CN1156474C - Chiral isoquinoline compound with cardiac vascular activity and its synthesis process - Google Patents

Chiral isoquinoline compound with cardiac vascular activity and its synthesis process Download PDF

Info

Publication number
CN1156474C
CN1156474C CNB021383251A CN02138325A CN1156474C CN 1156474 C CN1156474 C CN 1156474C CN B021383251 A CNB021383251 A CN B021383251A CN 02138325 A CN02138325 A CN 02138325A CN 1156474 C CN1156474 C CN 1156474C
Authority
CN
China
Prior art keywords
compound
preparation
quinolizine
tetrahydrochysene
dibenzo
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.)
Expired - Lifetime
Application number
CNB021383251A
Other languages
Chinese (zh)
Other versions
CN1403456A (en
Inventor
华维一
戴德哉
张灿
戴茵
林云
王永庆
黄文龙
孙立
冯瑜
李欣欣
崔冰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Pharmaceutical University
Original Assignee
China Pharmaceutical University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by China Pharmaceutical University filed Critical China Pharmaceutical University
Priority to CNB021383251A priority Critical patent/CN1156474C/en
Publication of CN1403456A publication Critical patent/CN1403456A/en
Application granted granted Critical
Publication of CN1156474C publication Critical patent/CN1156474C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Landscapes

  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention relates to N-substituted chiral tetrahydroberberine quarternary ammonium compounds and a preparing method thereof. The preparing method comprises the following steps of resolving (+/-) tetrahydroberberine into (+)-13aR and (-)-13aS tetrahydroberberine at a room temperature in methanol by a resolution agent (-)DPT or (+)DPT, making the (+)-13aR and (-)-13aS tetrahydroberberine respectively react with p-chlorobenzyl chloride, p-nitrobenzyl bromide or benzyl chloride; separating the reaction products by column chromatography; eluting the separated products by methylene chloride and ethanol in a gradient mode; collecting eluted components to obtain compounds (from 1 to 12). The compounds can optimize the activity of heart and blood vessels, improve pharmacological selectivety, increase dissolvability, improve biological utilization and improve and enlarge the adaptability of clinical treatment, and can be used for treating pulmonary hypertension, myocardial ischemia, cerebral ischemia, cerebral infarction, heart failure, myocardial hypertrophy, etc.

Description

Chiral isoquinoline compound and synthetic method thereof with cardiac vascular activity
Technical field
The invention belongs to and have the inclination vasoactive chiral isoquinoline compound and synthetic method thereof, relate in particular to proto-berberine chipal compounds and synthetic method thereof.
Background technology
Chiral drug to cardiovascular, to the effect of beta receptor, α acceptor and ionic channel, has tangible stereoselectivity, referring to: Humphrey S J, et al.Cardiovascular effects of the R-andS-enantiomers of ibutilide in conscious beagle dogs.Methods Find Exp ClinPharmacol.2001; 23 (8): 449-58.The chiral centre C of chiral isoquinoline compound and N atom constitute chipal compounds, and when macromole combined in the body, the steric configuration of medicine was subjected to obviously influencing of chiral centre.Show as easily on three-dimensional binding site and agree with, or be difficult for agreeing with, this just forms the basis of medicine to the biomacromolecule selectively acting.
Chinese patent CN91107511.9 and U.S. Pat 5, in 470,852, announced that the protoberberine compound p-p-chlorobenzyl N-1 series of isoquinoline 99.9 (is called for short CPU-86017, down with) chemosynthesis, and to the research of cardiovascular acceptor, ionic channel.Found that CPU-86017 has C and two chiral centres of N, pointed out its different optical antipode that cardiovascular acceptor and ionic channel are had optionally effect.In the spectrum of berberine compounds, owing to have-O-CH 2-O-is connected with the bridge shape of phenyl ring, and activity and toxicity are all increased, and is also strong to the blocking effect of ionic channel, especially has tangible alpha block effect, and significant calcium channel blocking effect.When the iv administration, obvious to the effect of blood pressure, heart rate, the powerful restraining effect owing to blood pressure and heart rate makes the tolerance of iv administration poor, and toxicity is big.CPU-86017 is that isoquinoline compound belongs to the barberry bases, have the blocking effect to the different kinds of ions passage mostly, and selectivity is not strong.When the pharmacological agent cardiovascular disorder, as control the outbreak of acute tachyarrhythmia, treatment is in heart failure, all need be with the iv administration.CPU-86017 has obvious blocking effect to ionic channel, and obvious to calcium, potassium and sodium channel blocking effect, especially the blocking effect to calcium and potassium channel is stronger, and on gene level modulation of ion channels.In multiple ARR animal model, good antiarrhythmic effect is arranged.But CPU-86017 solubleness is less, and bioavailability is low, and toxicity is big, and especially the toxicity of iv administration is big.In clinical application, exist potential restricted.
Summary of the invention
The technical issues that need to address of the present invention are chirality N-1 compounds that synthetic a series of N replace, its activity to cardiovascular effect is optimized, improves the selectivity of pharmacological action, increase solubleness, improve bioavailability, improve and enlarge the adaptability of clinical treatment.
The technical issues that need to address of the present invention also comprise the method for the chirality N-1 compound optical isomer that the synthetic N of research replaces, and make its favorable reproducibility, and operating procedure is simple.
For solving the problems of the technologies described above, the invention provides following technical scheme.
The chirality N-1 quaternary ammonium compound that N replaces is characterized in that possessing following structure:
Compound 1 be (7R, 13aR), R is Cl, X is Cl;
Compound 2 be (7S, 13aR), R is Cl, X is Cl;
Compound 3 be (7S, 13aS), R is Cl, X is Cl;
Compound 4 be (7R, 13aS), R is Cl, X is Cl;
Compound 5 is that (7R, 13aR), R is NO 2, X is Br;
Compound 6 is that (7S, 13aR), R is NO 2, X is Br;
Compound 7 is that (7S, 13aS), R is NO 2, X is Br;
Compound 8 is that (7R, 13aS), R is NO 2, X is Br;
Compound 9 be (7R, 13aR), R is H, X is Cl;
Compound 10 be (7S, 13aR), R is H, X is Cl;
Compound 11 be (7S, 13aS), R is H, X is Cl;
Compound 12 be (7R, 13aS), R is H, X is Cl.
The preparation method of the chirality N-1 quaternary ammonium compound that a kind of N replaces is characterized in that:
With (±) N-1 and resolving agent (-) DPT or (+) DPT, under the room temperature condition, in methyl alcohol, react, split into corresponding (+)-13aR N-1 and (-)-13aS N-1.
The preparation method of the chirality N-1 quaternary ammonium compound that a kind of N replaces is characterized in that: be prepared as follows 1 to 12 compound,
Figure C0213832500061
Compound 1 be (7R, 13aR), R is Cl, X is Cl;
Compound 2 be (7S, 13aR), R is Cl, X is Cl;
Compound 3 be (7S, 13aS), R is Cl, X is Cl;
Compound 4 be (7R, 13aS), R is Cl, X is Cl;
Compound 5 is that (7R, 13aR), R is NO 2, X is Br;
Compound 6 is that (7S, 13aR), R is NO 2, X is Br;
Compound 7 is that (7S, 13aS), R is NO 2, X is Br;
Compound 8 is that (7R, 13aS), R is NO 2, X is Br;
Compound 9 be (7R, 13aR), R is H, X is Cl;
Compound 10 be (7S, 13aR), R is H, X is Cl;
Compound 11 be (7S, 13aS), R is H, X is Cl;
Compound 12 be (7R, 13aS), R is H, X is Cl;
(+)-13aR N-1 and (-)-13aS N-1 are reacted with the halo benzyl respectively; Reactant separates with silica gel column chromatography, and elutriant is a methylene dichloride: ethanol, gradient elution; Collect eluant component; Get compound 1～12 respectively.
Among the preparation method of the chirality N-1 quaternary ammonium compound that above-mentioned N replaces: the halo benzyl is 4-chlorobenzyl chloride, to nitro bromobenzyl or benzyl chloride, and the solvent of reaction is anhydrous acetonitrile and/or acetone.
The preparation method of the chirality N-1 quaternary ammonium compound that described N replaces is characterized in that: with (+)-13aR N-1 and 4-chlorobenzyl chloride, in anhydrous acetonitrile, refluxed 5～7 hours; Reactant separates with silica gel column chromatography, and elutriant is a methylene dichloride: ethanol, and gradient elution is collected eluant component; According to silica gel thin-layer chromatography (CH 2Cl 2: CH 3CH 2OH: NH 3.H 2O=9: 1: 0.1, down together), R fBe that 0.57 component is a compound 1; R fBe that 0.59 component is a compound 2.
The preparation method of the chirality N-1 quaternary ammonium compound that described N replaces is characterized in that: with (-)-13aS N-1 and 4-chlorobenzyl chloride, in anhydrous acetonitrile, refluxed 5～7 hours; Reactant separates with silica gel column chromatography, and elutriant is a methylene dichloride: ethanol, gradient elution; Collect eluant component; R fBe that 0.57 component is a compound 3; R fBe that 0.59 component is a compound 4.
The preparation method of the chirality N-1 quaternary ammonium compound that described N replaces is characterized in that: with (+)-13aR N-1 and to the nitro bromobenzyl, in acetone, refluxed 5～7 hours; After reactant is separated out, separate with silica gel column chromatography, elutriant is a methylene dichloride: ethanol, gradient elution; Collect eluant component; R fBe that 0.56 component is a compound 5; R fBe that 0.58 component is a compound 6.
The preparation method of the chirality N-1 quaternary ammonium compound that described N replaces is characterized in that: with (-)-13aS N-1 and to the nitro bromobenzyl, in acetone, refluxed 5～7 hours; After reactant is separated out, separate with silica gel column chromatography, elutriant is a methylene dichloride: ethanol, gradient elution; Collect eluant component; R fBe that 0.56 component is a compound 7; R fBe that 0.58 component is a compound 8.
The preparation method of the chirality N-1 quaternary ammonium compound that described N replaces is characterized in that: with (+)-13aR N-1 and benzyl chloride, in 90-110 ℃, reacted 3-5 hour; Reactant separates with silica gel column chromatography, and elutriant is a methylene dichloride: ethanol, gradient elution; Collect eluant component; R fBe that 0.57 component is a compound 9; R fBe that 0.59 component is a compound 10.
The preparation method of the chirality N-1 quaternary ammonium compound that described N replaces is characterized in that: with (-)-13aS N-1 and benzyl chloride, in 90-110 ℃, reacted 3-5 hour; Reactant separates with silica gel column chromatography, and elutriant is a methylene dichloride: ethanol, gradient elution; Collect eluant component; R fBe that 0.57 component is a compound 11; R fBe that 0.59 component is a compound 12.
Exist two chiral centres (13a-C and 7-N) in the CPU-86017 N-1 quarternary ammonium salt compound, have four enantiomorphs.In order to explore the influence of chirality to drug effect, pharmacokinetics, we have prepared this four isomer.Set about from its precursor N-1, the method by chemistry splits obtains (-) S, (+) R N-1 earlier, and each individual isomer is quaternized more then, obtains two diastereomers respectively, separates again.Because optically active (-) S, (+) R N-1 carry out should obtaining two diastereomers in theory when quaternized, easily detect and separate.
In view of the above, we have not only prepared four pure individual isomer of CPU-86017, and 8 of chirality N-1 quaternary ammonium compounds that have two kinds of different substituents on the two class N have been synthesized in design simultaneously.12 compound corresponding structure parameters see Table 1 altogether.
The chemical structure of the chirality N-1 that table 1:N replaces
Compound R X - Compound R X -
1、(7R，13aR) Cl Cl 2、(7S，13aR) Cl Cl 3、(7S，13aS) Cl Cl 4、(7R，13aS) Cl Cl 5、(7R，13aR) NO 2 Br 6、(7S，13aR) NO 2 Br 7、(7S，13aS) NO 2 Br 8、(7R，13aS) NO 2 Br 9、(7R，13aR) H Cl 10、(7S，13aR) H Cl 11、(7S，13aS) H Cl 12、(7R，13aS) H Cl
The synthetic route of the chirality N-1 quaternary ammonium compound that above-mentioned N replaces
(1) synthetic route of resolving agent, according to document J.Yamahara, T.Konoshima, Y.Sakakibara, et al.Chem.Pham.Bull.1976,24,1909-1912
Figure C0213832500081
(2) synthetic route of chirality N-1 quaternary ammonium compound
Figure C0213832500091
The substituent R of compound 1～12 and X are referring to table 1.
The present invention has synthesized the chirality N-1 compound that a series of N replace, and its activity to cardiovascular effect is optimized, and improves the selectivity of pharmacological action, increases solubleness, improves bioavailability, improves and enlarge the adaptability of clinical treatment.
The present invention has also studied the method for the chirality N-1 compound optical isomer of synthetic N replacement, makes its favorable reproducibility, and operating procedure is simple.
Embodiment
Berberine: the new numerous pharmaceutical factory in Sichuan, content＞99%
POTASSIUM BOROHYDRIDE: Shen, Shanghai space pharmaceutical raw material factory, content＞99%
L (+) tartrate: Shanghai reagent company, import packing, content＞99%
D (-) tartrate: Shanghai reagent company, import packing, content＞99%
All the other reagent are analytical pure
Chromatography used silica gel: Haiyang Chemical Plant, Qingdao, 200 orders～300 orders
Embodiment 1:
Preparation 2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine (N-1 is called for short THB, down together)
Add Berberine 30g (0.089mol) in the 1000mL three-necked bottle, 90% ethanol (or methyl alcohol) 600mL slowly is heated to backflow, and berberine all dissolves.Add POTASSIUM BOROHYDRIDE 9g (0.17mol), insulation 20min reacted 3.5 hours under room temperature then in batches, had a large amount of faint yellow solids to produce, and leached, and was washed to neutrality, and oven dry gets pale yellow powder 25g.Dehydrated alcohol (or anhydrous methanol, benzene) recrystallization, near-white crystal 19g, productive rate 63%.mp：169～171℃
1HNMR(300MHz，CDCl 3，δ)：6.87～6.76(2H，AB，ArH 11，12)，6.72(1H，s，ArH)，6.59(1H，s，ArH)5.91(2H，s，-OCH 2O-)，4.24(1H，d，CH)，3.84(6H，s，2×-OCH 3)，3.53(2H，m，CH)，3.15(3H，m，CH)，2.83(1H，m，CH)，2.64(2H，m，CH)
MS(ESI(+)150V，m/z)：340.1[M+H] + base peak，176
Embodiment 2:
Two pairs of toluyl tartrate of preparation resolution reagent (being called for short DPT, down together)
Preparation (-)-two pair toluyl tartrate
15g L (+) tartrate (0.10mol) 20mL toluene and 30g paratolunitrile (0.22mol) are placed the four-necked bottle of 200mL together, and oil bath is heated to about 85 ℃, splashes into 29.8g SOCl in the 1h 2(0.25mol), behind the stirring 1h, oil bath temperature rises to 125 ℃, insulation 2h, and the adularescent solid is separated out, and temperature is reduced to about 80 ℃ then, splashes into 15g SOCl in the 1h 2(0.136mol) stir 1h, be warming up to 125 ℃ again, behind the backflow 6h, add 40mL toluene, reaction solution filters after being chilled to room temperature, and crystal is washed with toluene, and vacuum-drying gets 30g white powder solid.Re-crystallizing in ethyl acetate gets mp 203-205 ℃ of two couples of toluyl winestone acid anhydrides white needle-like crystals 24g (productive rate 62.4%).
IR (cm -1): 2975 (CH 3), 2955 (CH), 1884,1810 (C=O, acid anhydrides), 1732,1708 (C=O, esters), 1610 (aromatic ring C=C), 749 (phenyl ring replaces two)
Two pairs of toluyl winestones of gained 19g (0.0515mol) acid anhydrides is dissolved in the 96mL acetone, adds water 4.8mL, back flow reaction 2h, evaporated under reduced pressure acetone and water, add the benzene dissolving, filtered while hot is placed and is separated out (-)-two couple toluyl tartrate white crystal 13.4g (productive rate 67%).mp：165～167℃
[α] D 20＝-132.28，C 2H 5OH
IR (cm -1): 3400～2500 (OH), 1739 (C=O, esters), 1672 (C=O, acid), 1611,1578,1509 (phenyl ring C=C), 1248 (C-O), 749 (phenyl ring replaces two)
MS(ESI(-)70V，m/z)：3 85.1[M-H] -base peak
Preparation (+)-two pair toluyl tartrate
By the preparation of D (-) tartrate, the preparation method is the same.mp：167～169℃
[α] D 20+138.02，C 2H 5OH
IR (cm -1): 3400～2500 (OH), 1739 (C=O, esters), 1672 (C=O, acid), 1611,1578,1509 (phenyl ring C=C), 1248 (C-O), 749 (phenyl ring replaces two)
MS(ESI(-)70V，m/z)：385.1[M-H] -base peak
Embodiment 3:
Preparation (+)-13a R N-1
8.8g (0.0259mol) ± THB is dissolved in the 500mL methyl alcohol (or ethanol), to 20mL methyl alcohol (or ethanol) solution that wherein adds (-) DPT10.5g (0.0259mol), room temperature placed for two weeks, obtain light yellow needle-like crystal 7.1g productive rate 73.8%, recrystallization is almost constant to optically-active in the methyl alcohol (or ethanol).
(-)DPT(+)THB：mp：158～159℃ [α] D 28+101.64，CHCl 3
Anal(C 40H 39NO 12，C％，H％，N％) Req：66.21，5.38，1.93
Found：65.85，5.30，1.54
With 3g (-) DPT (+) THB 10%Na 2CO 3Alkalization, CHCl 3Extraction, CHCl 3Also laminated, saturated common salt washing, anhydrous K 2CO 3Dried overnight, CHCl 3Layer is concentrated into dried, gets faint yellow solid 1.25g, and recrystallizing methanol gets 13aR THB near-white needle-like crystal 1.0g, productive rate 71.4%.
(+)13aR THB：mp：130～132℃
IR (cm -1): 3050～2800 (C-H), 1611,1494,1488 (aromatic ring C=C), 1275,1217,1081,1034 (C-O)
1HNMR(300MHz，CDCl 3，δ)：6.87～6.76(2H，AB，ArH 11，12)，6.73(1H，s，ArH)，6.59(1H，s，ArH)5.91(2H，s，-OCH 2O-)，4.24(1H，d，H 8)，3.84(6H，s，2×-OCH 3)，3.53(2H，m，CH)，3.18(3H，m，CH)，2.82(1H，m，CH)，2.61(2H，m，CH)
MS(ESI(+)150V，m/z)：340.1[M+H] +base peak，176.1
Embodiment 4:
Preparation (-)-13a S THB
By (+) DPT preparation, the preparation method is the same.
(+)DPT(-)THB：mp：156～157℃ [α] D 28-101.36，CHCl 3
Anal(C 40H 39NO 12，C％，H％，N％)Req：66.21，5.38，1.93
Found：66.49，5.50，1.53
(-)-13a S THB：mp：132～134℃ [α] D 25-303.45，CHCl 3
IR (cm -1): 3050～2800 (C-H), 1611,1494,1488 (aromatic ring C=C), 1275,1217,1081,1034 (C-O)
1HNMR(300MHz，CDCl 3，δ)：6.88～6.77(2H，AB，ArH 11，12)，6.72(1H，s，ArH)，6.59(1H，s，ArH)5.91(2H，s，-OCH 2O-)，4.24(1H，d，CH)，3.84(6H，s，2×-OCH 3)，3.53(2H，m，CH)，3.18(3H，m，CH)，2.82(1H，m，CH)，2.62(2H，m，CH)
MS(ESI(+)120V，m/z)：340.1[M+H] +base peak，176.1
Embodiment 5:
Preparation compound 1 and compound 2
Preparation (+) 7R, 13aR-N-p-chlorobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate (compound 1 in the table 1)
In the three-necked bottle of 25mL, add 2.0g (5.93 * 10 -3Mol) (+)-13aR THB1.3g (8.07 * 10 -3The mol 4-chlorobenzyl chloride, the anhydrous second eyeball of 4mL, backflow 6h gets the reddish-brown viscous liquid, silica gel 100～200 order column chromatography (CH 2Cl 2-C 2H 5The OH gradient elution), differentiate (CH according to silica gel thin-layer chromatography 2Cl 2: CH 3CH 2OH: NH 3.H 2O=9: 1: 0.1, down together), collect R f=0.57 component gets light yellow solid powder (+) 7R, 13aR-N-p-chlorobenzyl-2, and 3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate, promptly compound 1; Collect R f=0.59 component gets light yellow solid powder (+) 7S, 13a R-N-p-chlorobenzyl-2, and 3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate, promptly compound 2.
Compound 1:mp:147～149 ℃ [α] D 20+ 80.70 (c=0.2, CHCl 3)
Anal(C 27H 27NO 4Cl·Cl，C％，H％，N％) Req：64.80，5.40，2.80
Found：64.72，5.43，2.35
IR (cm -1): 3600～3200 (O-H), 3050～2800 (C-H), 1608,1596,1499 (aromatic ring C=C), 1282,1235,1092,1032 (C-O)
1HNMR(300MHz，CDCl 3，δ)：7.42(2H，d，ArH 3’，5’)7.10(3H，d，ArH 2’，6’，12)，7.00(1H，d，ArH 11)6.81(1H，s，ArH 1)，6.74(1H，s，ArH 4)，6.28(1H，d-d，H 13a)，6.01(2H，s，-OCH 2O-)，5.85(1H，d，H 8)，5.09(1H，m，H 6)，4.55(1H，d，H 8)4.00(2H，s，-CH 2Ar)，3.96(1H，m，H 13)，3.91(3H，s，-OCH 3)，3.86(3H，s，-OCH 3)3.38(3H，m，H 5，6)，3.17(1H，m，H 13)
MS(ESI(+)100V，m/z)：464.2[M +]base peak
Preparation (+) 7S, 13a R-N-p-chlorobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate (compound 2)
mp：140～142℃ [α] D 20+57.24(c＝0.3，CHCl 3)
Anal(C 27H 27NO 4Cl·Cl，C％，H％，N％) Req：64.80，5.40，2.80
Found：64.47，5.36，2.35
IR (cm -1): 3600～3200 (OH), 3050～2800 (C-H), 1595,1500,1485 (aromatic ring C=C), 1282,1232,1084,1032 (C-O)
1HNMR(300MHz，CDCl 3，δ)：7.58(2H，d，ArH 2’，6’)，7.40(2H，d，ArH 3’，5’)，6.85(2H，AB，ArH 11，12)，6.73(2H，s，ArH 1，4)，6.00(2H，d，-OCH 2O-)，5.49(1H，d，-CH 2Ar)，5.19(1H，m，H 13a)，5.02(1H，d，-CH 2Ar)，4.94～4.79(1H，AB，H 8)，4.44(1H，m，H 6)，3.88(3H，s，-OCH 3)，3.81(3H，s，-OCH 3)，3.51(3H，m，H 5，6，13)，3.15(2H，m，H 5，13)
MS(ESI(+)70V，m/z)：464.1[M +]base peak
Embodiment 6:
Preparation compound 3 and compound 4
Preparation (-) 7S, 13aS-N-p-chlorobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate (compound 3)
By (-)-13aS THB preparation, method is with the preparation method of compound 1.
mp：145～146℃ [α] D 20-79.46(c＝0.2，CHCl 3)
Anal(C 27H 27NO 4Cl·Cl，C％，H％，N％) Req：64.80，5.40，2.80
Found：64.47，5.33，2.43
IR (cm -1): 3600～3200 (O-H), 3050～2800 (C-H), 1609,1596,1499 (aromatic ring C=C), 1282,1233,1083,1033 (C-O)
1HNMR(300MHz，CDCl 3，δ)：7.40(2H，d，ArH 3’，5’)，7.08(3H，m，ArH 2’，6’，12)，6.99(1H，d，ArH 11)，6.79(1H，s，ArH 1)，6.73(1H，s，ArH 4)6.25(1H，d-d，H 13a)，5.98(2H，s，-OCH 2O-)，5.82(1H，d，H 8)，5.03(1H，m，H 6)，4.53(1H，d，H 8)4.04(2H，s，-CH 2Ar)，3.95(1H，m，H 13)，3.89(3H，s，-OCH 3)，3.84(3H，s，-OCH 3)3.39(3H，m，H 5，6)，3.19(1H，m，H 13)
MS(ESI(+)70V，m/z)：464.0[M +]base peak
Preparation (-) 7R, 13a S-N-p-chlorobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate (compound 4)
Compound 4 is by (-)-13a S THB preparation, and method is with the preparation method of compound 2.
mp：138～139℃ [α] D 20-52.04(c＝0.2，CHCl 3)
Anal(C 27H 27NO 4Cl·Cl，C％，H％，N％) Req：64.80，5.40，2.80
Found：64.97，5.22，2.42
IR (cm -1): 3600～3200 (O-H), 3050～2800 (C-H), 1609,1596,1499 (aromatic ring C=C), 1282,1232,1084,1033 (C-O)
1HNMR(300MHz，CDCl 3，δ)：7.56(2H，d，ArH 2’，6’)，7.36(2H，d，ArH 3’，5’)，6.82(2H，m，ArH 11，12)，6.70(2H，s，ArH 1，4)，5.95(2H，d，-OCH 2O-)，538(1H，d，-CH 2Ar)，5.11(1H，m，H 13a)，4.98(1H，d，-CH 2Ar)，4.86(1H，d，H 8)，4.75(1H，d，H 8)，4.32(1H，m，H 6)，3.84(3H，s，-OCH 3)，3.78(3H，s，-OCH 3)，3.50(3H，m，H 5，6，13)，3.12(2H，m，H 5，13)
MS(ESI(+)100V，m/z)：464.2[M +] base peak
Embodiment 7:
Preparation compound 5 and compound 6
Preparation (+) 7R, 13aR-N-is to nitrobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine bromide (compound 5)
In the three-necked bottle of 25mL, add 1.0g (2.97 * 10 -3Mol) (+)-13a R THB, 0.74g (3.42 * 10 -3Mol) to the nitro bromobenzyl, 8mL acetone, backflow 6h has light yellow solid to separate out, and crosses filter solid, carries out column chromatography, (CH with 200～300 order silica gel 2Cl 2-C 2H 5OH) gradient elution.Differentiate according to silica gel thin-layer chromatography, collect R f=0.56 component, light yellow solid powdered compounds (+) 7R, 13a R-N-is to nitrobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine bromide 5, collection R f=0.58 component, light yellow solid powdered compounds (+) 7S, 13a R-N-is to nitrobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine bromide 6.
Compound 5:mp:140～142 ℃ [α] D 20+ 63.76 (c=0.6, CHCl 3)
Anal(C 27H 27N 2O 6·Br，C％，H％，N％) Req：58.39，4.86，5.04
Found：58.55，4.70，4.58
IR (cm -1): 3600～3200 (O-H), 3050～2800 (C-H), 1607,1525,1500,1489 (aromatic ring C=C, NO 2), 1347 (NO 2), 1282,1234,1032 (C-O)
1HNMR(300MHz，CDCl 3，δ)：8.30(2H，d，ArH 3’，5’)，7.40(2H，d，ArH 2’，6’)，7.01～7.14(2H，AB，ArH 11，12)，6.83(1H，s，ArH)，6.76(1H，s，ArH)，6.34(1H，d-d，H 13a)，6.01(2H，s，-OCH 2O-)，5.90(1H，d，H 8)，5.09(1H，m，H 6)，4.53(1H，d，H 8)，4.16(2H，s，-CH 2Ar)，3.96(1H，m，H 13)，3.92(3H，s，-OCH 3)，3.86(3H，s，-OCH 3)，3.45(3H，m，H 5，6)，3.26(1H，m，H 13)
MS(ESI(+)100V，m/z)：4475.1[M +]base peak
Preparation (+) 7S, 13a R-N-is to nitrobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine bromide (compound 6)
Anal(C 27H 27N 2O 6·Br，C％，H％，N％) Req：58.39，4.86，5.04
Found：58.29，4.73，4.57
IR (cm -1): 3600～3200 (O-H), 3050～2800 (C-H), 1607,1525,1500,1485 (aromatic ring C=C, NO 2), 1347 (NO 2), 1281,1233,1032 (C-O)
1HNMR(300MHz，CDCl 3，δ)：8.30(2H，d，ArH 2’，6’)，7.95(2H，d，ArH 3’，5’)，6.92～6.84(2H，m，ArH 11，12)，6.77(2H，s，ArH 1，4)，6.03(2H，d，-OCH 2O-)，5.78(1H，d，-CH 2Ar)，5.30(1H，m，H 13a)，5.20(1H，d，-CH 2Ar)，5.00～4.85(2H，AB，H 8)，4.51(1H，m，H 6)，3.92(3H，s，-OCH 3)，3.84(3H，s，-OCH 3)，3.53(3H，m，H 5，6，13)，3.22(2H，m，H 5，13)
MS(ESI(+)100V，m/z)：464.2[M +]base peak
Embodiment 8:
Preparation compound 7 and compound 8
Preparation (-) 7S, 13aS-N-is to nitrobenzyl-2,3-methylenedioxy group-9,0-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine bromide (compound 7)
By (-)-13a S THB preparation, method is with the preparation method of compound 5
mp：144～146℃ [α] D 20-62.26 (c＝0.5，CHCl 3)
Anal(C 27H 27N 2O 6·Br，C％，H％，N％) Req：58.39，4.86，5.04
Found：58.45，4.75，4.61
IR (cm -1): 3600～3200 (O-H), 3050～2800 (C-H), 1607,1525,1500,1488 (aromatic ring C=C, NO 2), 1347 (NO 2), 1282,1234,1032 (C-O)
1HNMR(300MHz，CDCl 3，δ)：8.32(2H，d，ArH 3’，5’)，7.40(2H，d，ArH 2’，6’)，7.02～7.14(2H，AB，ArH 11，12)，6.83(1H，s，ArH)，6.77(1H，s，ArH)，6.34(1H，d-d，H 13a)，6.03(2H，s，-OCH 2O-)，5.92(1H，d，H 8)，5.14(1H，m，H 6)，4.55(1H，d，H 8)4.18(2H，s，-CH 2Ar)，4.00(1H，m，H 13)，3.94(3H，s，-OCH 3)，3.88(3H，s，-OCH 3)，3.45(3H，m，H 5，6)，3.22(1H，m，H 13)
MS(ESI(+)100V，m/z)：475.1[M +]base peak
Preparation (-) 7R, 13aS-N-is to nitrobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine bromide (compound 8)
By (-)-13a S THB preparation, method is with the preparation method of compound 6.
mp：155～157℃ [α] D 20-46.54(c＝0.3，CHCl 3)
Anal(C 27H 27N 2O 6·Br，C％，H％，N％) Req：58.39，4.86，5.04
Found：58.24，4.79，4.62
IR (cm -1): 3600～3200 (O-H), 3050～2800 (C-H), 1606,1525,1499,1485 (aromatic ring C=C, NO 2), 1347 (NO 2), 1282,1233,1033 (C-O)
1HNMR(300MHz，CDCl 3，δ)：8.29(2H，d，ArH 2’，6’)，7.95(2H，d，ArH 3’，5’)，6.91～6.83(2H，m，ArH 11，12)，6.77(2H，s，ArH 1，4)，6.02(2H，d，-OCH 2O-)，5.76(1H，d，-CH 2Ar)，5.31(1H，m，H 13a)，5.22(1H，d，-CH 2Ar)，5.00～4.85(2H，AB，H 8)，4.49(1H，m，H 6)，3.91(3H，s，-OCH 3)，3.83(3H，s，-OCH 3)，3.53(3H，m，H 5，6，13)，3.21(2H，m，H 5，13)
MS(ESI(+)100V，m/z)：475.1[M +]base peak
Embodiment 8:
Preparation compound 9 and compound 10
Preparation (+) 7R, 13aR-N-benzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate (compound 9)
In the three-necked bottle of 25mL, add 1.0g (2.97 * 10 -3Mol) (+)-13a R THB, the 3.3mL benzyl chloride, 95～100 ℃ of reaction 4h get the reddish-brown viscous liquid, with 200 order silica gel column chromatography (CH 2Cl 2-C 2H 5OH) gradient elution.Differentiate according to silica gel thin-layer chromatography, collect R f=0.57 component gets light yellow solid powder (+) 7R, 13aR-N-benzyl-2, and 3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate, promptly compound 9; Collect R f=0.59 component gets light yellow solid powder (+) 7S, 13aR-N-benzyl-2, and 3-methylenedioxy group-9,10-dimethoxy-5,6,13,13a-tetrahydrochysene-8H-Dibenzo [a, g] quinolizine muriate, promptly compound 10.
Compound 9:mp:135～137 ℃ [α] D 20+ 70.68 (c=0.2, CHCl 3)
Anal(C 27H 28NO 4·Cl·0.5H 2O)，C％，H％，N％) Req：68.28，6.1l，2.95
Found：68.11，6.20，2.55
IR (cm -1): 3600～3200 (O-H), 3050～2800 (C-H), 1632,1610,1499,1480 (aromatic ring C=C), 1282,1234,1030 (C-O)
1HNMR(300MHz，CDCl 3，δ)：7.51～7.43(3H，m，ArH 3’，4’，5’)，7.21(2H，d，ArH 2’，6’)，7.10～6.99(2H，AB，ArH 11，12)，6.82(1H，s，ArH)，6.74(1H，s，ArH)，6.29(1H，d-d，H 13a)，6.01(2H，s，-OCH 2O-)，5.90(1H，d，H 8)，5.14(1H，m，H 6)，4.64(1H，d，H 8)，4.05(2H，d，-CH 2Ar)，4.00(1H，m，H 13)，3.92(3H，s，-OCH 3)，3.83(3H，s，-OCH 3)，3.42(3H，m，H 5，6)，3.20(1H，m，H 13)
MS(ESI(+)100V，m/z)：430.2[M +]base peak
(+) 7S of preparation, 13aR-N-benzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,6,13,13a-tetrahydrochysene-8H-Dibenzo [a, g] quinolizine muriate (compound 10)
mp：144～146℃ [α] D 20+45.18(c＝0.3，CHCl 3)
Anal(C 27H 28NO 4·Cl·0.5H 2O)，C％，H％，N％) Req：68.28，6.11，2.95
Found：68.09，6.22，2.59
IR (cm -1): 3600～3200 (O-H), 3050～2800 (C-H), 1608,1500,1485 (aromatic ring C=C), 1282,1233,1032 (C-O)
1HNMR(300MHz，CDCl 3，δ)：7.63～7.44(5H，m，ArH 2’，3’，4’，5’，6’)，6.89～6.81(2H，m，ArH 11，12)，6.75(2H，d，ArH 1，4)，6.01(2H，d，H 1”，-OCH 2O-)，5.53(1H，d，H 2”，-CH 2Ar)，5.27(1H，m，H 13a)，5.06(1H，d，H 2”，-CH 2Ar)，5.00～4.85(2H，AB，H 8)，4.57(1H，m，H 6)，3.92(3H，s，H 3”/4”-OCH 3)，3.83(3H，s，H 3”/4”，-OCH 3)，3.51(3H，m，H 5，6，13)，3.15(2H，m，H 5，13)
MS(ESI(+)70V，m/z)：430.2[M +]base peak
Embodiment 9:
Preparation compound 11 and compound 12
Preparation (-) 7S, 13aS-N-benzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate (compound 11)
By (-)-13a S THB preparation, method is with the preparation method of compound 9
mp：138～140℃ [α] D 20-72.37(c＝0.2，CHCl 3)
Anal(C 27H 28NO 4·Cl·0.5H 2O)，C％，H％，N％) Req：68.28，6.11，2.95
Found：67.90，6.19，2.63
IR (cm -1): 3600～3200 (O-H), 3050～2800 (C-H), 1625,1609,1500,1488 (aromatic ring C=C), 1282,1234,1031 (C-O)
1HNMR(300MHz，CDCl 3，δ)：7.51～7.43(3H，m，ArH 3’，4’，5’)，7.16(2H，d，ArH 2’，6’)，7.10～6.99(2H，AB，ArH 11，12)，6.82(1H，s，ArH)，6.74(1H，s，ArH)，6.27(1H，d-d，H 13a)，6.02(2H，s，-OCH 2O-)，5.89(1H，d，H 8)，5.12(1H，m，H 6)，4.65(1H，d，H 8)，4.04(2H，d，-CH 2Ar)，3.99(1H，m，H 13)，3.92(3H，s，-OCH 3)，3.85(3H，s，-OCH 3)，3.41(3H，m，H 5，6)，3.20(1H，m，H 13)
MS(ESI(+)70V，m/z)：430.2[M +]base peak
Preparation (-) 7R, 13aS-N-benzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,3a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate (compound 12)
By (-)-13a S THB preparation, method is with the preparation method of compound 10.
mp：147～149℃ [α] D 20-45.57(c＝0.2，CHCl 3)
Anal(C 27H 28NO 4·Cl·H 2O，C％，H％，N％) Req：67.01，6.20，2.90
Found：67.29，6.32，2.63
IR (cm -1): 3600～3200 (O-H), 3050～2800 (C-H), 1608,1499,1485 (aromatic ring C=C), 1282,1232,1032 (C-O)
1HNMR(300MHz，CDCl 3，δ)：7.63～7.44(5H，m，ArH 2’，3’，4’，5’，6’)，6.89～6.81(2H，m，ArH 11，12)，6.75(2H，d，ArH 1，4)，6.01(2H，d，-OCH 2O-)，5.53(1H，d，-CH 2Ar)，5.27(1H，m，H 13a)，5.04(1H，m，-CH 2Ar)，5.00～4.85(2H，AB，H 8)，4.57(1H，m，H 6)，3.93(3H，s，-OCH 3)，3.83(3H，s，-OCH 3)，3.50(3H，m，H 5，6，13)，3.16(2H，m，H 5，13)
MS(ESI(+)70V，m/z)：430.2[M +]base peak
Embodiment 10:
Chipal compounds of the present invention is pharmacological evaluation according to a conventional method
1, blocking-up L-type calcium channel activity research.
(1) purpose: mensuration and comparison optical isomer are to the blocking-up of the calcium channel on the vascular smooth muscle (VSM)
Effect reaches Ca 2+-Ca 2+The blocking effect of interior calcium releasing mechanism.
(2) method and result:
1), the inhibition strength that has calcium liquid medium vessels to shrink to high potassium compares;
2), high potassium does not have and suppresses vasoconstriction in the calcium liquid and (suppress Ca 2+-Ca 2+Interior calcium discharge) strength ratio.
3), high potassium does not have in the calcium liquid, and the strength ratio that suppresses vasoconstriction (blocking-up L-type calcium channel) behind the multiple calcium.
Four kinds of optical antipodes: the activity intensity of compound 1,2,3,4 relatively see Table 2.
Table 2, four kinds of optical antipode blocking-up Ca 2+-Ca 2+Interior calcium discharge and VDC (pIC 50And relative intensity) relatively
Pharmacological action type 86,017 1234
(1) vascular smooth muscle of the high potassium of antagonism (high potassium has calcium) shrinks:
pIC 50 4.43 4.50 4.74 4.28 4.42
Relative intensity 1 1.17 2.04 0.71 0.98
(2) blocking-up Ca 2+-Ca 2+Interior calcium discharge (suppress high potassium and do not have calcium liquid medium vessels smooth muscle contraction)
pIC 50 4.81 4.87 4.98 4.61 4.75
Relative intensity 1 1.15 1.48 0.63 0.87
(3) blocking-up L-type calcium channel (being suppressed at high potassium does not have in the calcium liquid, adds the vascular smooth muscle that causes behind the calcium and shrinks)
pIC 50 4.51 4.86 4.95 4.48 4.46
Relative intensity 1 2.24 2.75 0.94 0.93
(3) conclusion:
Blocking-up Ca 2+-Ca 2+The activity that interior calcium discharges: compound 1, compound 2 are better than CPU-86017 slightly.
The blocking-up L-type calcium channel (VDC) activity: compound 2, compound 1 be better than CPU-86017 and
Compound 3, compound 4.
2, the vascular effect that contracts of blocking-up alpha-2-adrenoceptor
(1) purpose: measure 4 kinds of optical isomers to the blocking effect of the alpha-receptor on the vascular smooth muscle (VSM) and the blocking effect that cellular calcium is discharged.
(2) method and result:
Suppress activity intensity relatively:
1), has in the calcium KH liquid, add phyenlephrinium 1 μ M and cause that VSM shrinks;
2), no calcium KH liquid adds Phe10 μ M again, causes that VSM shrinks;
3), add CaCl on this basis 2, final concentration is 3.0mM, causes that VSM shrinks.
The activity intensity of blocking-up α effect relatively sees Table 3.
Table 3, four kinds of optical antipode blocking-up α effects (ROC) and interior calcium discharge active (pIC 50And relative reactivity)
Comparison
Pharmacological action type 86,017 1234
1) the total α effect (pIC of antagonism 50) 4.87 5.65 4.51 4.38 4.22
Relative intensity 1 6.02 0.44 0.32 0.22
2) calcium discharges (blocking-up IP in the antagonism α effect 3Cause
Interior calcium discharge) (pIC 50) 5.85 6.25 4.82 4.79 4.61
Relative intensity 1 2.51 0.093 0.087 0.058
3) antagonism α effect (ROC) (blocking-up
Stream in the outer calcium) (pIC 50) 4.50 5.12 0.10 4.30 4.27
Relative intensity 1 4.17 0 0.63 0.59
(3) conclusion:
Blocking-up α effect: compound 2, compound 3, compound 4 all weakens, and compound 1 blocking-up α effect strengthens, and marked difference is arranged.
Blocking-up IP 3The interior calcium release effects that causes: compound 1＞CPU-86017＞compound 3＞compound 4＞compound 2.Active minimum with compound 2 has marked difference.
Blocking-up α effect (ROC): compound 1＞CPU-86017＞compound 3＞compound 2＞compound 4.Marked difference is arranged.
3, behind the intravenous injection optical antipode, to blood pressure, the influence of heart rate.
To blood pressure, the influence of heart rate reduces behind the rat intravenous injection.Optical antipode obviously improves the iv tolerance studies
The iv tolerance of optical isomer is improved, and with compound 3, the tolerance of compound 2 is best.Compound 3, compound 2＞compound 4, compound 1＞86017.
4, acute toxicity is (iv) observed:
The iv acute toxicity of optical antipode has obvious minimizing mostly.
Compound 1＞CPU-86017＞compound 2＞compound 4＞compound 3.
5. conclusion: the cardiovascular drug effect of optical antipode strengthens, and toxicity obviously reduces
Referring to:
1、Dai De-Zai，et al.p-Chloro-benzyl-tetrahydro-berberine inhibitsvascular smooth muscle contractions caused by Ca2 +，Act PharmacolSin，1998；19：543-547.
2, He Lingshuai etc., p-chlorobenzyl N-1 (CPU-86017) and Levothyroxinnatrium be to rat aorta ring α 1A, the selectivity of α 1 β hypotype, China Medicine University's journal, 2002,33:245-249
3, Jiang Jianmin etc., the p-chlorobenzyl N-1 is to the effect of normal and hyperthyroidism isolated rat aortic annulus, Chinese J Pharmacol Toxicol, 1999; 13 (2): 131-133.

Claims (10)

1, the chirality N-1 quaternary ammonium compound of N replacement is characterized in that possessing following structure:
Compound 1 is (+) 7R, 13aR-N-p-chlorobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate; Compound 2 is (+) 7S, 13a R-N-p-chlorobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate; Compound 3 is (-) 7S, 13aS-N-p-chlorobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate; Compound 4 is (-) 7R, 13a S-N-p-chlorobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate; Compound 5 is (+) 7R, and 13a R-N-is to nitrobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine bromide; Compound 6 is (+) 7S, and 13a R-N-is to nitrobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine bromide; Compound 7 is (-) 7S, and 13aS-N-is to nitrobenzyl-2,3-methylenedioxy group-9,0-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine bromide; Compound 8 is (-) 7R, and 13aS-N-is to nitrobenzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine bromide; Compound 9 is (+) 7R, 13aR-N-benzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate; Compound 10 is (+) 7S, 13aR-N-benzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,6,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate; Compound 11 is (-) 7S, 13aS-N-benzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,13a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate; Compound 12 is (-) 7R, 13aS-N-benzyl-2,3-methylenedioxy group-9,10-dimethoxy-5,8,13,3a-tetrahydrochysene-6H-Dibenzo [a, g] quinolizine muriate.
2, the method for a kind of preparation (+)-13aR and (-)-13aS N-1 is characterized in that:
With (±) N-1 and resolving agent (-) DPT or (+) DPT, under the room temperature condition, in methyl alcohol, react, split into corresponding (+)-13aR N-1 and (-)-13aS N-1.
3, the preparation method of the compound of claim 1 is characterized in that:
(+)-13aR N-1 and (-)-13aS N-1 are reacted with the halo benzyl respectively; Reactant separates with silica gel column chromatography, and elutriant is a methylene dichloride: ethanol, gradient elution; Collect eluant component; Get compound 1～12 respectively.
4, the preparation method of the chirality N-1 quaternary ammonium compound that replaces according to the described N of claim 3 is characterized in that: the halo benzyl is 4-chlorobenzyl chloride, to nitro bromobenzyl or benzyl chloride, and the solvent of reaction is anhydrous acetonitrile and/or acetone.
5, the preparation method of the chirality N-1 quaternary ammonium compound that replaces according to the described N of one of claim 3 to 4 is characterized in that: with (+)-13aR N-1 and 4-chlorobenzyl chloride, in anhydrous acetonitrile, refluxed 5～7 hours; Reactant separates with silica gel column chromatography, and elutriant is a methylene dichloride: ethanol, gradient elution; Collect eluant component; Obtain compound 1 and compound 2 respectively.
6, the preparation method of the chirality N-1 quaternary ammonium compound that replaces according to the described N of one of claim 3 to 4 is characterized in that: with (-)-13aS N-1 and 4-chlorobenzyl chloride, in anhydrous acetonitrile, refluxed 5～7 hours; Reactant separates with silica gel column chromatography, and elutriant is a methylene dichloride: ethanol, gradient elution; Collect eluant component; Obtain compound 3 and compound 4 respectively.
7, the preparation method of the chirality N-1 quaternary ammonium compound that replaces according to the described N of one of claim 3 to 4 is characterized in that: will (+)-13aR N-1 and to the nitro bromobenzyl, in acetone, refluxed 5～7 hours; After reactant is separated out, separate with silica gel column chromatography, elutriant is a methylene dichloride: ethanol, gradient elution; Collect eluant component; Obtain compound 5 and compound 6 respectively.
8, the preparation method of the chirality N-1 quaternary ammonium compound that replaces according to the described N of one of claim 3 to 4 is characterized in that: will (-)-13aS N-1 and to the nitro bromobenzyl, in acetone, refluxed 5～7 hours; After reactant is separated out, separate with silica gel column chromatography, elutriant is a methylene dichloride: ethanol, gradient elution; Collect eluant component; Obtain compound 7 and compound 8 respectively.
9, the preparation method of the chirality N-1 quaternary ammonium compound that replaces according to the described N of one of claim 3 to 4 is characterized in that: with (+)-13aR N-1 and benzyl chloride, in 90-110 ℃, reacted 3-5 hour; Reactant separates with silica gel column chromatography, and elutriant is a methylene dichloride: ethanol, gradient elution; Collect eluant component; Obtain compound 9 and compound 10 respectively.
10, the preparation method of the chirality N-1 quaternary ammonium compound that replaces according to the described N of one of claim 3 to 4 is characterized in that: with (-)-13aS N-1 and benzyl chloride, in 90-110 ℃, reacted 3-5 hour; Reactant separates with silica gel column chromatography, and elutriant is a methylene dichloride: ethanol, gradient elution; Collect eluant component; Obtain compound 11 and compound 12 respectively.
CNB021383251A 2002-09-24 2002-09-24 Chiral isoquinoline compound with cardiac vascular activity and its synthesis process Expired - Lifetime CN1156474C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CNB021383251A CN1156474C (en) 2002-09-24 2002-09-24 Chiral isoquinoline compound with cardiac vascular activity and its synthesis process

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CNB021383251A CN1156474C (en) 2002-09-24 2002-09-24 Chiral isoquinoline compound with cardiac vascular activity and its synthesis process

Publications (2)

Publication Number Publication Date
CN1403456A CN1403456A (en) 2003-03-19
CN1156474C true CN1156474C (en) 2004-07-07

Family

ID=4749414

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB021383251A Expired - Lifetime CN1156474C (en) 2002-09-24 2002-09-24 Chiral isoquinoline compound with cardiac vascular activity and its synthesis process

Country Status (1)

Country Link
CN (1) CN1156474C (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102210678B (en) * 2011-03-28 2012-08-01 中国药科大学 Application of CPURS86017 in treating anoxia concurrent testis and cerebral lesion
CN106822117B (en) * 2016-12-21 2019-09-17 陈绍良 The medical usage of jamaicin
CN113786405B (en) * 2021-09-30 2023-04-25 哈尔滨医科大学 Application of tetrahydroberberine in preparing heart protection medicine

Also Published As

Publication number Publication date
CN1403456A (en) 2003-03-19

Similar Documents

Publication Publication Date Title
CN1028991C (en) Tetrahydronaphthalene derivatives
CN1020095C (en) Process for dichloroaniline derivatives
CN1835923A (en) Process for preparation of 4-amino-3-quinolinecarbonitriles
CN1027368C (en) Process for preparing substituted quinoline derivatives
CN1845921A (en) Adamantane and azabicyclo-octane and nonane derivatives, process of their preparation and their use as DPP-IV inhibitors
CN1042133C (en) N-substituted azabicycloheptane derivatives, the preparation and use thereof
CN1032361C (en) Imidazopyridazines, their production and use
CN1033325C (en) Antiinflammatory hydroxamic acids and N-hydroxyureas
CN1157376C (en) Arylpiperidinopropanol and arylpiperaznipropanol derivatives and pharmaceuticals containing the same
CN1049658C (en) Pyrazolo[4,3-c]pyridines, a process for their preparation and their use as serotonin reuptake inhibitors
CN1105990A (en) Phenylalkanolamine derivatives
CN1942434A (en) Indene derivatives and process for the preparation thereof
CN1058207A (en) New piperidine compounds and preparation method thereof
CN1305462A (en) Novel 1,5 and 3-O-substituted 1H-indazoles with anti-asthmatic, anti-allergic, anti-inflammatory, immuno-modulating and neuro-protective effect, and method for the production and use thereof as medica
CN1079745A (en) New 9-fluoro-7-oxo-7H-pyrido [1,2,3-d, e] [1,4] benzoxazine-6-carboxylic acids and ester thereof
CN1156474C (en) Chiral isoquinoline compound with cardiac vascular activity and its synthesis process
CN1038582C (en) Benzene derivative useful for ischemic diseases
CN1228082A (en) Synthesis of bisindolylmalimides
CN1910136A (en) Organic compounds
CN1281607C (en) Quaternary ammonium salt compound of piperazine with pain relieving effect
CN1353698A (en) Novel morpholine derivatives, method for production thereof and pharmaceutical preparations containing said derivatives
CN88102858A (en) The preparation method who can be used as the hydrazine derivative of hypotensive agent
CN1023599C (en) Chloroaniline derivatives
CN100345835C (en) Method for producing benzofuran derivative
CN1028531C (en) 1-oxa-2-oxo-8-azaspiro [4,5] decane derivatives, pharmaceutical compositions containing them and process for preparing same

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CX01 Expiry of patent term
CX01 Expiry of patent term

Granted publication date: 20040707