)1.26(d,J=6.7Hz,3H,-CH
3),4.19(q,J=6.7Hz,1H,-CH-),4.68(d,J=15.5Hz,1H,-CH
2-),4.92(d,J=15.9Hz,1H,-CH
2-),6.82(d,J=8.7Hz,1H,Ar-H),7.31(d,J=8.7Hz,1H,Ar-H),8.92(1H,-OH),10.39(1H,-OH).
13C?NMR(DMSO-D
6,75MHz):δ(ppm)194.8,150.8,139.8,130.3,121.7,119.0,114.6,76.8,62.6,15.9。HR-MS(ESI)calcd?for?C
10H
11O
4[M+H]
+:195.0652,found?195.0650。
Embodiment 11
The configuration of enantiomorph calculates: adopt Gaussian 09 program, calculation formula is as follows:
The S configuration data that calculation result obtains approaches with the dextrorotatory form that experiment records; The calculating configuration data of R configuration approaches with the levo form recording with experiment, specific as follows:
Embodiment 12
Tablet
Get above-mentioned formula, by ordinary method, be prepared into tablet.
Claims (5)
2. prepare S-(+)-3-methyl-7, the different chroman-4-on-of 8-dihydroxyl and R-(-)-3-methyl-7, the method for the different chroman-4-on-of 8-dihydroxyl.
3. the method for claim 2, it comprises that chirality is synthetic with racemic mixture to be carried out to column chromatography separated.
4. the method for claim 2, wherein said column chromatography is separated into chiral chromatography separation or HPLC chromatographic separation.
5. the purposes of the compound of claim 1 aspect anti-cardiovascular disease, comprises hypertension, atherosclerosis, anti-heart failure, anti-oxidant, anti-angiogenic inflammation and cardiovascular protection effect thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210253664.XA CN103570665A (en) | 2012-07-23 | 2012-07-23 | Enantiomers of 3-methyl-7, 8-dihydroxy-isochroman-4-one, and applications thereof in controlling cardiovascular diseases |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210253664.XA CN103570665A (en) | 2012-07-23 | 2012-07-23 | Enantiomers of 3-methyl-7, 8-dihydroxy-isochroman-4-one, and applications thereof in controlling cardiovascular diseases |
Publications (1)
Publication Number | Publication Date |
---|---|
CN103570665A true CN103570665A (en) | 2014-02-12 |
Family
ID=50043450
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201210253664.XA Pending CN103570665A (en) | 2012-07-23 | 2012-07-23 | Enantiomers of 3-methyl-7, 8-dihydroxy-isochroman-4-one, and applications thereof in controlling cardiovascular diseases |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103570665A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104177323A (en) * | 2014-08-29 | 2014-12-03 | 中国药科大学 | Synthesis method of single enantiomer (+/-)-3-methyl-7,8-dihydroxy-isochroman-4-one |
CN108558817A (en) * | 2018-03-30 | 2018-09-21 | 宁波大学 | A kind of isocoumarin analog derivative and its preparation method and application |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101016290A (en) * | 2007-03-01 | 2007-08-15 | 中国药科大学 | Method of synthesizing 3-methyl-7-,8-dihydroxyisochromanone-4 |
CN102532087A (en) * | 2011-10-09 | 2012-07-04 | 中国药科大学 | Method for synthesizing 3-methyl-7,8-dimethoxy-chroman-4-one |
-
2012
- 2012-07-23 CN CN201210253664.XA patent/CN103570665A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101016290A (en) * | 2007-03-01 | 2007-08-15 | 中国药科大学 | Method of synthesizing 3-methyl-7-,8-dihydroxyisochromanone-4 |
CN102532087A (en) * | 2011-10-09 | 2012-07-04 | 中国药科大学 | Method for synthesizing 3-methyl-7,8-dimethoxy-chroman-4-one |
Non-Patent Citations (5)
Title |
---|
CHAOLEI WANG ET AL.: "First total synthesis of antihypertensive natural products S-(+)-XJP and R-(-)-XJP", 《ORG. BIOMOL. CHEM.》 * |
JIE LIU ET AL.: "Total synthesis and antihypertensive activity of (±)7,8-dihydroxy-3-methyl-isochromanone-4", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
RENREN BAI ET AL.: "Chiral separation, configurational identification and antihypertensive evaluation of (±)-7,8-dihydroxy-3-methyl-isochromanone-4", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
RONG FU ET AL.: "XJP-1, a novel ACEI, with anti-inflammatory properties in HUVECs", 《ATHEROSCLEROSIS》 * |
许磊 等: "辽细辛地上部分化学成分的分离与鉴定(2)", 《沈阳药科大学学报》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104177323A (en) * | 2014-08-29 | 2014-12-03 | 中国药科大学 | Synthesis method of single enantiomer (+/-)-3-methyl-7,8-dihydroxy-isochroman-4-one |
CN108558817A (en) * | 2018-03-30 | 2018-09-21 | 宁波大学 | A kind of isocoumarin analog derivative and its preparation method and application |
CN108558817B (en) * | 2018-03-30 | 2021-07-09 | 宁波大学 | Isocoumarin derivative and preparation method and application thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101421245A (en) | Preparation of eslicarbazepine and related compounds by asymmetric hydrogenation | |
Schobert et al. | An expedient synthesis of 3-acyltetramic acids of the melophlin family from α-aminoesters and immobilized Ph3PCCO | |
Kwak et al. | Highly enantioselective Rh-catalyzed transfer hydrogenation of N-sulfonyl ketimines | |
Fabio et al. | Synthesis and evaluation of potent and selective human V1a receptor antagonists as potential ligands for PET or SPECT imaging | |
Gimbert et al. | Tributylphosphine, excellent organocatalyst for conjugate additions of non-nucleophilic N-containing compounds | |
CN103570665A (en) | Enantiomers of 3-methyl-7, 8-dihydroxy-isochroman-4-one, and applications thereof in controlling cardiovascular diseases | |
CN102977068A (en) | Nitric oxide donor type isochromanone derivatives, preparation methods and uses thereof | |
Leśniak et al. | Lactic acid derived aziridinyl alcohols as highly effective catalysts for asymmetric additions of an organozinc species to aldehydes | |
Creech et al. | Theory-guided design of Brønsted acid-assisted phosphine catalysis: synthesis of dihydropyrones from aldehydes and allenoates | |
Camps et al. | (R)-and (S)-3-Hydroxy-4, 4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries in the enantioselective preparation of α-aryloxypropanoic acid herbicides and α-chlorocarboxylic acids | |
Cabrera et al. | Homochiral l-prolinamido-sulfonamides and their use as organocatalysts in aldol reactions | |
Midura et al. | Asymmetric cyclopropanation of chiral (1-dimethoxyphosphoryl-2-phenyl) vinyl p-tolyl sulfoxide: a new synthesis of enantiomerically pure 2-amino-3-phenyl-1-cyclopropane-phosphonic acid—a constrained analog of phaclofen | |
Escorihuela et al. | C2 symmetrical nickel complexes derived from α-amino amides as efficient catalysts for the enantioselective addition of dialkylzinc reagents to aldehydes | |
de Mattos Duarte et al. | New optimized piperamide analogues with potent in vivo hypotensive properties | |
Pallavicini et al. | Highly efficient racemisation of a key intermediate of the antibiotic moxifloxacin | |
CN102875516B (en) | Isochromanone derivatives with beta-receptor blocking activity, and preparation method and application thereof | |
Miranda et al. | (±)-cis-(6-Ethyl-tetrahydropyran-2-yl)-formic acid: a novel substance with antinociceptive properties | |
Cardillo et al. | Asymmetric synthesis of 5-isopropyl-oxazoline-4-imide as syn-hydroxyleucine precursor | |
Peng et al. | Conjugate addition of unactivated thiols to α, β-unsaturated ketones catalyzed by a bifunctional rhenium (V)–oxo complex | |
Harmata et al. | Benzothiazines in synthesis: studies directed toward the synthesis of erogorgiaene | |
Jiang et al. | An expedient route for the practical preparation of optically active (−)-gossypol | |
ES2400713T3 (en) | Pyridyl-acetylenes for use as radio-trackers and imaging agents | |
Merino et al. | Stereoselective 1, 3-dipolar cycloadditions of nitrones derived from amino acids. Asymmetric synthesis of N-(alkoxycarbonylmethyl)-3-hydroxypyrrolidin-2-ones | |
Zhao et al. | An efficient synthesis of α-aryl β-(N-tosyl) amino phosphonate derivatives from α-diazophosphonate | |
Parsons | Free radical cyclisation of enamides leading to biologically important γ-lactams |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140212 |